Sample records for gene therapy images

  1. Human gene therapy and imaging: cardiology

    Microsoft Academic Search

    Joseph C. Wu; Seppo Yla-Herttuala

    2005-01-01

    This review discusses the basics of cardiovascular gene therapy, the results of recent human clinical trials, and the rapid progress in imaging techniques in cardiology. Improved understanding of the molecular and genetic basis of coronary heart disease has made gene therapy a potential new alternative for the treatment of cardiovascular diseases. Experimental studies have established the proof-of-principle that gene transfer

  2. Gene Therapy Progress and Prospects: Noninvasive imaging of gene therapy in living subjects

    Microsoft Academic Search

    JJ Min; SS Gambhir

    2004-01-01

    Recent progress in the development of noninvasive imaging technologies should allow molecular imaging to play a major role in the field of gene therapy. These tools have recently been validated in gene therapy models for continuous quantitative monitoring of the location(s), magnitude, and time variation of gene delivery and\\/or expression. This article reviews the use of radionuclide, magnetic resonance, and

  3. Gene Therapy

    PubMed Central

    Baum, Bruce J

    2014-01-01

    Applications of gene therapy have been evaluated in virtually every oral tissue, and many of these have proved successful at least in animal models. While gene therapy will not be used routinely in the next decade, practitioners of oral medicine should be aware of the potential of this novel type of treatment that doubtless will benefit many patients with oral diseases. PMID:24372817

  4. Gene Therapy

    PubMed Central

    Scheller, E.L.; Krebsbach, P.H.

    2009-01-01

    Gene therapy is defined as the treatment of disease by transfer of genetic material into cells. This review will explore methods available for gene transfer as well as current and potential applications for craniofacial regeneration, with emphasis on future development and design. Though non-viral gene delivery methods are limited by low gene transfer efficiency, they benefit from relative safety, low immunogenicity, ease of manufacture, and lack of DNA insert size limitation. In contrast, viral vectors are nature’s gene delivery machines that can be optimized to allow for tissue-specific targeting, site-specific chromosomal integration, and efficient long-term infection of dividing and non-dividing cells. In contrast to traditional replacement gene therapy, craniofacial regeneration seeks to use genetic vectors as supplemental building blocks for tissue growth and repair. Synergistic combination of viral gene therapy with craniofacial tissue engineering will significantly enhance our ability to repair and replace tissues in vivo. PMID:19641145

  5. Polysaccharide-Coated Magnetic Nanoparticles for Imaging and Gene Therapy

    PubMed Central

    Uthaman, Saji; Cherukula, Kondareddy; Cho, Chong-Su; Park, In-Kyu

    2015-01-01

    Today, nanotechnology plays a vital role in biomedical applications, especially for the diagnosis and treatment of various diseases. Among the many different types of fabricated nanoparticles, magnetic metal oxide nanoparticles stand out as unique and useful tools for biomedical applications, because of their imaging characteristics and therapeutic properties such as drug and gene carriers. Polymer-coated magnetic particles are currently of particular interest to investigators in the fields of nanobiomedicine and fundamental biomaterials. Theranostic magnetic nanoparticles that are encapsulated or coated with polymers not only exhibit imaging properties in response to stimuli, but also can efficiently deliver various drugs and therapeutic genes. Even though a large number of polymer-coated magnetic nanoparticles have been fabricated over the last decade, most of these have only been used for imaging purposes. The focus of this review is on polysaccharide-coated magnetic nanoparticles used for imaging and gene delivery. PMID:26078971

  6. Gene therapy for radioprotection.

    PubMed

    Everett, W H; Curiel, D T

    2015-03-01

    Radiation therapy is a critical component of cancer treatment with over half of patients receiving radiation during their treatment. Despite advances in image-guided therapy and dose fractionation, patients receiving radiation therapy are still at risk for side effects due to off-target radiation damage of normal tissues. To reduce normal tissue damage, researchers have sought radioprotectors, which are agents capable of protecting tissue against radiation by preventing radiation damage from occurring or by decreasing cell death in the presence of radiation damage. Although much early research focused on small-molecule radioprotectors, there has been a growing interest in gene therapy for radioprotection. The amenability of gene therapy vectors to targeting, as well as the flexibility of gene therapy to accomplish ablation or augmentation of biologically relevant genes, makes gene therapy an excellent strategy for radioprotection. Future improvements to vector targeting and delivery should greatly enhance radioprotection through gene therapy. PMID:25721205

  7. Concise review: Nanoparticles and cellular carriers-allies in cancer imaging and cellular gene therapy?

    PubMed Central

    Tang, Catherine; Russell, Pamela J; Martiniello-Wilks, Rosetta; J Rasko, John E; Khatri, Aparajita

    2010-01-01

    Ineffective treatment and poor patient management continue to plague the arena of clinical oncology. The crucial issues include inadequate treatment efficacy due to ineffective targeting of cancer deposits, systemic toxicities, suboptimal cancer detection and disease monitoring. This has led to the quest for clinically relevant, innovative multifaceted solutions such as development of targeted and traceable therapies. Mesenchymal stem cells (MSCs) have the intrinsic ability to “home” to growing tumors and are hypoimmunogenic. Therefore, these can be used as (a) “Trojan Horses” to deliver gene therapy directly into the tumors and (b) carriers of nanoparticles to allow cell tracking and simultaneous cancer detection. The camouflage of MSC carriers can potentially tackle the issues of safety, vector, and/or transgene immunogenicity as well as nanoparticle clearance and toxicity. The versatility of the nanotechnology platform could allow cellular tracking using single or multimodal imaging modalities. Toward that end, noninvasive magnetic resonance imaging (MRI) is fast becoming a clinical favorite, though there is scope for improvement in its accuracy and sensitivity. In that, use of superparamagnetic iron-oxide nanoparticles (SPION) as MRI contrast enhancers may be the best option for tracking therapeutic MSC. The prospects and consequences of synergistic approaches using MSC carriers, gene therapy, and SPION in developing cancer diagnostics and therapeutics are discussed. STEM CELLS 2010; 28:1686–1702. PMID:20629172

  8. Gene Therapy: Ethical Issues

    Microsoft Academic Search

    Isaac Rabino

    2003-01-01

    To discern the ethical issues involved incurrent gene therapy research, to explore theproblems inherent in possible future genetherapies, and to encourage debate within thescientific community about ethical questionsrelevant to both, we surveyed American Societyof Human Genetics scientists who engage inhuman genetics research. This study of theopinions of U.S. scientific experts about theethical issues discussed in the literature ongene therapy contributes

  9. Vectors for cancer gene therapy

    Microsoft Academic Search

    J. Zhang; S. J. Russell

    1996-01-01

    Many viral and non-viral vector systems have now been developed for gene therapy applications. In this article, the pros and cons of these vector systems are discussed in relation to the different cancer gene therapy strategies. The protocols used in cancer gene therapy can be broadly divided into six categories including gene transfer to explanted cells for use as cell-based

  10. Sodium Iodide Symporter for Nuclear Molecular Imaging and Gene Therapy: From Bedside to Bench and Back

    PubMed Central

    Ahn, Byeong-Cheol

    2012-01-01

    Molecular imaging, defined as the visual representation, characterization and quantification of biological processes at the cellular and subcellular levels within intact living organisms, can be obtained by various imaging technologies, including nuclear imaging methods. Imaging of normal thyroid tissue and differentiated thyroid cancer, and treatment of thyroid cancer with radioiodine rely on the expression of the sodium iodide symporter (NIS) in these cells. NIS is an intrinsic membrane protein with 13 transmembrane domains and it takes up iodide into the cytosol from the extracellular fluid. By transferring NIS function to various cells via gene transfer, the cells can be visualized with gamma or positron emitting radioisotopes such as Tc-99m, I-123, I-131, I-124 and F-18 tetrafluoroborate, which are accumulated by NIS. They can also be treated with beta- or alpha-emitting radionuclides, such as I-131, Re-186, Re-188 and At-211, which are also accumulated by NIS. This article demonstrates the diagnostic and therapeutic applications of NIS as a radionuclide-based reporter gene for trafficking cells and a therapeutic gene for treating cancers. PMID:22539935

  11. Apoptotic Genes in Cancer Therapy

    Microsoft Academic Search

    Bertram Opalka; Alexandra Dickopp; Hans-Christoph Kirch

    2002-01-01

    Induction of apoptosis in malignant cells is a major goal of cancer therapy in general and of certain cancer gene therapy strategies in particular. Numerous apoptosis-regulating genes have been evaluated for this purpose. Besides the most prominent p53 gene others include p16, p21, p27, E2F genes, FHIT, PTEN and CASPASE genes. Recently, the potential for therapy of an adenoviral gene,

  12. Alphaviruses in Gene Therapy

    PubMed Central

    Lundstrom, Kenneth

    2015-01-01

    Alphavirus vectors present an attractive approach for gene therapy applications due to the rapid and simple recombinant virus particle production and their broad range of mammalian host cell transduction. Mainly three types of alphavirus vectors, namely naked RNA, recombinant particles and DNA/RNA layered vectors, have been subjected to preclinical studies with the goal of achieving prophylactic or therapeutic efficacy, particularly in oncology. In this context, immunization with alphavirus vectors has provided protection against challenges with tumor cells. Moreover, alphavirus intratumoral and systemic delivery has demonstrated substantial tumor regression and significant prolonged survival rates in various animal tumor models. Recent discoveries of the strong association of RNA interference and disease have accelerated gene therapy based approaches, where alphavirus-based gene delivery can play an important role. PMID:25961488

  13. Gene therapy for sarcoma.

    PubMed

    Fruehauf, S; Veldwijk, M R; Berlinghoff, S; Basara, N; Baum, C; Flasshove, M; Hegewisch-Becker, S; Kröger, N; Licht, T; Moritz, T; Hengge, U R; Zeller, W J; Laufs, S

    2002-01-01

    Soft tissue sarcomas are mesenchymal tumors which respond poorly to systemic therapy. Recent studies suggest a higher response rate with an increased doxorubicin dosage. However, this was parallel with a profound hematotoxicity in 75% of patients. Transfer of the human multidrug resistance 1 (MDR1) gene to normal hematopoietic stem cells and transplantation may significantly reduce the hematotoxicity of anthracyclin-based chemotherapy. To test this concept of supportive gene therapy in advance of a clinical study, we transduced mobilized peripheral blood progenitor cells (PBPC) with the retroviral vector SF91m3 containing the human MDR1 gene, transplanted these cells to immune-deficient mice, allowed 6 weeks for engraftment to occur and treated the animals with MDR1-based chemotherapy. In the MDR1-transduced group the human leukocytes were significantly protected from the toxicity of chemotherapy (p < 0.05). While the gene transfer rate was in the range of 10% and thus comparable to recent clinical trials, the gene expression was 59% of transduced cells and thus significantly higher than previously reported for less-advanced vectors. On the other hand, ifosfamide, a drug which has been used successfully for stem cell mobilization, is active in soft tissue sarcoma. Due to these favorable characteristics sarcoma is an attractive target to test the efficacy of MDR1 gene therapy in a clinical setting. Gene therapeutic strategies may also be used to directly target sarcoma cells, e.g. by transfer of suicide genes. We found that adenoassociated virus 2 (AAV-2) vectors efficiently transduce human HS-1 and HT1080 sarcoma cells (>90%) while other tumor cell lines and primary human PBPC were less susceptible. The thymidine kinase (TK) suicide gene was cloned into an AAV-2 vector and a complete kill of TK-transduced HS-1 and HT1080 cells was observed following exposure to aciclovir or ganciclovir (GCV), while >90% of mock-transduced HS-1 cells survived at these dosages. Transplantation of those sarcoma cells to nonobese diabetic (NOD)/LtSz-severe-combined immunodeficient (scid)/scid (NOD/SCID) mice resulted in a survival of >5 months in the AAV-TK-transduced/GCV-treated group, while the mice in the mock-transduced/GCV-treated group had died after 3 weeks. These data show that soft tissue sarcomas are a particularly suitable model system for the development and clinical testing of new gene therapeutic concepts. PMID:12426490

  14. Experimental Study of Nasopharyngeal Carcinoma Radionuclide Imaging and Therapy Using Transferred Human Sodium/Iodide Symporter Gene

    PubMed Central

    Zhong, Xing; Shi, Changzheng; Gong, Jian; Guo, Bin; Li, Mingzhu; Xu, Hao

    2015-01-01

    Purpose The aim of this study was to design a method of radionuclide for imaging and therapy of nasopharyngeal carcinoma (NPC) using the transferred human sodium/iodide symporter (hNIS) gene. Methods A stable NPC cell line expressing hNIS was established (CNE-2-hNIS). After 131I treatment, we detected proliferation and apoptosis of NPC cells, both in vitro and vivo. In vivo, the radioactivity of different organs of nude mice was counted and 99mTc imaging using SPECT was performed. The apparent diffusion coefficient (ADC) value changes of tumor xenografts were observed by diffusion-weighted magnetic resonance imaging (DW-MRI) within 6–24 days of 131I treatment. The correlation of ADC changes with apoptosis and proliferation was investigated. Post-treatment expression levels of P53, Bax, Bcl-2, Caspase-3, and Survivin proteins were detected by western blotting. Results 131I uptake was higher in CNE-2-hNIS than in CNE-2 cells. The proliferation and apoptosis rate decreased and increased respectively both in vitro and vivo in the experimental group after 131I treatment. The experimental group tumors accumulated 99mTc in vivo, leading to a good visualization by SPECT. DW-MRI showed that ADC values increased in the experimental group 6 days after treatment, while ADC values were positively and negatively correlated with the apoptotic and Ki-67 proliferation indices, respectively. After treatment, CNE-2-hNIS cells up-regulated the expression of P53 and Survivin proteins and activated Caspase-3, and down-regulated the expression of Bcl-2 proteins. Conclusions The radionuclide imaging and therapy technique for NPC hNIS-transfected cell lines can provide a new therapy strategy for monitoring and treatment of NPC. PMID:25615643

  15. Gene Therapy and Vaccination

    Microsoft Academic Search

    William J. Bowers; Michelle C. Janelsins; Howard J. Federoff

    Central nervous system (CNS) diseases represent a class of complex disorders for which cures have been largely unmet due to\\u000a the general lack of knowledge regarding underlying pathogenic mechanisms. Gene-based therapies directed at ameliorating neurodegenerative\\u000a diseases exhibit great potential due to rapid scientific advances made regarding delivery modalities, neurosurgical methods,\\u000a neuroimaging, and molecular biological manipulation. Given these breakthroughs, the diseased

  16. Gene therapy in pancreatic cancer

    PubMed Central

    Liu, Si-Xue; Xia, Zhong-Sheng; Zhong, Ying-Qiang

    2014-01-01

    Pancreatic cancer (PC) is a highly lethal disease and notoriously difficult to treat. Only a small proportion of PC patients are eligible for surgical resection, whilst conventional chemoradiotherapy only has a modest effect with substantial toxicity. Gene therapy has become a new widely investigated therapeutic approach for PC. This article reviews the basic rationale, gene delivery methods, therapeutic targets and developments of laboratory research and clinical trials in gene therapy of PC by searching the literature published in English using the PubMed database and analyzing clinical trials registered on the Gene Therapy Clinical Trials Worldwide website (http://www. wiley.co.uk/genmed/ clinical). Viral vectors are main gene delivery tools in gene therapy of cancer, and especially, oncolytic virus shows brighter prospect due to its tumor-targeting property. Efficient therapeutic targets for gene therapy include tumor suppressor gene p53, mutant oncogene K-ras, anti-angiogenesis gene VEGFR, suicide gene HSK-TK, cytosine deaminase and cytochrome p450, multiple cytokine genes and so on. Combining different targets or combination strategies with traditional chemoradiotherapy may be a more effective approach to improve the efficacy of cancer gene therapy. Cancer gene therapy is not yet applied in clinical practice, but basic and clinical studies have demonstrated its safety and clinical benefits. Gene therapy will be a new and promising field for the treatment of PC. PMID:25309069

  17. nanosheets for gene therapy

    NASA Astrophysics Data System (ADS)

    Kou, Zhongyang; Wang, Xin; Yuan, Renshun; Chen, Huabin; Zhi, Qiaoming; Gao, Ling; Wang, Bin; Guo, Zhaoji; Xue, Xiaofeng; Cao, Wei; Guo, Liang

    2014-10-01

    A new class of two-dimensional (2D) nanomaterial, transition metal dichalcogenides (TMDCs) such as MoS2, MoSe2, WS2, and WSe2 which have fantastic physical and chemical properties, has drawn tremendous attention in different fields recently. Herein, we for the first time take advantage of the great potential of MoS2 with well-engineered surface as a novel type of 2D nanocarriers for gene delivery and therapy of cancer. In our system, positively charged MoS2-PEG-PEI is synthesized with lipoic acid-modified polyethylene glycol (LA-PEG) and branched polyethylenimine (PEI). The amino end of positively charged nanomaterials can bind to the negatively charged small interfering RNA (siRNA). After detection of physical and chemical characteristics of the nanomaterial, cell toxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Polo-like kinase 1 (PLK1) was investigated as a well-known oncogene, which was a critical regulator of cell cycle transmission at multiple levels. Through knockdown of PLK1 with siRNA carried by novel nanovector, qPCR and Western blot were used to measure the interfering efficiency; apoptosis assay was used to detect the transfection effect of PLK1. All results showed that the novel nanocarrier revealed good biocompatibility, reduced cytotoxicity, as well as high gene-carrying ability without serum interference, thus would have great potential for gene delivery and therapy.

  18. Gene therapy in keratoconus

    PubMed Central

    Farjadnia, Mahgol; Naderan, Mohammad; Mohammadpour, Mehrdad

    2015-01-01

    Keratoconus (KC) is the most common ectasia of the cornea and is a common reason for corneal transplant. Therapeutic strategies that can arrest the progression of this disease and modify the underlying pathogenesis are getting more and more popularity among scientists. Cumulating data represent strong evidence of a genetic role in the pathogenesis of KC. Different loci have been identified, and certain mutations have also been mapped for this disease. Moreover, Biophysical properties of the cornea create an appropriate candidate of this tissue for gene therapy. Immune privilege, transparency and ex vivo stability are among these properties. Recent advantage in vectors, besides the ability to modulate the corneal milieu for accepting the target gene for a longer period and fruitful translation, make a big hope for stupendous results reasonable. PMID:25709266

  19. Hematopoietic Stem Cell Gene Therapy

    Microsoft Academic Search

    David W. Emery; Tamon Nishino; Ken Murata; Michalis Fragkos; George Stamatoyannopoulos

    2002-01-01

    Gene therapy applications that target hematopoietic stem cells (HSCs) offer great potential for the treatment of hematologic\\u000a disease. Despite this promise, clinical success has been limited by poor rates of gene transfer, poor engraftment of modified\\u000a cells, and poor levels of gene expression. We describe here the basic approach used for HSC gene therapy, briefly review some\\u000a of the seminal

  20. Gene therapy for hemophilia

    PubMed Central

    Rogers, Geoffrey L.; Herzog, Roland W.

    2015-01-01

    Hemophilia is an X-linked inherited bleeding disorder consisting of two classifications, hemophilia A and hemophilia B, depending on the underlying mutation. Although the disease is currently treatable with intravenous delivery of replacement recombinant clotting factor, this approach represents a significant cost both monetarily and in terms of quality of life. Gene therapy is an attractive alternative approach to the treatment of hemophilia that would ideally provide life-long correction of clotting activity with a single injection. In this review, we will discuss the multitude of approaches that have been explored for the treatment of both hemophilia A and B, including both in vivo and ex vivo approaches with viral and nonviral delivery vectors. PMID:25553466

  1. GENE THERAPY FOR LUNG NEOPLASMS

    PubMed Central

    Vachani, Anil; Moon, Edmund; Wakeam, Elliot; Haas, Andrew R.; Sterman, Daniel H.; Albelda, Steven M.

    2011-01-01

    SYNOPSIS Both advanced stage lung cancer and malignant pleural mesothelioma are associated with a poor prognosis. Although there have been advances in treatment regimens for both diseases, these have had only a modest effect on their progressive course. Gene therapy for thoracic malignancies represents a novel therapeutic approach and has been evaluated in a number of clinical trials over the last two decades. Strategies have included induction of apoptosis, tumor suppressor gene replacement, suicide gene expression, cytokine based therapy, various vaccination approaches, and adoptive transfer of modified immune cells. This review will consider the clinical results, limitations, and future directions of gene therapy trials for thoracic malignancies. PMID:22054892

  2. Gene therapy for hematological malignancies

    Microsoft Academic Search

    G. D. Schmidt-Wolf; I. G. H. Schmidt-Wolf

    2003-01-01

    .   Since cancer is the result of genetic mutations, it should be well suited for correction through gene therapy. Hematological\\u000a malignancies in which human gene transfer has been performed are leukemias, lymphomas, graft-versushost disease after allogeneic\\u000a bone marrow transplantation in leukemia, and multiple myeloma. Gene therapy may be used to induce or enhance an antitumor\\u000a immunological reaction, to correct a

  3. Gene therapy for Parkinson's disease.

    PubMed

    Yasuhara, Takao; Date, Isao

    2009-01-01

    Parkinson's disease is characterized by the degeneration of the nigrostriatal dopaminergic neurons with the manifestation of tremor, rigidity, akinesia, and disturbances of postural reflexes. Medication using L-DOPA and surgeries including deep brain stimulation are the established therapies for Parkinson's disease. Cell therapies are also effective and have rapidly developed with the recent advancement in molecular biological technology including gene transfer. In this review, ex vivo gene therapy using genetically engineered cell transplantation for Parkinson's disease model of animals is described, including catecholamine/neurotrophic factor-secreting cell transplantation with or without encapsulation, as well as in vivo gene therapy using direct injection of viral vector to increase dopamine-production, ameliorate the survival of dopaminergic neurons, correct the deteriorated microenvironment, or normalize genetic abnormality. Furthermore, the future directions for clinical application are described together with recent clinical trials of gene therapy. PMID:20411788

  4. Nanoparticles for Retinal Gene Therapy

    PubMed Central

    Conley, Shannon M.; Naash, Muna I.

    2010-01-01

    Ocular gene therapy is becoming a well-established field. Viral gene therapies for the treatment of Leber’s congentinal amaurosis (LCA) are in clinical trials, and many other gene therapy approaches are being rapidly developed for application to diverse ophthalmic pathologies. Of late, development of non-viral gene therapies has been an area of intense focus and one technology, polymer-compacted DNA nanoparticles, is especially promising. However, development of pharmaceutically and clinically viable therapeutics depends not only on having an effective and safe vector but also on a practical treatment strategy. Inherited retinal pathologies are caused by mutations in over 220 genes, some of which contain over 200 individual disease-causing mutations, which are individually very rare. This review will focus on both the progress and future of nanoparticles and also on what will be required to make them relevant ocular pharmaceutics. PMID:20452457

  5. 716. The Human Norepinephrine Transporter and [11C]-mHED, a Novel Reporter Gene-Tracer Combination for PET Imaging of Gene Therapy

    Microsoft Academic Search

    Antoine M. J. Beerens; Anne Rixt Buursma; Marianne G. Rots; Aren van Waarde; Hidde J. Haisma; Erik F. J. de Vries

    2004-01-01

    Currently many clinical protocols for gene therapy are being evaluated for use in the treatment of human disease. In the majority of these protocols however, it is difficult to determine the exact fate of the vector, or to determine the location and extend of expression of the introduced gene. Data about the expression of transgenes is not only invaluable in

  6. Gene therapy on the move

    PubMed Central

    Kaufmann, Kerstin B; Büning, Hildegard; Galy, Anne; Schambach, Axel; Grez, Manuel

    2013-01-01

    The first gene therapy clinical trials were initiated more than two decades ago. In the early days, gene therapy shared the fate of many experimental medicine approaches and was impeded by the occurrence of severe side effects in a few treated patients. The understanding of the molecular and cellular mechanisms leading to treatment- and/or vector-associated setbacks has resulted in the development of highly sophisticated gene transfer tools with improved safety and therapeutic efficacy. Employing these advanced tools, a series of Phase I/II trials were started in the past few years with excellent clinical results and no side effects reported so far. Moreover, highly efficient gene targeting strategies and site-directed gene editing technologies have been developed and applied clinically. With more than 1900 clinical trials to date, gene therapy has moved from a vision to clinical reality. This review focuses on the application of gene therapy for the correction of inherited diseases, the limitations and drawbacks encountered in some of the early clinical trials and the revival of gene therapy as a powerful treatment option for the correction of monogenic disorders. PMID:24106209

  7. Somatostatin Receptor Based Imaging and Radionuclide Therapy

    PubMed Central

    Zhang, Hong

    2015-01-01

    Somatostatin (SST) receptors (SSTRs) belong to the typical 7-transmembrane domain family of G-protein-coupled receptors. Five distinct subtypes (termed SSTR1-5) have been identified, with SSTR2 showing the highest affinity for natural SST and synthetic SST analogs. Most neuroendocrine tumors (NETs) have high expression levels of SSTRs, which opens the possibility for tumor imaging and therapy with radiolabeled SST analogs. A number of tracers have been developed for the diagnosis, staging, and treatment of NETs with impressive results, which facilitates the applications of human SSTR subtype 2 (hSSTr2) reporter gene based imaging and therapy in SSTR negative or weakly positive tumors to provide a novel approach for the management of tumors. The hSSTr2 gene can act as not only a reporter gene for in vivo imaging, but also a therapeutic gene for local radionuclide therapy. Even a second therapeutic gene can be transfected into the same tumor cells together with hSSTr2 reporter gene to obtain a synergistic therapeutic effect. However, additional preclinical and especially translational and clinical researches are needed to confirm the value of hSSTr2 reporter gene based imaging and therapy in tumors. PMID:25879040

  8. Gene therapy of multiple sclerosis

    Microsoft Academic Search

    Roberto Furlan; Chiara Maiorino; Alberto Gatta; Francesca Ruffini; Gianvito Martino

    \\u000a Multiple sclerosis (MS) constitutes a difficult challenge for the design of innovative therapies: the aetiology is unknown,\\u000a the pathogenesis only partially understood, and the whole process is multi-focal, chronic, and occurring beyond anatomical\\u000a barriers, making the delivery of potentially therapeutic molecules difficult. Gene therapy, thus, constitutes a realistic\\u000a alternative to ensure prolonged, and site-specific delivery of therapies. Recent advancements in

  9. Gene Therapy for Cartilage Repair

    PubMed Central

    Madry, Henning; Orth, Patrick; Cucchiarini, Magali

    2011-01-01

    The concept of using gene transfer strategies for cartilage repair originates from the idea of transferring genes encoding therapeutic factors into the repair tissue, resulting in a temporarily and spatially defined delivery of therapeutic molecules to sites of cartilage damage. This review focuses on the potential benefits of using gene therapy approaches for the repair of articular cartilage and meniscal fibrocartilage, including articular cartilage defects resulting from acute trauma, osteochondritis dissecans, osteonecrosis, and osteoarthritis. Possible applications for meniscal repair comprise meniscal lesions, meniscal sutures, and meniscal transplantation. Recent studies in both small and large animal models have demonstrated the applicability of gene-based approaches for cartilage repair. Chondrogenic pathways were stimulated in the repair tissue and in osteoarthritic cartilage using genes for polypeptide growth factors and transcription factors. Although encouraging data have been generated, a successful translation of gene therapy for cartilage repair will require an ongoing combined effort of orthopedic surgeons and of basic scientists.

  10. Gene therapy in status epilepticus.

    PubMed

    Walker, Matthew C; Schorge, Stephanie; Kullmann, Dimitri M; Wykes, Robert C; Heeroma, Joost H; Mantoan, Laura

    2013-09-01

    Gene therapy in human disease has expanded rapidly in recent years with the development of safer and more effective viral vectors, and presents a novel approach to the treatment of epilepsy. Studies in animals models have demonstrated that overexpression of inhibitory peptides can modify seizure threshold, prevent the development of epilepsy, and modify established epilepsy. More recently there has been a flurry of studies using optogenetics in which light-activated channels expressed in neurons can transiently change neuronal excitability on exposure to light, thereby enabling the development of closed loop systems to detect and stop seizure activity. The treatment of status epilepticus presents its own challenges. Because of both the delay in gene expression following transfection and also the necessity of using focal transfection, there are a limited number of situations in which gene therapy can be used in status epilepticus. One such condition is epilepsia partialis continua (EPC). We have used gene therapy in a model of EPC and have shown that we can "cure" the condition. Recent evidence suggesting that gene therapy targeting subcortical regions can modify generalized or more diffuse epilepsies, indicates that the range of situations in status epilepticus in which gene therapy could be used will expand. PMID:24001071

  11. Delivery systems for gene therapy

    PubMed Central

    Mali, Shrikant

    2013-01-01

    The structure of DNA was unraveled by Watson and Crick in 1953, and two decades later Arber, Nathans and Smith discovered DNA restriction enzymes, which led to the rapid growth in the field of recombinant DNA technology. From expressing cloned genes in bacteria to expressing foreign DNA in transgenic animals, DNA is now slated to be used as a therapeutic agent to replace defective genes in patients suffering from genetic disorders or to kill tumor cells in cancer patients. Gene therapy provides modern medicine with new perspectives that were unthinkable two decades ago. Progress in molecular biology and especially, molecular medicine is now changing the basics of clinical medicine. A variety of viral and non-viral possibilities are available for basic and clinical research. This review summarizes the delivery routes and methods for gene transfer used in gene therapy. PMID:23901186

  12. Gene Therapy in Corneal Transplantation

    PubMed Central

    Qazi, Yureeda; Hamrah, Pedram

    2014-01-01

    Corneal transplantation is the most commonly performed organ transplantation. Immune privilege of the cornea is widely recognized, partly because of the relatively favorable outcome of corneal grafts. The first-time recipient of corneal allografts in an avascular, low-risk setting can expect a 90% success rate without systemic immunosuppressive agents and histocompatibility matching. However, immunologic rejection remains the major cause of graft failure, particularly in patients with a high risk for rejection. Corticosteroids remain the first-line therapy for the prevention and treatment of immune rejection. However, current pharmacological measures are limited in their side-effect profiles, repeated application, lack of targeted response, and short duration of action. Experimental ocular gene therapy may thus present new horizons in immunomodulation. From efficient viral vectors to sustainable alternative splicing, we discuss the progress of gene therapy in promoting graft survival and postulate further avenues for gene-mediated prevention of allogeneic graft rejection. PMID:24138037

  13. Cancer gene therapy: an awkward adolescence

    Microsoft Academic Search

    Michael M Gottesman

    2003-01-01

    At the Eleventh International Conference on Gene Therapy of Cancer (December 12–14, 2002, San Diego, CA) progress on using gene transfer technology to treat cancer was presented. Although there is as yet no cancer gene therapy being marketed, considerable progress has been made in defining likely strategies and likely targets for gene therapy of cancer. These strategies, including viral and

  14. Gene therapy for atherosclerosis

    Microsoft Academic Search

    D. J. Rader

    1997-01-01

    Although considerable progress has been made in the prevention and treatment of atherosclerotic cardiovascular disease, new\\u000a therapeutic strategies are still needed. Atherosclerosis is a systemic disease and represents an attractive target for the\\u000a development of somatic gene transfer intended to modulate systemic factors with the goal of inhibiting disease progression.\\u000a This approach should be differentiated from localized vascular gene delivery

  15. Orthopedic Gene Therapy in 2008

    Microsoft Academic Search

    Christopher H Evans; Steven C Ghivizzani; Paul D Robbins

    2009-01-01

    Orthopedic disorders, although rarely fatal, are the leading cause of morbidity and impose a huge socioeconomic burden. Their prevalence will increase dramatically as populations age and gain weight. Many orthopedic conditions are difficult to treat by conventional means; however, they are good candidates for gene therapy. Clinical trials have already been initiated for arthritis and the aseptic loosening of prosthetic

  16. ADENOVIRAL GENE THERAPY FOR OVARIAN CANCER

    E-print Network

    Hemminki, Akseli

    ADENOVIRAL GENE THERAPY FOR OVARIAN CANCER Anna Kanerva Cancer Gene Therapy Group Rational Drug;SUPERVISED BY Docent Akseli Hemminki, M.D., Ph.D. Cancer Gene Therapy Group, Rational Drug Design Program experience is the mysterious. It is the source of all true art and science. Albert Einstein (1879-1955) #12

  17. Gene therapy of benign gynecological diseases?

    PubMed Central

    Hassan, Memy H.; Othman, Essam E.; Hornung, Daniela; Al-Hendy, Ayman

    2015-01-01

    Gene therapy is the introduction of genetic material into patient’s cells to achieve therapeutic benefit. Advances in molecular biology techniques and better understanding of disease pathogenesis have validated the use of a variety of genes as potential molecular targets for gene therapy based approaches. Gene therapy strategies include: mutation compensation of dysregulated genes; replacement of defective tumor-suppressor genes; inactivation of oncogenes; introduction of suicide genes; immunogenic therapy and antiangiogenesis based approaches. Preclinical studies of gene therapy for various gynecological disorders have not only shown to be feasible, but also showed promising results in diseases such as uterine leiomyomas and endometriosis. In recent years, significant improvement in gene transfer technology has led to the development of targetable vectors, which have fewer side-effects without compromising their efficacy. This review provides an update on developing gene therapy approaches to treat common gynecological diseases such as uterine leiomyoma and endometriosis. PMID:19446586

  18. Gene therapy for carcinoma of the breast

    PubMed Central

    Stoff-Khalili, MA; Dall, P; Curiel, DT

    2007-01-01

    In view of the limited success of available treatment modalities for breast cancer, alternative and complementary strategies need to be developed. The delineation of the molecular basis of breast cancer provides the possibility of specific intervention by gene therapy through the introduction of genetic material for therapeutic purposes. In this regard, several gene therapy approaches for carcinoma of the breast have been developed. These approaches can be divided into six broad categories: (1) mutation compensation, (2) molecular chemotherapy, (3) proapoptotic gene therapy, (4) antiangiogenic gene therapy, (5) genetic immunopotentiation, and (6) genetic modulation of resistance/sensitivity. Clinical trials for breast cancer have been initiated to evaluate safety, toxicity, and efficacy. Combined modality therapy with gene therapy and chemotherapy or radiation therapy has shown promising results. It is expected that as new therapeutic targets and approaches are identified and advances in vector design are realized, gene therapy will play an increasing role in clinical breast cancer treatment. PMID:16410823

  19. Gene therapy for viral hepatitis.

    PubMed

    Gonzalez-Aseguinolaza, Gloria; Crettaz, Julien; Ochoa, Laura; Otano, Itziar; Aldabe, Rafael; Paneda, Astrid

    2006-12-01

    Hepatitis B and C infections are two of the most prevalent viral diseases in the world. Existing therapies against chronic viral hepatitis are far from satisfactory due to low response rates, undesirable side effects and selection of resistant viral strains. Therefore, new therapeutic approaches are urgently needed. This review, after briefly summarising the in vitro and in vivo systems for the study of both diseases and the genetic vehicles commonly used for liver gene transfer, examines the existing status of gene therapy-based antiviral strategies that have been employed to prevent, eliminate or reduce viral infection. In particular, the authors focus on the results obtained in clinical trials and experimental clinically relevant animal models. PMID:17223736

  20. Advancement and prospects of tumor gene therapy

    PubMed Central

    Zhang, Chao; Wang, Qing-Tao; Liu, He; Zhang, Zhen-Zhu; Huang, Wen-Lin

    2011-01-01

    Gene therapy is one of the most attractive fields in tumor therapy. In past decades, significant progress has been achieved. Various approaches, such as viral and non-viral vectors and physical methods, have been developed to make gene delivery safer and more efficient. Several therapeutic strategies have evolved, including gene-based (tumor suppressor genes, suicide genes, antiangiogenic genes, cytokine and oxidative stress-based genes) and RNA-based (antisense oligonucleotides and RNA interference) approaches. In addition, immune response-based strategies (dendritic cell– and T cell–based therapy) are also under investigation in tumor gene therapy. This review highlights the progress and recent developments in gene delivery systems, therapeutic strategies, and possible clinical directions for gene therapy. PMID:21352695

  1. Gene therapy on demand: site specific regulation of gene therapy.

    PubMed

    Jazwa, Agnieszka; Florczyk, Urszula; Jozkowicz, Alicja; Dulak, Jozef

    2013-08-10

    Since 1990 when the first clinical gene therapy trial was conducted, much attention and considerable promise have been given to this form of treatment. Gene therapy has been used with success in patients suffering from severe combined immunodeficiency syndromes (X-SCID and ADA-deficiency), Leber's congenital amaurosis, hemophilia, ?-thalassemia and adrenoleukodystrophy. Last year, the first therapeutic vector (Glybera) for treatment of lipoprotein lipase deficiency has been registered in the European Union. Nevertheless, there are still several numerous issues that need to be improved to make this technique more safe, effective and easily accessible for patients. Introduction of the therapeutic gene to the given cells should provide the level of expression which will restore the production of therapeutic protein to normal values or will provide therapeutic efficacy despite not fully physiological expression. However, in numerous diseases the expression of therapeutic genes has to be kept at certain level for some time, and then might be required to be switched off to be activated again when worsening of the symptoms may aggravate the risk of disease relapse. In such cases the promoters which are regulated by local conditions may be more required. In this article the special emphasis is to discuss the strategies of regulation of gene expression by endogenous stimuli. Particularly, the hypoxia- or miRNA-regulated vectors offer the possibilities of tight but, at the same time, condition-dependent and cell-specific expression. Such means have been already tested in certain pathophysiological conditions. This creates the chance for the translational approaches required for development of effective treatments of so far incurable diseases. PMID:23566848

  2. Gene therapy for sensorineural hearing loss.

    PubMed

    Chien, Wade W; Monzack, Elyssa L; McDougald, Devin S; Cunningham, Lisa L

    2015-01-01

    Gene therapy is a promising treatment modality that is being explored for several inherited disorders. Multiple human gene therapy clinical trials are currently ongoing, but few are directed at hearing loss. Hearing loss is one of the most prevalent sensory disabilities in the world, and genetics play an important role in the pathophysiology of hearing loss. Gene therapy offers the possibility of restoring hearing by overcoming the functional deficits created by the underlying genetic mutations. In addition, gene therapy could potentially be used to induce hair cell regeneration by delivering genes that are critical to hair cell differentiation into the cochlea. In this review, we examine the promises and challenges of applying gene therapy to the cochlea. We also summarize recent studies that have applied gene therapy to animal models of hearing loss. PMID:25166629

  3. Hematopoietic Stem Cell Expansion and Gene Therapy

    PubMed Central

    Watts, Korashon Lynn; Adair, Jennifer; Kiem, Hans-Peter

    2012-01-01

    Hematopoietic stem cell (HSC) gene therapy remains a highly attractive treatment option for many disorders including hematologic conditions, immunodeficiencies including HIV/AIDS, and other genetic disorders like lysosomal storage diseases, among others. In this review, we discuss the successes, side effects, and limitations of current gene therapy protocols. In addition, we describe the opportunities presented by implementing ex vivo expansion of gene-modified HSCs, as well as summarize the most promising ex vivo expansion techniques currently available. We conclude by discussing how some of the current limitations of HSC gene therapy could be overcome by combining novel HSC expansion strategies with gene therapy. PMID:21999373

  4. Gene therapy for obesity: progress and prospects.

    PubMed

    Gao, Mingming; Liu, Dexi

    2014-06-01

    Advances in understanding the molecular basis of obesity and obesity-associated diseases have made gene therapy a vital approach in coping with this world-wide epidemic. Gene therapy for obesity aims to increase or decrease gene product in favor of lipolysis and energy expenditure, leading toward fat reduction and loss of body weight. It involves successful delivery and expression of therapeutic genes in appropriate cells. The ultimate goal of gene therapy is to restore and maintain energy homeostasis. Here we summarize progress made in recent years in identifying genes responsible for obesity and present examples where the gene therapy approach has been applied to treating or preventing obesity. Discussion on advantages and limitations of gene therapy strategies employed is provided. The intent of this review is to inspire further studies toward the development of new strategies for successful treatment of obesity and obesity-associated diseases. PMID:24979252

  5. A short perspective on gene therapy: Clinical experience on gene therapy of gliomablastoma multiforme

    PubMed Central

    Wirth, Thomas

    2011-01-01

    More than two decades have passed since the first gene therapy clinical trial was conducted. During this time, we have gained much knowledge regarding gene therapy in general, but also learned to understand the fear that persists in society. We have experienced drawbacks and successes. More than 1700 clinical trials have been conducted where gene therapy is used as a means for therapy. In the very first trial, patients with advanced melanoma were treated with tumor infiltrating lymphocytes genetically modified ex-vivo to express tumor necrosis factor. Around the same time the first gene therapy trial was conducted, the ethical aspects of performing gene therapy on humans was intensively discussed. What are the risks involved with gene therapy? Can we control the technology? What is ethically acceptable and what are the indications gene therapy can be used for? Initially, gene therapy was thought to be implemented mainly for the treatment of monogenetic diseases, such as adenosine deaminase deficiency. However, other therapeutic areas have become of interest and currently cancer is the most studied therapeutic area for gene therapy based medicines. In this review I will be giving a short introduction into gene therapy and will direct the discussion to where we should go from here. Furthermore, I will focus on the use of the Herpes simplex virus-thymidine kinase for gene therapy of malignant gliomas and highlight the efficacy of gene therapy for the treatment of malignant gliomas, but other strategies will also be mentioned. PMID:24520527

  6. Progress in Gene Therapy for Prostate Cancer

    PubMed Central

    Ahmed, Kamran A.; Davis, Brian J.; Wilson, Torrence M.; Wiseman, Gregory A.; Federspiel, Mark J.; Morris, John C.

    2012-01-01

    Gene therapy has held promise to correct various disease processes. Prostate cancer represents the second leading cause of cancer death in American men. A number of clinical trials involving gene therapy for the treatment of prostate cancer have been reported. The ability to efficiently transduce tumors with effective levels of therapeutic genes has been identified as a fundamental barrier to effective cancer gene therapy. The approach utilizing gene therapy in prostate cancer patients at our institution attempts to address this deficiency. The sodium-iodide symporter (NIS) is responsible for the ability of the thyroid gland to transport and concentrate iodide. The characteristics of the NIS gene suggest that it could represent an ideal therapeutic gene for cancer therapy. Published results from Mayo Clinic researchers have indicated several important successes with the use of the NIS gene and prostate gene therapy. Studies have demonstrated that transfer of the human NIS gene into prostate cancer using adenovirus vectors in vitro and in vivo results in efficient uptake of radioactive iodine and significant tumor growth delay with prolongation of survival. Preclinical successes have culminated in the opening of a phase I trial for patients with advanced prostate disease which is currently accruing patients. Further study will reveal the clinical promise of NIS gene therapy in the treatment of prostate as well as other malignancies. PMID:23181221

  7. Gene therapy for carcinoma of the breast

    Microsoft Academic Search

    M A Stoff-Khalili; P Dall; D T Curiel; DT Curiel

    2006-01-01

    In view of the limited success of available treatment modalities for breast cancer, alternative and complementary strategies need to be developed. The delineation of the molecular basis of breast cancer provides the possibility of specific intervention by gene therapy through the introduction of genetic material for therapeutic purposes. In this regard, several gene therapy approaches for carcinoma of the breast

  8. Gene therapy approaches for spinal cord injury

    Microsoft Academic Search

    Corinne Bright

    2005-01-01

    As the biomedical engineering field expands, combination technologies are demonstrating enormous potential for treating human disease. In particular, intersections between the rapidly developing fields of gene therapy and tissue engineering hold promise to achieve tissue regeneration. Nonviral gene therapy uses plasmid DNA to deliver therapeutic proteins in vivo for extended periods of time. Tissue engineering employs biomedical materials, such as

  9. PET imaging of adoptive progenitor cell therapies.

    SciTech Connect

    Gelovani, Juri G.

    2008-05-13

    Objectives. The overall objective of this application is to develop novel technologies for non-invasive imaging of adoptive stem cell-based therapies with positron emission tomography (PET) that would be applicable to human patients. To achieve this objective, stem cells will be genetically labeled with a PET-reporter gene and repetitively imaged to assess their distribution, migration, differentiation, and persistence using a radiolabeled reporter probe. This new imaging technology will be tested in adoptive progenitor cell-based therapy models in animals, including: delivery pro-apoptotic genes to tumors, and T-cell reconstitution for immunostimulatory therapy during allogeneic bone marrow progenitor cell transplantation. Technical and Scientific Merits. Non-invasive whole body imaging would significantly aid in the development and clinical implementation of various adoptive progenitor cell-based therapies by providing the means for non-invasive monitoring of the fate of injected progenitor cells over a long period of observation. The proposed imaging approaches could help to address several questions related to stem cell migration and homing, their long-term viability, and their subsequent differentiation. The ability to image these processes non-invasively in 3D and repetitively over a long period of time is very important and will help the development and clinical application of various strategies to control and direct stem cell migration and differentiation. Approach to accomplish the work. Stem cells will be genetically with a reporter gene which will allow for repetitive non-invasive “tracking” of the migration and localization of genetically labeled stem cells and their progeny. This is a radically new approach that is being developed for future human applications and should allow for a long term (many years) repetitive imaging of the fate of tissues that develop from the transplanted stem cells. Why the approach is appropriate. The novel approach to stem cell imaging is proposed to circumvent the major limitation of in vitro radiolabeling – the eventual radiolabel decay. Stable transduction of stem cells in vitro would allow for the selection of high quality stem cells with optimal functional parameters of the transduced reporter systems. The use of a long-lived radioisotope 124I to label a highly specific reporter gene probe will allow for ex vivo labeling of stem cells and their imaging immediately after injection and during the following next week. The use of short-lived radioisotopes (i.e., 18F) to label highly specific reporter gene probes will allow repetitive PET imaging for the assessment of to stem cell migration, targeting, differentiation, and long-term viability of stem cell-derived tissues. Qualifications of the research team and resources. An established research team of experts in various disciplines has been assembled at MD Anderson Cancer Center (MDACC) over the past two years including the PI, senior co-investigators and collaborators. The participants of this team are recognized internationally to be among the leaders in their corresponding fields of research and clinical medicine. The resources at MDACC are exceptionally well developed and have been recently reinforced by the installation of a microPET and microSPECT/CT cameras, and a 7T MRI system for high resolution animal imaging; and by integrating a synthetic chemistry core for the development and production of precursors for radiolabeling.

  10. Imaging progress of herpes simplex virus type 1 thymidine kinase suicide gene therapy in living subjects with positron emission tomography

    Microsoft Academic Search

    Shahriar S Yaghoubi; Jorge R Barrio; Mohammad Namavari; Nagichettiar Satyamurthy; Michael E Phelps; Harvey R Herschman; Sanjiv S Gambhir

    2005-01-01

    Molecular imaging of a suicide transgene's expression will aid the development of efficient and precise targeting strategies, and imaging for cancer cell viability may assess therapeutic efficacy. We used the PET reporter probe, 9-(4-[18F]fluoro-3-(hydroxymethyl)butyl)guanine ([18F]FHBG) to monitor the expression of a mutant Herpes Simplex Virus 1 thymidine kinase (HSV1-sr39tk) in C6 glioma tumors implanted subcutaneously in nude mice that were

  11. International progress in cancer gene therapy

    Microsoft Academic Search

    B A Guinn; R Mulherkar

    2008-01-01

    We overview the current status and most recent developments in the field of cancer gene therapy from an international viewpoint. We have largely based our review on presentations from the eigth annual meeting of the International Society for Cell and Gene Therapy of Cancer held in Mumbai, India (www.iscgt.com and www.iscgtindia.com). This has afforded us with the opportunity to describe

  12. Gene therapy for autoimmune diseases: quo vadis?

    Microsoft Academic Search

    David J. Gould; Osvaldo L. Podhajcer; Yuti Chernajovsky

    2004-01-01

    Biological therapies using antibodies and cytokines are becoming widespread for the treatment of chronic inflammatory autoimmune diseases. However, these treatments have several limitations — such as expense, the need for repeated injections and unwanted side-effects — that can be overcome by genetic delivery. This review summarizes the ingenuity, sophistication and variety of gene-therapy approaches that have been taken in the

  13. Cardiovascular gene therapy for myocardial infarction

    PubMed Central

    Scimia, Maria C; Gumpert, Anna M; Koch, Walter J

    2014-01-01

    Introduction Cardiovascular gene therapy is the third most popular application for gene therapy, representing 8.4% of all gene therapy trials as reported in 2012 estimates. Gene therapy in cardiovascular disease is aiming to treat heart failure from ischemic and non-ischemic causes, peripheral artery disease, venous ulcer, pulmonary hypertension, atherosclerosis and monogenic diseases, such as Fabry disease. Areas covered In this review, we will focus on elucidating current molecular targets for the treatment of ventricular dysfunction following myocardial infarction (MI). In particular, we will focus on the treatment of i) the clinical consequences of it, such as heart failure and residual myocardial ischemia and ii) etiological causes of MI (coronary vessels atherosclerosis, bypass venous graft disease, in-stent restenosis). Expert opinion We summarise the scheme of the review and the molecular targets either already at the gene therapy clinical trial phase or in the pipeline. These targets will be discussed below. Following this, we will focus on what we believe are the 4 prerequisites of success of any gene target therapy: safety, expression, specificity and efficacy (SESE). PMID:24328708

  14. Progress toward liver-based gene therapy.

    PubMed

    Suda, Takeshi; Kamimura, Kenya; Kubota, Tomoyuki; Tamura, Yasushi; Igarashi, Masato; Kawai, Hirokazu; Aoyagi, Yutaka; Liu, Dexi

    2009-04-01

    The liver is involved in the synthesis of serum proteins, regulation of metabolism and maintenance of homeostasis and provides a variety of opportunities for gene therapy. The enriched vasculature and blood circulation, fenestrated endothelium, abundant receptors on the plasma membranes of the liver cells, and effective transcription and translation machineries in the hepatocytes are some unique features that have been explored for delivery, and functional analysis, of genetic sequences in the liver. Both viral and non-viral methods have been developed for effective gene delivery and liver-based gene therapy. This review describes the fundamentals of gene delivery, and the preclinical and clinical progress that has been made toward gene therapy using the liver as a target. PMID:19207594

  15. Why commercialization of gene therapy stalled; examining the life cycles of gene therapy technologies.

    PubMed

    Ledley, F D; McNamee, L M; Uzdil, V; Morgan, I W

    2014-02-01

    This report examines the commercialization of gene therapy in the context of innovation theories that posit a relationship between the maturation of a technology through its life cycle and prospects for successful product development. We show that the field of gene therapy has matured steadily since the 1980s, with the congruent accumulation of >35?000 papers, >16?000 US patents, >1800 clinical trials and >$4.3 billion in capital investment in gene therapy companies. Gene therapy technologies comprise a series of dissimilar approaches for gene delivery, each of which has introduced a distinct product architecture. Using bibliometric methods, we quantify the maturation of each technology through a characteristic life cycle S-curve, from a Nascent stage, through a Growing stage of exponential advance, toward an Established stage and projected limit. Capital investment in gene therapy is shown to have occurred predominantly in Nascent stage technologies and to be negatively correlated with maturity. Gene therapy technologies are now achieving the level of maturity that innovation research and biotechnology experience suggest may be requisite for efficient product development. Asynchrony between the maturation of gene therapy technologies and capital investment in development-focused business models may have stalled the commercialization of gene therapy. PMID:24305420

  16. Gene therapy for chronic granulomatous disease

    Microsoft Academic Search

    Akihiro Kume; Mary C Dinauer

    2000-01-01

    Recent progress in the development of gene therapy for chronic granulomatous disease (CGD), an inherited immunodeficiency syndrome, is reviewed. This disorder results from defects in any of the four genes encoding essential subunits of respiratory burst oxidase, the superoxide-generating enzyme complex in phagocytic leukocytes. The absence of respiratory burst oxidants results in recurrent bacterial and fungal infections and can also

  17. Review Article Gene Therapy in Cardiac Arrhythmias

    Microsoft Academic Search

    Johnson Francis

    Gene therapy has progressed from a dream to a bedside reality in quite a few human diseases. From its first application in adenosine deaminase deficiency, through the years, its application has evolved to vascular angiogenesis and cardiac arrhythmias. Gene based biological pacemakers using viral vectors or mesenchymal cells tested in animal models hold much promise. Induction of pacemaker activity within

  18. Gene replacement therapy for hereditary emphysema

    SciTech Connect

    Skolnick, A.

    1989-11-10

    Investigators suggest that human trials of gene therapy to correct a genetic disorder that usually leads to emphysema early in life may be only a few years away. Speaking at the American Lung Association's Second Annual Science Writers' Forum, R. G. Crystal, chief of the Pulmonary Branch of the National Heart, Lung, and Blood Institute offered an explanation of how hereditary emphysema may be more amenable to genetic therapy than other such diseases. In persons who lack a functioning gene for alpha{sup 1}-antitrypsin, a proteolytic enzyme, neutrophil elastase, attacks the walls of the lungs' alveoli, eventually leading to progressive pulmonary function loss. Two animal models of gene insertion are described.

  19. Anticytokine gene therapy of autoimmune diseases.

    PubMed

    Prud'homme, G J; Lawson, B R; Theofilopoulos, A N

    2001-05-01

    Viral and nonviral gene therapy vectors have been successfully employed to deliver inflammatory cytokine inhibitors (anticytokines), or anti-inflammatory cytokines, such as transforming growth factor beta-1 (TGF-beta 1), which protect against experimental autoimmune diseases. These vectors carry the relevant genes into a variety of tissues, for either localised or systemic release of the encoded protein. Administration of cDNA encoding soluble IFN-gamma receptor (IFN-gamma R)/IgG-Fc fusion proteins, soluble TNF-alpha receptors, or IL-1 receptor antagonist (IL-1ra), protects against either lupus, various forms of arthritis, autoimmune diabetes, or other autoimmune diseases. These inhibitors, unlike many cytokines, have little or no toxic potential. Similarly, TGF-beta 1 gene therapy protects against numerous forms of autoimmunity, though its administration entails more risk than anticytokine therapy. We have relied on the injection of naked plasmid DNA into skeletal muscle, with or without enhancement of gene transfer by in vivo electroporation. Expression plasmids offer interesting advantages over viral vectors, since they are simple to produce, non-immunogenic and nonpathogenic. They can be repeatedly administered and after each treatment the encoded proteins are produced for relatively long periods, ranging from weeks to months. Moreover, soluble receptors which block cytokine action, encoded by gene therapy vectors, can be constructed from non-immunogenic self elements that are unlikely to be neutralised by the host immune response (unlike monoclonal antibodies [mAbs]), allowing long-term gene therapy of chronic inflammatory disorders. PMID:11727511

  20. Advanced Imaging Applications to Cardiac Resynchronization Therapy

    E-print Network

    Zanibbi, Richard

    D ultrasound, and electron paramagnetic imaging. His research includes the development of novelAdvanced Imaging Applications to Cardiac Resynchronization Therapy Justin D. Pearlman Professor of the Center for Imaging Science For Cardiac Resynchronization Therapy the goal is to identify where cardiac

  1. Gene Therapy for Neurologic Manifestations of Mucopolysaccharidoses

    PubMed Central

    Wolf, Daniel A.; Banerjee, Sharbani; Hackett, Perry B.; Whitley, Chester B.; McIvor, R. Scott; Low, Walter C.

    2015-01-01

    Introduction Mucopolysaccharidoses are a family of lysosomal disorders caused by mutations in genes that encode enzymes involved in the catabolism of glycoaminoglycans. These mutations affect multiple organ systems and can be particularly deleterious to the nervous system. At the present time, enzyme replacement therapy and hematopoietic stem-cell therapy are used to treat patients with different forms of these disorders. However, to a great extent the nervous system is not adequately responsive to current therapeutic approaches. Areas Covered Recent advances in gene therapy show great promise for treating mucopolysaccharidoses. This article reviews the current state of the art for routes of delivery in developing genetic therapies for treating the neurologic manifestations of mucopolysaccharidoses. Expert Opinion Gene therapy for treating neurological manifestations of mucopolysaccharidoses can be achieved by intraventricular, intrathecal, intranasal, and systemic administration. The intraventricular route of administration appears to provide the most wide-spread distribution of gene therapy vectors to the brain. The intrathecal route of delivery results in predominant distribution to the caudal areas of the brain while the intranasal route of delivery results in good distribution to the rostral areas of brain. The systemic route of delivery via intravenous delivery can also achieve wide spread delivery to the CNS, however, the distribution to the brain is greatly dependent on the vector system. Intravenous delivery using lentiviral vectors appear to be less effective than adeno-associated viral (AAV) vectors. Moreover, some subtypes of AAV vectors are more effective than others in crossing the blood-brain-barrier. In summary, the recent advances in gene vector technology and routes of delivery to the CNS will facilitate the clinical translation of gene therapy for the treatment of the neurological manifestations of mucopolysaccharidoses. PMID:25510418

  2. A Comprehensive Review of Retinal Gene Therapy

    PubMed Central

    Boye, Shannon E; Boye, Sanford L; Lewin, Alfred S; Hauswirth, William W

    2013-01-01

    Blindness, although not life threatening, is a debilitating disorder for which few, if any treatments exist. Ocular gene therapies have the potential to profoundly improve the quality of life in patients with inherited retinal disease. As such, tremendous focus has been given to develop such therapies. Several factors make the eye an ideal organ for gene-replacement therapy including its accessibility, immune privilege, small size, compartmentalization, and the existence of a contralateral control. This review will provide a comprehensive summary of (i) existing gene therapy clinical trials for several genetic forms of blindness and (ii) preclinical efficacy and safety studies in a variety of animal models of retinal disease which demonstrate strong potential for clinical application. To be as comprehensive as possible, we include additional proof of concept studies using gene replacement, neurotrophic/neuroprotective, optogenetic, antiangiogenic, or antioxidative stress strategies as well as a description of the current challenges and future directions in the ocular gene therapy field to this review as a supplement. PMID:23358189

  3. Gene therapy for the inner ear

    PubMed Central

    Fukui, Hideto; Raphael, Yehoash

    2012-01-01

    Animal studies on inner ear development, repair and regeneration provide understanding of molecular pathways that can be harnessed for treating inner ear disease. Use of transgenic mouse technology, in particular, has contributed knowledge of genes that regulate development of hair cells and innervation, and of molecular players that can induce regeneration, but this technology is not applicable for human treatment, for practical and ethical reasons. Therefore other means for influencing gene expression in the inner ear are needed. We describe several gene vectors useful for inner ear gene therapy and the practical aspects of introducing these vectors into the ear. We then review the progress toward using gene transfer for therapies in both auditory and balance systems, and discuss the technological milestones needed to advance to clinical application of these methods. PMID:23265411

  4. Positron Emission Tomography Reporter Genes and Reporter Probes: Gene and Cell Therapy Applications

    PubMed Central

    Yaghoubi, Shahriar S.; Campbell, Dean O.; Radu, Caius G.; Czernin, Johannes

    2012-01-01

    Positron emission tomography (PET) imaging reporter genes (IRGs) and PET reporter probes (PRPs) are amongst the most valuable tools for gene and cell therapy. PET IRGs/PRPs can be used to non-invasively monitor all aspects of the kinetics of therapeutic transgenes and cells in all types of living mammals. This technology is generalizable and can allow long-term kinetics monitoring. In gene therapy, PET IRGs/PRPs can be used for whole-body imaging of therapeutic transgene expression, monitoring variations in the magnitude of transgene expression over time. In cell or cellular gene therapy, PET IRGs/PRPs can be used for whole-body monitoring of therapeutic cell locations, quantity at all locations, survival and proliferation over time and also possibly changes in characteristics or function over time. In this review, we have classified PET IRGs/PRPs into two groups based on the source from which they were derived: human or non-human. This classification addresses the important concern of potential immunogenicity in humans, which is important for expansion of PET IRG imaging in clinical trials. We have then discussed the application of this technology in gene/cell therapy and described its use in these fields, including a summary of using PET IRGs/PRPs in gene and cell therapy clinical trials. This review concludes with a discussion of the future direction of PET IRGs/PRPs and recommends cell and gene therapists collaborate with molecular imaging experts early in their investigations to choose a PET IRG/PRP system suitable for progression into clinical trials. PMID:22509201

  5. Gene Therapy Approaches for Musculoskeletal Tissue Regeneration

    Microsoft Academic Search

    Renny T. Franceschi

    \\u000a Safe, effective methods for bone and cartilage regeneration are needed to reverse bone loss caused by trauma, disease, tumor\\u000a resection and osteoarthritis. Unfortunately, all current or emerging therapies have serious limitations. As will be developed\\u000a in this chapter, gene therapy offers a promising approach for musculoskeletal regeneration because it can mimic the natural\\u000a biological processes of bone development and fracture

  6. Gene and cell therapy for muscle regeneration.

    PubMed

    Stilhano, Roberta Sessa; Martins, Leonardo; Ingham, Sheila Jean McNeill; Pesquero, João Bosco; Huard, Johnny

    2015-06-01

    Skeletal muscle injury and healing are multifactorial processes, involving three steps of healing: (1) degeneration and inflammation, (2) regeneration, and (3) fibrosis. Fibrous tissue hinders the muscle's complete recovery and current therapies fail in achieving total muscle recovery. Gene and cell therapy (or both) are potential future treatments for severe muscular injuries. Stem cells' properties associated with growth factors or/and cytokines can improve muscle healing and permit long-term recovery. PMID:25899573

  7. Advance of Molecular Imaging Technology and Targeted Imaging Agent in Imaging and Therapy

    PubMed Central

    Chen, Zhi-Yi; Wang, Yi-Xiang; Lin, Yan; Zhang, Jin-Shan; Yang, Feng; Zhou, Qiu-Lan; Liao, Yang-Ying

    2014-01-01

    Molecular imaging is an emerging field that integrates advanced imaging technology with cellular and molecular biology. It can realize noninvasive and real time visualization, measurement of physiological or pathological process in the living organism at the cellular and molecular level, providing an effective method of information acquiring for diagnosis, therapy, and drug development and evaluating treatment of efficacy. Molecular imaging requires high resolution and high sensitive instruments and specific imaging agents that link the imaging signal with molecular event. Recently, the application of new emerging chemical technology and nanotechnology has stimulated the development of imaging agents. Nanoparticles modified with small molecule, peptide, antibody, and aptamer have been extensively applied for preclinical studies. Therapeutic drug or gene is incorporated into nanoparticles to construct multifunctional imaging agents which allow for theranostic applications. In this review, we will discuss the characteristics of molecular imaging, the novel imaging agent including targeted imaging agent and multifunctional imaging agent, as well as cite some examples of their application in molecular imaging and therapy. PMID:24689058

  8. Gene Therapy for Parkinson's Disease

    Microsoft Academic Search

    Kari Andersen

    2012-01-01

    Background: Parkinson’s disease (PD) is a neurodegenerative disorder of unknown cause. The characteristic motor impairments of PD including resting tremor, rigidity, slowed movement, decreased dexterity, small handwriting, flexed posture, gait disorder, and imbalance predominantly arise from the loss of neurons in the substantia nigra region of the midbrain that produce the neurotransmitter dopamine. Dopamine replacement therapy provides temporary relief of

  9. Vectors for gene therapy of cardiovascular disease

    Microsoft Academic Search

    Jean-François Dedieu; Abderrahim Mahfoudi; Aude Le Roux; Didier Branellec

    2000-01-01

    Several phase I\\/II clinical trials are currently ongoing in gene therapy of cardiovascular disease. Whereas the indications\\u000a vary, including peripheral artery disease, ischemic heart disease, post-angioplasty restenosis, and vein graft failure, these\\u000a trials are mostly based on the use of adenoviral vectors and nonviral vectors. Novel vectors aimed at improving the efficacy\\u000a and safety of gene delivery in target organs,

  10. New strategies for cardiovascular gene therapy

    Microsoft Academic Search

    Jozef Dulak; Anna Zagorska; Barbara Wegiel; Agnieszka Loboda; Alicja Jozkowicz

    2006-01-01

    Cardiovascular diseases are among the major targets for gene therapy. Initially, clinical experiments of gene transfer of\\u000a vascular endothelial growth factor (VEGF) improved vascularization and prevented the amputation in patients with critical\\u000a leg ischemia. However, the majority of trials did not provide conclusive results and therefore further preclinical studies\\u000a are required. Importantly, data indicate the necessity of regulated expression of

  11. Orthopedic gene therapy--lost in translation?

    PubMed

    Evans, C H; Ghivizzani, S C; Robbins, P D

    2012-02-01

    Orthopedic gene therapy has been the topic of considerable research for two decades. The preclinical data are impressive and many orthopedic conditions are well suited to genetic therapies. But there have been few clinical trials and no FDA-approved product exists. This paper examines why this is so. The reasons are multifactorial. Clinical translation is expensive and difficult to fund by traditional academic routes. Because gene therapy is viewed as unsafe and risky, it does not attract major funding from the pharmaceutical industry. Start-up companies are burdened by the complex intellectual property environment and difficulties in dealing with the technology transfer offices of major universities. Successful translation requires close interactions between scientists, clinicians and experts in regulatory and compliance issues. It is difficult to create such a favorable translational environment. Other promising fields of biological therapy have contemplated similar frustrations approximately 20 years after their founding, so there seem to be more general constraints on translation that are difficult to define. Gene therapy has noted some major clinical successes in recent years, and a sense of optimism is returning to the field. We hope that orthopedic applications will benefit collaterally from this upswing and move expeditiously into advanced clinical trials. PMID:21948071

  12. [Developments in gene delivery vectors for ocular gene therapy].

    PubMed

    Khabou, Hanen; Dalkara, Deniz

    2015-05-01

    Gene therapy is quickly becoming a reality applicable in the clinic for inherited retinal diseases. Its remarkable success in safety and efficacy, in clinical trials for Leber's congenital amaurosis (LCA) type II generated significant interest and opened up possibilities for a new era of retinal gene therapies. Success in these clinical trials was mainly due to the favorable characteristics of the retina as a target organ. The eye offers several advantages as it is readily accessible and has some degree of immune privilege making it suitable for application of viral vectors. The viral vectors most frequently used for retinal gene delivery are lentivirus, adenovirus and adeno-associated virus (AAV). Here we will discuss the use of these viral vectors in retinal gene delivery with a strong focus on favorable properties of AAV. Thanks to its small size, AAV diffuses well in the inter-neural matrix making it suitable for applications in neural retina. Building on this initial clinical success with LCA II, we have now many opportunities to extend this proof-of-concept to other retinal diseases using AAV as a vector. This article will discuss what are some of the most imminent cellular targets for such therapies and the AAV toolkit that has been built to target these cells successfully. We will also discuss some of the challenges that we face in translating AAV-based gene therapies to the clinic. PMID:26059304

  13. Gene therapy for the mucopolysaccharidoses (review)

    Microsoft Academic Search

    Donald S. Anson

    1998-01-01

    Summary The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders in which the storage material is glycosaminoglycan. Each MPS is caused by the genetic deficiency of a single lysosomal enzyme. Due to the nature of these diseases and the characteristics of the enzymes that are deficient most of the MPS are good candidates for gene therapy. Studies in animal

  14. Gene therapy in dentistry: present and future.

    PubMed

    Baum, Bruce J

    2014-12-01

    Gene therapy is one of several novel biological treatments under active study for a wide variety of clinical applications, including many relevant to dentistry. This review will provide some background on this therapeutic approach, assess the current state of its applications generally, and in the oral cavity, and suggest the implications for its use in the next 25 years. PMID:25707089

  15. [Gene therapy in Germany: from past to present].

    PubMed

    Kim, Young; Schmidt-Wolf, Ingo G H

    2015-04-01

    In 1994, the first clinical gene therapy trial was performed in Germany. Since then more than 2000 clinical gene therapy trials have been performed worldwide. After 20 years, a short résumé is drawn here. PMID:25924050

  16. Gene and splicing therapies for neuromuscular diseases.

    PubMed

    Benchaouir, Rachid; Robin, Valerie; Goyenvalle, Aurelie

    2015-01-01

    Neuromuscular disorders (NMD) are heterogeneous group of genetic diseases characterized by muscle weakness and wasting. Duchenne Muscular dystrophy (DMD) and Spinal muscular atrophy (SMA) are two of the most common and severe forms in humans and although the molecular mechanisms of these diseases have been extensively investigated, there is currently no effective treatment. However, new gene-based therapies have recently emerged with particular noted advances in using conventional gene replacement strategies and RNA-based technology. Whilst proof of principle have been demonstrated in animal models, several clinical trials have recently been undertaken to investigate the feasibility of these strategies in patients. In particular, antisense mediated exon skipping has shown encouraging results and hold promise for the treatment of dystrophic muscle. In this review, we summarize the recent progress of therapeutic approaches to neuromuscular diseases, with an emphasis on gene therapy and splicing modulation for DMD and SMA, focusing on the advantages offered by these technologies but also their challenges. PMID:25961553

  17. The gene therapy revolution in ophthalmology.

    PubMed

    Al-Saikhan, Fahad I

    2013-04-01

    The advances in gene therapy hold significant promise for the treatment of ophthalmic conditions. Several studies using animal models have been published. Animal models on retinitis pigmentosa, Leber's Congenital Amaurosis (LCA), and Stargardt disease have involved the use of adeno-associated virus (AAV) to deliver functional genes into mice and canines. Mice models have been used to show that a mutation in cGMP phosphodiesterase that results in retinitis pigmentosa can be corrected using rAAV vectors. Additionally, rAAV vectors have been successfully used to deliver ribozyme into mice with a subsequent improvement in autosomal dominant retinitis pigmentosa. By using dog models, researchers have made progress in studying X-linked retinitis pigmentosa which results from a RPGR gene mutation. Mouse and canine models have also been used in the study of LCA. The widely studied form of LCA is LCA2, resulting from a mutation in the gene RPE65. Mice and canines that were injected with normal copies of RPE65 gene showed signs such as improved retinal pigment epithelium transduction, visual acuity, and functional recovery. Studies on Stargardt disease have shown that mutations in the ABCA4 gene can be corrected with AAV vectors, or nanoparticles. Gene therapy for the treatment of red-green color blindness was successful in squirrel monkeys. Plans are at an advanced stage to begin clinical trials. Researchers have also proved that CD59 can be used with AMD. Gene therapy is also able to treat primary open angle glaucoma (POAG) in animal models, and studies show it is economically viable. PMID:24227970

  18. Gene therapy for lung cancer

    Microsoft Academic Search

    Eric B. Haura; Eduardo Sotomayor; Scott J. Antonia

    2003-01-01

    Lung cancer continues to be the largest killer of Americans due to cancer. Although progress has been made, with advances\\u000a in chemotherapy, the majority of patients diagnosed with lung cancer ultimately succumb to the disease. A better understanding\\u000a of the molecular pathogenesis of lung cancer is demonstrating how alterations in oncogenes and tumor suppressor genes control\\u000a lung cancer initiation, growth,

  19. Aerosolized Medications for Gene and Peptide Therapy.

    PubMed

    Laube, Beth L

    2015-06-01

    Inhalation therapy has matured to include drugs that: (1) deliver nucleic acids that either lead to the restoration of a gene construct or protein coding sequence in a population of cells or suppress or disrupt production of an abnormal gene product (gene therapy); (2) deliver peptides that target lung diseases such as asthma, sarcoidosis, pulmonary hypertension, and cystic fibrosis; and (3) deliver peptides to treat diseases outside the lung whose target is the systemic circulation (systemic drug delivery). These newer applications for aerosol therapy are the focus of this paper, and I discuss the status of each and the challenges that remain to their successful development. Drugs that are highlighted include: small interfering ribonucleic acid to treat lung cancer and Mycobacterium tuberculosis; vectors carrying the normal alpha-1 antitrypsin gene to treat alpha-1 antitrypsin deficiency; vectors carrying the normal cystic fibrosis transmembrane conductance regulator gene to treat cystic fibrosis; vasoactive intestinal peptide to treat asthma, pulmonary hypertension, and sarcoidosis; glutathione to treat cystic fibrosis; granulocyte-macrophage colony-stimulating factor to treat pulmonary alveolar proteinosis; calcitonin for postmenopausal osteoporosis; and insulin to treat diabetes. The success of these new aerosol applications will depend on many factors, such as: (1) developing gene therapy formulations that are safe for acute and chronic administrations to the lung, (2) improving the delivery of the genetic material beyond the airway mucus barrier and cell membrane and transferring the material to the cell cytoplasm or the cell nucleus, (3) developing aerosol devices that efficiently deliver genetic material and peptides to their lung targets over a short period of time, (4) developing devices that increase aerosol delivery to the lungs of infants, (5) optimizing the bioavailability of systemically delivered peptides, and (6) developing peptide formulations for systemic delivery that do not cause persistent cough or changes in lung function. PMID:26070576

  20. Gene therapy: implications for craniofacial regeneration.

    PubMed

    Scheller, Erica L; Villa-Diaz, Luis G; Krebsbach, Paul H

    2012-01-01

    Gene therapy in the craniofacial region provides a unique tool for delivery of DNA to coordinate protein production in both time and space. The drive to bring this technology to the clinic is derived from the fact that more than 85% of the global population may at one time require repair or replacement of a craniofacial structure. This need ranges from mild tooth decay and tooth loss to temporomandibular joint disorders and large-scale reconstructive surgery. Our ability to insert foreign DNA into a host cell has been developing since the early uses of gene therapy to alter bacterial properties for waste cleanup in the 1980s followed by successful human clinical trials in the 1990s to treat severe combined immunodeficiency. In the past 20 years, the emerging field of craniofacial tissue engineering has adopted these techniques to enhance regeneration of mineralized tissues, salivary gland, and periodontium and to reduce tumor burden of head and neck squamous cell carcinoma. Studies are currently pursuing research on both biomaterial-mediated gene delivery and more clinically efficacious, although potentially more hazardous, viral methods. Although hundreds of gene therapy clinical trials have taken place in the past 20 years, we must still work to ensure an ideal safety profile for each gene and delivery method combination. With adequate genotoxicity testing, we can expect gene therapy to augment protein delivery strategies and potentially allow for tissue-specific targeting, delivery of multiple signals, and increased spatial and temporal control with the goal of natural tissue replacement in the craniofacial complex. PMID:22337437

  1. Theranostic agents for intracellular gene delivery with spatiotemporal imaging

    PubMed Central

    Knipe, Jennifer M.; Peters, Jonathan T.; Peppas, Nicholas A.

    2013-01-01

    Gene therapy is the modification of gene expression to treat a disease. However, efficient intracellular delivery and monitoring of gene therapeutic agents is an ongoing challenge. Use of theranostic agents with suitable targeted, controlled delivery and imaging modalities has the potential to greatly advance gene therapy. Inorganic nanoparticles including magnetic nanoparticles, gold nanoparticles, and quantum dots have been shown to be effective theranostic agents for the delivery and spatiotemporal tracking of oligonucleotides in vitro and even a few cases in vivo. Major concerns remain to be addressed including cytotoxicity, particularly of quantum dots; effective dosage of nanoparticles for optimal theranostic effect; development of real-time in vivo imaging; and further improvement of gene therapy efficacy. PMID:23606894

  2. Gene Therapy Applications to Cancer Treatment

    PubMed Central

    2003-01-01

    Over the past ten years significant advances have been made in the fields of gene therapy and tumour immunology, such that there now exists a considerable body of evidence validating the proof in the principle of gene therapy based cancer vaccines. While clinical benefit has so far been marginal, data from preclinical and early clinical trials of gene therapy combined with standard therapies are strongly suggestive of additional benefit. Many reasons have been proposed to explain the paucity of clinical responses to single agent vaccination strategies including the poor antigenicity of tumour cells and the development of tolerance through down-regulation of MHC, costimulatory, signal transduction, and other molecules essential for the generation of strong immune responses. In addition, there is now evidence from animal models that the growing tumour may actively inhibit the host immune response. Removal of the primary tumour prior to T cell transfer from the spleen of cancer bearing animals, led to effective tumour cell line specific immunity in the recipient mouse suggesting that there is an ongoing tumour-host interaction. This model also illustrates the potential difficulties of clinical vaccine trials in patients with advanced stage disease. PMID:12686721

  3. Progress in gene targeting and gene therapy for retinitis pigmentosa

    SciTech Connect

    Farrar, G.J.; Humphries, M.M.; Erven, A. [Trinity College, Dublin (Ireland)] [and others

    1994-09-01

    Previously, we localized disease genes involved in retinitis pigmentosa (RP), an inherited retinal degeneration, close to the rhodopsin and peripherin genes on 3q and 6p. Subsequently, we and others identified mutations in these genes in RP patients. Currently animal models for human retinopathies are being generated using gene targeting by homologous recombination in embryonic stem (ES) cells. Genomic clones for retinal genes including rhodopsin and peripherin have been obtained from a phage library carrying mouse DNA isogenic with the ES cell line (CC1.2). The peripherin clone has been sequenced to establish the genomic structure of the mouse gene. Targeting vectors for rhodopsin and peripherin including a neomycin cassette for positive selection and thymidine kinase genes enabling selection against random intergrants are under construction. Progress in vector construction will be presented. Simultaneously we are developing systems for delivery of gene therapies to retinal tissues utilizing replication-deficient adenovirus (Ad5). Efficacy of infection subsequent to various methods of intraocular injection and with varying viral titers is being assayed using an adenovirus construct containing a CMV promoter LacZ fusion as reporter and the range of tissues infected and the level of duration of LacZ expression monitored. Viral constructs with the LacZ reporter gene under the control of retinal specific promoters such as rhodopsin and IRBP cloned into pXCJL.1 are under construction. An update on developments in photoreceptor cell-directed expression of virally delivered genes will be presented.

  4. In Vivo Imaging of Gene Expression: MR and Optical Technologies1

    Microsoft Academic Search

    Christoph Bremer; Ralph Weissleder

    With the ability to readily engineer genes, create knock-in and knock-out models of human disease, and replace and insert genes in clinical trials of gene therapy, it has become clear that imaging will play a critical role in these fields. Imaging is particularly helpful in recording temporal and spatial resolution of gene expression in vivo, determining vector distribu- tion, and,

  5. Newer Gene Editing Technologies toward HIV Gene Therapy

    PubMed Central

    Manjunath, N.; Yi, Guohua; Dang, Ying; Shankar, Premlata

    2013-01-01

    Despite the great success of highly active antiretroviral therapy (HAART) in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called “Berlin patient” who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy. PMID:24284874

  6. Gene Therapy Shows Promise for Inherited Eye Disease

    MedlinePLUS

    ... HealthDay . All rights reserved. More Health News on: Genes and Gene Therapy Vision Impairment and Blindness Recent Health News Related MedlinePlus Health Topics Genes and Gene Therapy Retinal Disorders Vision Impairment and Blindness About MedlinePlus ...

  7. New gene therapy strategies for hepatic fibrosis.

    PubMed

    Salazar-Montes, Adriana M; Hernández-Ortega, Luis D; Lucano-Landeros, Martha S; Armendariz-Borunda, Juan

    2015-04-01

    The liver is the largest internal organ of the body, which may suffer acute or chronic injury induced by many factors, leading to cirrhosis and hepatocarcinoma. Cirrhosis is the irreversible end result of fibrous scarring and hepatocellular regeneration, characterized by diffuse disorganization of the normal hepatic structure, regenerative nodules and fibrotic tissue. Cirrhosis is associated with a high co-morbidity and mortality without effective treatment, and much research has been aimed at developing new therapeutic strategies to guarantee recovery. Liver-based gene therapy has been used to downregulate specific genes, to block the expression of deleterious genes, to delivery therapeutic genes, to prevent allograft rejection and to augment liver regeneration. Viral and non-viral vectors have been used, with viral vectors proving to be more efficient. This review provides an overview of the main strategies used in liver-gene therapy represented by non-viral vectors, viral vectors, novel administration methods like hydrodynamic injection, hybrids of two viral vectors and blocking molecules, with the hope of translating findings from the laboratory to the patient's bed-side. PMID:25852266

  8. [Gene therapy: where do we stand?].

    PubMed

    Cavazzana-Calvo, Marina

    2013-04-01

    Gene therapy is a form of molecular medicine based on the addition of a corrected copy of a gene to the somatic cells of an individual in order to cure or to alleviate the underlying disease. This approach provides new targeted therapies for an increasing number of acquired or inherited diseases. Since its very first beginning in the 90's essentially for cancer treatment, this therapeutical approach has met unpredicted obstacles as well as true success. Recently, significant clinical benefits have been reported for several inherited diseases of the hematopoietic system but also of the retina and some cancers, widening its application provided that severe adverse events can be efficiently and stably prevented. PMID:23682464

  9. Gene Therapy for Allergic Airway Diseases

    Microsoft Academic Search

    Tania Maes; Kurt G. Tournoy; Guy F. Joos

    2011-01-01

    Airway diseases such as allergic asthma and rhinitis are characterized by a T-helper type 2 (Th2) response. Treatment of allergic\\u000a airway diseases is currently limited to drugs that relieve disease symptoms and inflammation. In the search for new therapeutics,\\u000a efforts have been made to treat allergic airway disease with gene therapy, and many preclinical studies have demonstrated\\u000a its impressive potential.

  10. Adrenergic Receptor Signaling Components in Gene Therapy

    Microsoft Academic Search

    Andrea D. Eckhart; Walter J. Koch

    Adrenergic receptor (AR) signaling is a key regulator of normal cardiopulmonary homeostasis. Under pathophysiological conditions,\\u000a such as heart failure, asthma, and hypertension, there are alterations in the signaling cascades. Advances in the ability\\u000a to manipulate the adenoviral genome have allowed the development of gene therapy in which transgenes of interest are inserted\\u000a into the adenovirus and transferred to mammals in

  11. Gene Therapy to Create Biological Pacemakers

    Microsoft Academic Search

    Gerard J. J. Boink; Jurgen Seppen; Jacques M. T. Bakker; Hanno L. Tan

    Old age and a variety of cardiovascular disorders may disrupt normal sinus node function. Currently, this is successfully\\u000a treated with electronic pacemakers, which, however, leave room for improvement. During the past decade, different strategies\\u000a to initiate pacemaker function by gene therapy were developed. In the search for a biological pacemaker, various approaches\\u000a were explored, including ?\\u000a 2-adrenergic receptor overexpression, down

  12. Gene therapy approaches for spinal cord injury

    NASA Astrophysics Data System (ADS)

    Bright, Corinne

    As the biomedical engineering field expands, combination technologies are demonstrating enormous potential for treating human disease. In particular, intersections between the rapidly developing fields of gene therapy and tissue engineering hold promise to achieve tissue regeneration. Nonviral gene therapy uses plasmid DNA to deliver therapeutic proteins in vivo for extended periods of time. Tissue engineering employs biomedical materials, such as polymers, to support the regrowth of injured tissue. In this thesis, a combination strategy to deliver genes and drugs in a polymeric scaffold was applied to a spinal cord injury model. In order to develop a platform technology to treat spinal cord injury, several nonviral gene delivery systems and polymeric scaffolds were evaluated in vitro and in vivo. Nonviral vector trafficking was evaluated in primary neuronal culture to develop an understanding of the barriers to gene transfer in neurons and their supporting glia. Although the most efficient gene carrier in vitro differed from the optimal gene carrier in vivo, confocal and electron microscopy of these nonviral vectors provided insights into the interaction of these vectors with the nucleus. A novel pathway for delivering nanoparticles into the nuclei of neurons and Schwann cells via vesicle trafficking was observed in this study. Reporter gene expression levels were evaluated after direct and remote delivery to the spinal cord, and the optimal nonviral vector, dose, and delivery strategy were applied to deliver the gene encoding the basic fibroblast growth factor (bFGF) to the spinal cord. An injectable and biocompatible gel, composed of the amphiphillic polymer poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG) was evaluated as a drug and gene delivery system in vitro, and combined with the optimized nonviral gene delivery system to treat spinal cord injury. Plasmid DNA encoding the bFGF gene and the therapeutic NEP1--40 peptide were incorporated in the PEG-PCL-PEG gel and injected into a lesion transecting the main dorsomedial and minor ventral medial corticospinal tract (CST). The degree of collateralization of the transected CST was quantified as an indicator of the regenerative potential of these treatments. At one month post-injury, we observed the robust rostral collateralization of the CST tract in response to the bFGF plasmid-loaded gel. In conclusion, we hope that this platform technology can be applied to the sustained local delivery of other proteins for the treatment of spinal cord injury.

  13. Gene-modified bone marrow cell therapy for prostate cancer.

    PubMed

    Wang, H; Thompson, T C

    2008-05-01

    There is a critical need to develop new and effective cancer therapies that target bone, the primary metastatic site for prostate cancer and other malignancies. Among the various therapeutic approaches being considered for this application, gene-modified cell-based therapies may have specific advantages. Gene-modified cell therapy uses gene transfer and cell-based technologies in a complementary fashion to chaperone appropriate gene expression cassettes to active sites of tumor growth. In this paper, we briefly review potential cell vehicles for this approach and discuss relevant gene therapy strategies for prostate cancer. We further discuss selected studies that led to the conceptual development and preclinical testing of IL-12 gene-modified bone marrow cell therapy for prostate cancer. Finally, we discuss future directions in the development of gene-modified cell therapy for metastatic prostate cancer, including the need to identify and test novel therapeutic genes such as GLIPR1. PMID:18385769

  14. Prospects for gene therapy of inherited retinal disease

    Microsoft Academic Search

    J W B Bainbridge; JWB Bainbridge

    2009-01-01

    Gene-based therapies offer the means to address gene defects responsible for inherited retinal disorders. A number of studies in experimental and preclinical models have demonstrated proof-of-principle that gene replacement therapy can mediate significant quantifiable improvements in ocular morphology and visual function. The first results of clinical trials of gene therapy for early-onset severe retinal dystrophy caused by defects in RPE65show

  15. Curing Genetic Disease with Gene Therapy

    PubMed Central

    Williams, David A.

    2014-01-01

    Development of viral vectors that allow high efficiency gene transfer into mammalian cells in the early 1980s foresaw the treatment of severe monogenic diseases in humans. The application of gene transfer using viral vectors has been successful in diseases of the blood and immune systems, albeit with several curative studies also showing serious adverse events (SAEs). In children with X-linked severe combined immunodeficiency (SCID-X1), chronic granulomatous disease, and Wiskott-Aldrich syndrome, these SAEs were caused by inappropriate activation of oncogenes. Subsequent studies have defined the vector sequences responsible for these transforming events. Members of the Transatlantic Gene Therapy Consortium [TAGTC] have collaboratively developed new vectors that have proven safer in preclinical studies and used these vectors in new clinical trials in SCID-X1. These trials have shown evidence of early efficacy and preliminary integration analysis data from the SCID-X1 trial suggest an improved safety profile. PMID:25125725

  16. Corneal Gene Therapy: Basic Science and Translational Perspective

    PubMed Central

    Mohan, Rajiv R.; Rodier, Jason T.; Sharma, Ajay

    2013-01-01

    Corneal blindness is the third leading cause of blindness worldwide. Gene therapy is an emerging technology for corneal blindness due to the accessibility and immune-privileged nature of the cornea, ease of vector administration and visual monitoring, and ability to perform frequent noninvasive corneal assessment. Vision restoration by gene therapy is contingent upon vector and mode of therapeutic gene introduction into targeted cells/tissues. Numerous efficacious vectors, delivery techniques, and approaches have evolved in last decade for developing gene-based interventions for corneal diseases. Maximizing the potential benefits of gene therapy requires efficient and sustained therapeutic gene expression in target cells, low toxicity, and a high safety profile. This review describes the basic science associated with many gene therapy vectors and the present progress of gene therapy carried out for various ocular surface disorders and diseases. PMID:23838017

  17. The American Society of Gene Therapy original article

    E-print Network

    Cai, Long

    of viral genes specifically in cancer cells by incorporation of synthetic let- 7 complementary sequences let-7 activity in cancer cells would facilitate viral gene expression and subsequent oncolysis© The American Society of Gene Therapy original article Molecular Therapy vol. 16 no. 8, 1437

  18. Progress and Prospects: Gene Therapy Clinical Trials (Part 1)

    Microsoft Academic Search

    Eric Alton

    2007-01-01

    Over the last two decades gene therapy has moved from preclinical to clinical studies for many diseases ranging from single gene disorders such as cystic fibrosis and Duchenne muscular dystrophy, to more complex diseases such as cancer and cardiovascular disorders. Gene therapy for severe combined immunodeficiency (SCID) is the most significant success story to date, but progress in many other

  19. A realistic chance for gene therapy in the near future

    Microsoft Academic Search

    Stefan Worgall

    2005-01-01

    The expanding knowledge of the genetic and cellular mechanisms of human diseases in the post-genomic era coupled with the development of different vector systems to efficiently transfer genes to a variety of cell types and organs in vivo gave rise to the concept of gene therapy as a promising therapeutic option for genetic and acquired diseases. Gene therapy has been

  20. Cystic Fibrosis Gene Therapy: Key Questions and Prospects

    Microsoft Academic Search

    Isabelle Fajac; Stephanie Grosse; Annie-Claude Roche; Michel Monsigny

    2006-01-01

    Cystic fibrosis is a monogenic disorder with significant morbidity and mortality, despite advances in conventional treatment. It is a good candidate for gene therapy and this field has progressed rapidly since the cystic fibrosis transmembrane conductance regulator gene was cloned. We will review the specific questions to address for successful cystic fibrosis gene therapy, such as the extra- and intracellular

  1. Antioxidant gene therapy against neuronal cell death

    PubMed Central

    Navarro-Yepes, Juliana; Zavala-Flores, Laura; Annadurai, Anandhan; Wang, Fang; Skotak, Maciej; Chandra, Namas; Li, Ming; Pappa, Aglaia; Martinez-Fong, Daniel; Razo, Luz Maria Del; Quintanilla-Vega, Betzabet; Franco, Rodrigo

    2014-01-01

    Oxidative stress is a common hallmark of neuronal cell death associated with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, as well as brain stroke/ischemia and traumatic brain injury. Increased accumulation of reactive species of both oxygen (ROS) and nitrogen (RNS) has been implicated in mitochondrial dysfunction, energy impairment, alterations in metal homeostasis and accumulation of aggregated proteins observed in neurodegenerative disorders, which lead to the activation/modulation of cell death mechanisms that include apoptotic, necrotic and autophagic pathways. Thus, the design of novel antioxidant strategies to selectively target oxidative stress and redox imbalance might represent important therapeutic approaches against neurological disorders. This work reviews the evidence demonstrating the ability of genetically encoded antioxidant systems to selectively counteract neuronal cell loss in neurodegenerative diseases and ischemic brain damage. Because gene therapy approaches to treat inherited and acquired disorders offer many unique advantages over conventional therapeutic approaches, we discussed basic research/clinical evidence and the potential of virus-mediated gene delivery techniques for antioxidant gene therapy. PMID:24333264

  2. Technology evaluation: gene therapy (FGF-5), Vical.

    PubMed

    Li, K; Stewart, D J; Ward, H J

    1999-04-01

    Vical, in collaboration with Merck, is developing gene-based therapies, including its 'naked DNA', for the potential treatment of ischemic heart disease. Vical has obtained preclinical data in animal models showing that a gene for a potent growth factor, FGF-5, can be delivered and expressed in coronary arteries stimulating the formation of new blood vessels. This new blood vessel formation may provide supplemental blood flow and necessary cardiac tissue oxygenation in areas of the heart where atherosclerotic blockages are present. Vical anticipates that its FGF-5 gene-based product would be used in conjunction with balloon angioplasty to stimulate new blood vessel formation at the site of the blockage. A series of experiments have been conducted in rats, whereby genes encoding FGF-5 were injected directly into rat heart muscle. The DNA was absorbed and the FGF-5 protein was expressed by cardiac myocytes. Active FGF-5 was released into the extracellular spaces of the heart muscle cells and new blood vessels formed throughout the local area. Quantitative measurements of blood vessel formation indicated that capillary density increased significantly in the hearts of treated rats compared to untreated controls. Further studies are underway to evaluate the persistence of new blood vessels following FGF-5 gene injection, and measurements will be made to assess the extent of improved blood flow in the affected region [177118]. In December 1996, the US patent office issued patent number US-05580859, covering Vical's naked DNA technology [227199]. PMID:11715949

  3. Development of A Percutaneous Optical Imaging System for Tracking Vascular Gene Expression: An Ultrasound-Guided Ex Vivo Feasibility Study

    Microsoft Academic Search

    Sourav Kar; Ananda Kumar; Xiaoming Yang

    2004-01-01

    Vascular gene therapy is an exciting approach for the cure and mitigation of atherosclerosis and related cardiovascular diseases. Monitoring transgene expression using noninvasive imaging techniques is a necessary complement for the success of clinical gene therapy. Optical imaging based on fluorescence signal detection from biomarker genes holds promise in the area. Green fluorescent protein (GFP) is one of the most

  4. The Muscular Dystrophies: From Genes to Therapies

    PubMed Central

    Porter, Neil C; Bloch, Robert J

    2015-01-01

    The genetic basis of many muscular disorders, including many of the more common muscular dystrophies, is now known. Clinically, the recent genetic advances have improved diagnostic capabilities, but they have not yet provided clues about treatment or management. Thanks to better management strategies and therapeutic interventions, however, many patients with a muscular dystrophy are more active and are living longer. Physical therapists, therefore, are more likely to see a patient with a muscular dystrophy, so understanding these muscle disorders and their management is essential. Physical therapy offers the most promise in caring for the majority of patients with these conditions, because it is unlikely that advances in gene therapy will significantly alter their clinical treatment in the near future. This perspective covers some of the basic molecular biological advances together with the clinical manifestations of the muscular dystrophies and the latest approaches to their management. PMID:16305275

  5. Gene therapy in animal models of autosomal dominant retinitis pigmentosa

    PubMed Central

    Rossmiller, Brian; Mao, Haoyu

    2012-01-01

    Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation. Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression. In this review, we examine some of the gene delivery approaches used to treat animal models of autosomal dominant retinitis pigmentosa, focusing on those models associated with mutations in the gene for rhodopsin. We conclude that combinatorial approaches have the greatest promise for success. PMID:23077406

  6. Combinational adenovirus-mediated gene therapy and dendritic cell vaccine in combating well-established tumors

    Microsoft Academic Search

    Dajing Xia; Terence Moyana; Jim Xiang

    2006-01-01

    Recent developments in tumor immunology and biotechnology have made cancer gene therapy and immunotherapy feasible. The current efforts for cancer gene therapy mainly focus on using immunogenes, chemogenes and tumor suppressor genes. Central to all these therapies is the development of efficient vectors for gene therapy. By far, adenovirus (AdV)-mediated gene therapy is one of the most promising approaches, as

  7. Near-infrared light triggered photodynamic therapy in combination with gene therapy using upconversion nanoparticles for effective cancer cell killing

    NASA Astrophysics Data System (ADS)

    Wang, Xin; Liu, Kai; Yang, Guangbao; Cheng, Liang; He, Lu; Liu, Yumeng; Li, Yonggang; Guo, Liang; Liu, Zhuang

    2014-07-01

    Upconversion nanoparticles (UCNPs) have drawn much attention in cancer imaging and therapy in recent years. Herein, we for the first time report the use of UCNPs with carefully engineered surface chemistry for combined photodynamic therapy (PDT) and gene therapy of cancer. In our system, positively charged NaGdF4:Yb,Er UCNPs with multilayered polymer coatings are synthesized via a layer by layer strategy, and then loaded simultaneously with Chlorin e6 (Ce6), a photosensitizing molecule, and small interfering RNA (siRNA), which targets the Plk1 oncogene. On the one hand, under excitation by a near-infrared (NIR) light at 980 nm, which shows greatly improved tissue penetration compared with visible light, cytotoxic singlet oxygen can be generated via resonance energy transfer from UCNPs to photosensitizer Ce6, while the residual upconversion luminescence is utilized for imaging. On the other hand, the silencing of Plk1 induced by siRNA delivered with UCNPs could induce significant cancer cell apoptosis. As the result of such combined photodynamic and gene therapy, a remarkably enhanced cancer cell killing effect is realized. Our work thus highlights the promise of UCNPs for imaging guided combination therapy of cancer.Upconversion nanoparticles (UCNPs) have drawn much attention in cancer imaging and therapy in recent years. Herein, we for the first time report the use of UCNPs with carefully engineered surface chemistry for combined photodynamic therapy (PDT) and gene therapy of cancer. In our system, positively charged NaGdF4:Yb,Er UCNPs with multilayered polymer coatings are synthesized via a layer by layer strategy, and then loaded simultaneously with Chlorin e6 (Ce6), a photosensitizing molecule, and small interfering RNA (siRNA), which targets the Plk1 oncogene. On the one hand, under excitation by a near-infrared (NIR) light at 980 nm, which shows greatly improved tissue penetration compared with visible light, cytotoxic singlet oxygen can be generated via resonance energy transfer from UCNPs to photosensitizer Ce6, while the residual upconversion luminescence is utilized for imaging. On the other hand, the silencing of Plk1 induced by siRNA delivered with UCNPs could induce significant cancer cell apoptosis. As the result of such combined photodynamic and gene therapy, a remarkably enhanced cancer cell killing effect is realized. Our work thus highlights the promise of UCNPs for imaging guided combination therapy of cancer. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr02495h

  8. Peptide Receptor Imaging and Therapy

    Microsoft Academic Search

    Dik Kwekkeboom; Eric P. Krenning; Marion de Jong

    This article reviews the results of somatostatin receptor imaging (SRI) in patients with somatostatin receptor-positive neuroendo- crine tumors, such as pituitary tumors, endocrine pancreatic tumors, carcinoids, gastrinomas, and paragangliomas, or other diseases in which somatostatin receptors may also be ex- pressed, like sarcoidosis and autoimmune diseases. (111In- DTPA 0 )octreotide is a radiopharmaceutical that has great poten- tial for helping

  9. Interactive level set segmentation for image-guided therapy

    E-print Network

    Kiryati, Nahum

    Image-guided therapy procedures require the patient to remain still throughout the image acquisition, data analysis and therapy. This imposes a tight time constraint on the over-all process. Automatic extraction of the ...

  10. Gene Therapy for the Treatment of Oral Squamous Cell Carcinoma

    Microsoft Academic Search

    S. Xi; J. R. Grandis

    2003-01-01

    Despite advances in surgery, radiotherapy, and chemotherapy, the survival of patients with oral squamous cell carcinoma has not significantly improved over the past several decades. Treatment options for recurrent or refractory oral cancers are limited. Gene therapy for oral cancer is currently under investigation in clinical trials. The goal of cancer gene therapy is to introduce new genetic material into

  11. In Utero gene therapy: current challenges and perspectives

    Microsoft Academic Search

    Simon N. Waddington; M. Gabriela Kramer; Ruben Hernandez-Alcoceba; Suzanne M. K. Buckley; Michael Themis; Charles Coutelle; Jesus Prieto

    2005-01-01

    Over the past few years, considerable progress in prenatal diagnosis and surgery combined with improvements in vector design vindicate a reappraisal of the feasibility of in utero gene therapy for serious monogenetic diseases. As adult gene therapy gathers pace, several apparent obstacles to its application as a treatment may be overcome by pre- or early postnatal treatment. This review will

  12. Large deformation 3D image registration in image-guided radiation therapy

    E-print Network

    Utah, University of

    -guided radiation therapy 2 1. Introduction In radiation cancer therapy, the problem of organ motion over the courseLarge deformation 3D image registration in image-guided radiation therapy Mark Foskey, Brad Davis processing of serial 3D CT images used in image- guided radiation therapy. A major assumption in deformable

  13. Antiprotons for imaging and therapy

    NASA Astrophysics Data System (ADS)

    Kalogeropoulos, Theodore E.; Muratore, Robert

    1989-04-01

    Antiprotons are presently produced and stored at CERN and Fermilab at a rate of about 10 7 p/s. Efforts are underway to develop transportable storage devices, 'bottles', which would store as much as 10 12 antiprotons for months, or years and make the antiprotons available anywhere. A workshop held last year at the RAND Corporation assessed the science and technology of antimatter and the enabling tools. The biomedical potential of antiprotons was discussed and appears to be promising at current antimatter collection capabilities. Two applications have been studied using computer simulations: direct 3-D d E/d x imaging and the treatment of tumors with antiprotons. We discuss antiprotonic imaging and make comparisons with X-ray CT scans. The potential of antiprotons for monitoring precise delivery of radiation as well as treatment will also be discussed.

  14. A snapshot of gene therapy in Latin America

    PubMed Central

    Linden, Rafael; Matte, Ursula

    2014-01-01

    Gene therapy attempts the insertion and expression of exogenous genetic material in cells for therapeutic purposes. Conceived in the 1960s, gene therapy reached its first clinical trial at the end of the 1980s and by December 2013 around 600 genuine open clinical trials of gene therapy were registered at NIH Clinical Trials Database. Here, we summarize the current efforts towards the development of gene therapy in Latin America. Our survey shows that the number of scientists involved in the development of gene therapy and DNA vaccines in Latin America is still very low. Higher levels of investment in this technology are necessary to boost the advancement of innovation and intellectual property in this field in a way that would ease both the social and financial burden of various medical conditions in Latin America. PMID:24764763

  15. Gene therapy for cardiovascular disease mediated by ultrasound and microbubbles

    PubMed Central

    2013-01-01

    Gene therapy provides an efficient approach for treatment of cardiovascular disease. To realize the therapeutic effect, both efficient delivery to the target cells and sustained expression of transgenes are required. Ultrasound targeted microbubble destruction (UTMD) technique has become a potential strategy for target-specific gene and drug delivery. When gene-loaded microbubble is injected, the ultrasound-mediated microbubble destruction may spew the transported gene to the targeted cells or organ. Meanwhile, high amplitude oscillations of microbubbles increase the permeability of capillary and cell membrane, facilitating uptake of the released gene into tissue and cell. Therefore, efficiency of gene therapy can be significantly improved. To date, UTMD has been successfully investigated in many diseases, and it has achieved outstanding progress in the last two decades. Herein, we discuss the current status of gene therapy of cardiovascular diseases, and reviewed the progress of the delivery of genes to cardiovascular system by UTMD. PMID:23594865

  16. Gene Therapy in the Treatment of Heart Failure

    NSDL National Science Digital Library

    2007-04-01

    Heart failure is a major cause of morbidity and mortality in contemporary societies. Although progress in conventional treatment modalities is making steady and incremental gains to reduce this disease burden, there remains a need to explore new and potentially therapeutic approaches. Gene therapy, for example, was initially envisioned as a treatment strategy for inherited monogenic disorders. It is now apparent that gene therapy has broader potential that also includes acquired polygenic diseases, such as heart failure. Advances in the understanding of the molecular basis of conditions such as these, together with the evolution of increasingly efficient gene transfer technology, has placed congestive heart failure within reach of gene-based therapy.

  17. 75 FR 65640 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-26

    ...FDA-2010-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of...Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General...Branch, Office of Cellular, Tissue and Gene Therapies, Center for Biologics...

  18. 78 FR 70307 - Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-25

    ...Assessment of Investigational Cellular and Gene Therapy Products; Availability AGENCY...Assessment of Investigational Cellular and Gene Therapy Products'' dated November 2013...by the Office of Cellular, Tissue and Gene Therapies (OCTGT). The product...

  19. 78 FR 44133 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-23

    ...FDA-2013-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of...Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General...from the Office of Cellular, Tissue and Gene Therapies, Center for Biologics...

  20. 76 FR 22405 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-21

    ...FDA-2011-N-0002] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of...Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General...the committee will discuss cellular and gene therapy products for the treatment of...

  1. 78 FR 79699 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-31

    ...FDA-2013-N-0001] Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of...of Committee: Cellular, Tissue, and Gene Therapies Advisory Committee. General...from the Office of Cellular, Tissue, and Gene Therapies, Center for Biologics...

  2. 76 FR 81513 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-28

    ...FDA-2011-N-0002] Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of...of Committee: Cellular, Tissue, and Gene Therapies Advisory Committee. General...Branch, Office of Cellular, Tissue and Gene Therapies, Center for Biologics...

  3. 75 FR 66381 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-28

    ...FDA-2010-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of...Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General...Retroviral and Lentiviral Vector Based Gene Therapy Products. FDA intends to...

  4. 76 FR 9028 - Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-16

    ...Industry: Potency Tests for Cellular and Gene Therapy Products; Availability AGENCY...Industry: Potency Tests for Cellular and Gene Therapy Products'' dated January 2011...provides manufacturers of cellular and gene therapy (CGT) products with...

  5. 77 FR 65693 - Cellular, Tissue and Gene Therapies Advisory Committee; Amendment of Notice

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-30

    ...FDA-2012-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Amendment...a meeting of the Cellular, Tissue and Gene Therapies Advisory Committee. This meeting...a meeting of the Cellular, Tissue and Gene Therapies Advisory Committee would be...

  6. 77 FR 71194 - Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-29

    ...Assessment of Investigational Cellular and Gene Therapy Products; Availability AGENCY...Assessment of Investigational Cellular and Gene Therapy Products,'' dated November 2012...CBER), Office of Cellular, Tissue, and Gene Therapies (OCTGT). The product...

  7. Prodrugs for Gene-Directed Enzyme-Prodrug Therapy (Suicide Gene Therapy)

    PubMed Central

    2003-01-01

    This review focuses on the prodrugs used in suicide gene therapy. These prodrugs need to satisfy a number of criteria. They must be efficient and selective substrates for the activating enzyme, and be metabolized to potent cytotoxins preferably able to kill cells at all stages of the cell cycle. Both prodrugs and their activated species should have good distributive properties, so that the resulting bystander effects can maximize the effectiveness of the therapy, since gene transduction efficiencies are generally low. A total of 42 prodrugs explored for use in suicide gene therapy with 12 different enzymes are discussed, particularly in terms of their physiocochemical properties. An important parameter in determining bystander effects generated by passive diffusion is the lipophilicity of the activated form, a property conveniently compared by diffusion coefficients (log P for nonionizable compounds and log D7 for compounds containing an ionizable centre). Many of the early antimetabolite-based prodrugs provide very polar activated forms that have limited abilities to diffuse across cell membranes, and rely on gap junctions between cells for their bystander effects. Several later studies have shown that more lipophilic, neutral compounds have superior diffusion-based bystander effects. Prodrugs of DNA alkylating agents, that are less cell cycle-specific than antimetabolites and more effective against noncycling tumor cells, appear in general to be more active prodrugs, requiring less prolonged dosing schedules to be effective. It is expected that continued studies to optimize the bystander effects and other properties of prodrugs and the activated species they generate will contribute to improvements in the effectiveness of suicide gene therapy. PMID:12686722

  8. Human gene therapy: a brief overview of the genetic revolution.

    PubMed

    Misra, Sanjukta

    2013-02-01

    Advances in biotechnology have brought gene therapy to the forefront of medical research. The prelude to successful gene therapy i.e. the efficient transfer and expression of a variety of human gene into target cells has already been accomplished in several systems. Safe methods have been devised to do this, using several viral and no-viral vectors. Two main approaches emerged: in vivo modification and ex vivo modification. Retrovirus, adenovirus, adeno-associated virus are suitable for gene therapeutic approaches which are based on permanent expression of the therapeutic gene. Non-viral vectors are far less efficient than viral vectors, but they have advantages due to their low immunogenicity and their large capacity for therapeutic DNA. To improve the function of non-viral vectors, the addition of viral functions such as receptor mediated uptake and nuclear translocation of DNA may finally lead to the development of an artificial virus. Gene transfer protocols have been approved for human use in inherited diseases, cancers and acquired disorders. In 1990, the first successful clinical trial of gene therapy was initiated for adenosine deaminase deficiency. Since then, the number of clinical protocols initiated worldwide has increased exponentially. Although preliminary results of these trials are somewhat disappointing, but human gene therapy dreams of treating diseases by replacing or supplementing the product of defective or introducing novel therapeutic genes. So definitely human gene therapy is an effective addition to the arsenal of approaches to many human therapies in the 21st century. PMID:24471251

  9. Image-Guidance and Multimodal Dose Planning in Radiation Therapy

    E-print Network

    Paris-Sud XI, Université de

    Image-Guidance and Multimodal Dose Planning in Radiation Therapy A workshop held at MICCAI 2012 and image computing form the basis for radiation therapy. Examples range from pre-treatment delineation in radiation therapy have frequently been a driving force in the de- velopment of new image computing

  10. Gene therapy and gastrointestinal cancer: concepts and clinical facts

    Microsoft Academic Search

    Martin Hauses; Hans K. Schackert

    1999-01-01

    Background: Principles of the treatment of gastrointestinal cancer with gene therapy evolved from the advent of techniques in molecular\\u000a biology, from increasing insights into the molecular basis of tumorigenesis and from the need to develop more efficient treatment\\u000a modalities. Any gene therapy approach has to take two major tasks into consideration: the therapeutic gene has to be delivered\\u000a into the

  11. Gene and cell therapy for children — New medicines, new challenges??

    PubMed Central

    Buckland, Karen F.; Bobby Gaspar, H.

    2014-01-01

    The range of possible gene and cell therapy applications is expanding at an extremely rapid rate and advanced therapy medicinal products (ATMPs) are currently the hottest topic in novel medicines, particularly for inherited diseases. Paediatric patients stand to gain enormously from these novel therapies as it now seems plausible to develop a gene or cell therapy for a vast number of inherited diseases. There are a wide variety of potential gene and cell therapies in various stages of development. Patients who received first gene therapy treatments for primary immune deficiencies (PIDs) are reaching 10 and 15 years post-treatment, with robust and sustained immune recovery. Cell therapy clinical trials are underway for a variety of tissues including corneal, retinal and muscle repair and islet cell transplantation. Various cell therapy approaches are also being trialled to enhance the safety of bone marrow transplants, which should improve survival rates in childhood cancers and PIDs. Progress in genetic engineering of lymphocyte populations to target and kill cancerous cells is also described. If successful these ATMPs may enhance or replace the existing chemo-ablative therapy for several paediatric cancers. Emerging applications of gene therapy now include skin and neurological disorders such as epidermolysis bullosa, epilepsy and leukodystrophy. Gene therapy trials for haemophilia, muscular dystrophy and a range of metabolic disorders are underway. There is a vast array of potential advanced therapy medicinal products (ATMPs), and these are likely to be more cost effective than existing medicines. However, the first clinical trials have not been without setbacks and some of the key adverse events are discussed. Furthermore, the arrival of this novel class of therapies brings many new challenges for the healthcare industry. We present a summary of the key non-clinical factors required for successful delivery of these potential treatments. Technological advances are needed in vector design, raw material manufacture, cell culture and transduction methodology, and particularly in making all these technologies readily scalable. PMID:24583376

  12. Gene therapy progress and prospects: transcription regulatory systems

    Microsoft Academic Search

    C Toniatti; H Bujard; R Cortese; G Ciliberto

    2004-01-01

    The clinical efficacy and safety as well as the application range of gene therapy will be broadened by developing systems capable of finely modulating the expression of therapeutic genes. Transgene regulation will be crucial for maintaining appropriate levels of a gene product within the therapeutic range, thus preventing toxicity. Moreover, the possibility to modulate, stop or resume transgene expression in

  13. Gene therapy in the nervous system with superoxide dismutase

    Microsoft Academic Search

    Ilona Zemlyak; Vitaliy Nimon; Sheila Brooke; Tejaswini Moore; John McLaughlin; Robert Sapolsky

    2006-01-01

    Neuronal death following necrotic insults involves the generation of reactive oxygen species (ROS). We investigated the effects of antioxidant gene therapy on ROS accumulation after exposure to either sodium cyanide, kainic acid or oxygen glucose deprivation (OGD). Specifically, we generated herpes simplex virus-1 amplicon vector expressing the gene for the antioxidant enzyme CuZnSOD. Overexpression of this gene in primary hippocampal

  14. Gene therapy as future treatment of erectile dysfunction

    PubMed Central

    Yoshimura, Naoki; Kato, Ryuichi; Chencellor, Michael B.; Nelson, Joel B.; Glorioso, Joseph C.

    2011-01-01

    Importance of the field Erectile dysfunction (ED) is a major men’s health problem. Although the high success rate of treating ED by phosphodiesterase 5 (PDE5) inhibitors has been reported, there are a significant number of ED patients who do not respond to currently available treatment modalities. Areas covered in this review To understand the current status of gene therapy application for ED, gene therapy approaches for ED treatment are reviewed. What the reader will gain Gene therapy strategies that can enhance nitric oxide (NO) production or NO-mediated signaling pathways, growth factor-mediated nerve regeneration or K+ channel activity in the smooth muscle could be promising approaches for the treatment of ED. Although the majority of gene therapy studies are still in the preclinical phase, the first clinical trial using non-viral gene transfer of Ca2+-activated, large-conductance K+ channels into the corpus cavernosum of ED patients showed positive results. Take home message Gene therapy represents an exciting future treatment option for ED, especially for people with severe ED unresponsive to current first-line therapies such as PDE5 inhibitors although the long-term safety of both viral and non-viral gene therapies should be established. PMID:20662742

  15. Imaging Cell Therapy for Myocardial Regeneration

    PubMed Central

    Zhang, Hualei; Qiao, Hui; Ferrari, Victor A.

    2012-01-01

    Noninvasive or minimally invasive imaging techniques are essential for developing strategies and assessing outcomes of cell-based therapies for myocardial regeneration, also referred to as cellular cardiomyoplasty. Imaging-based monitoring of cell survival is useful for selection of optimal cell type and evaluating strategies to enhance engraftment. Imaging-derived surrogate end points including global and regional contractile function, myocardial blood flow, or perfusion and bioenergetics have been used in clinical trials or in relevant large animal models to evaluate the therapeutic effect and mechanisms of action of cellular cardiomyoplasty. New techniques are emerging to assess electrical integration of donor cells with host cardiomyocytes. This review will summarize and highlight important and informative findings revealed by imaging in clinical and preclinical cellular cardiomyoplasty studies over the past 3 years. PMID:22905280

  16. Use of hypoxia-regulated gene expression in tumor-specific gene therapy.

    PubMed

    Ruan, H; Deen, D F

    2001-06-01

    The presence of hypoxic cells in human solid tumors is an important factor leading to resistance to radiation therapy and chemotherapy. However, differences in the oxygen tension between normal tissues and tumors also provide the potential for designing tumor-specific gene therapy. The strategy is to selectively induce the expression of suicide genes under hypoxia and thereby preferentially kill hypoxic cells. The hypoxia-responsive vector regulates gene expression via the hypoxia-responsive element, which can be activated through the transcriptional complex hypoxia-inducible factor 1. A gene therapy that is based on hypoxia-regulated gene expression needs to consider the suicide gene, the genetic vector, the delivery method and the bystander effect. These factors pose considerable challenges for the development of a successful hypoxia-directed gene therapy, but once this has been achieved, this type of therapy in combination with traditional radiation and chemotherapy should provide an improved clinical outcome for patients with these diseases. PMID:11572667

  17. Interactive Fly: Early Zygotic Gene Expression Images

    NSDL National Science Digital Library

    PhD Thomas B Brody (NIH Laboratory of Neurochemistry)

    2006-12-12

    In situ images from an award-winning and comprehensive site, The Interactive Fly. Entering through an expression pattern, this site thoroughly discusses each genes and shows its expression relative to other genes at this stage.

  18. Image-guided radiation therapy: Physician's perspectives.

    PubMed

    Gupta, T; Narayan, C Anand

    2012-10-01

    The evolution of radiotherapy has been ontogenetically linked to medical imaging. Over the years, major technological innovations have resulted in substantial improvements in radiotherapy planning, delivery, and verification. The increasing use of computed tomography imaging for target volume delineation coupled with availability of computer-controlled treatment planning and delivery systems have progressively led to conformation of radiation dose to the target tissues while sparing surrounding normal tissues. Recent advances in imaging technology coupled with improved treatment delivery allow near-simultaneous soft-tissue localization of tumor and repositioning of patient. The integration of various imaging modalities within the treatment room for guiding radiation delivery has vastly improved the management of geometric uncertainties in contemporary radiotherapy practice ushering in the paradigm of image-guided radiation therapy (IGRT). Image-guidance should be considered a necessary and natural corollary to high-precision radiotherapy that was long overdue. Image-guided radiation therapy not only provides accurate information on patient and tumor position on a quantitative scale, it also gives an opportunity to verify consistency of planned and actual treatment geometry including adaptation to daily variations resulting in improved dose delivery. The two main concerns with IGRT are resource-intensive nature of delivery and increasing dose from additional imaging. However, increasing the precision and accuracy of radiation delivery through IGRT is likely to reduce toxicity with potential for dose escalation and improved tumor control resulting in favourable therapeutic index. The radiation oncology community needs to leverage this technology to generate high-quality evidence to support widespread adoption of IGRT in contemporary radiotherapy practice. PMID:23293448

  19. Gene Therapy, Early Promises, Subsequent Problems, and Recent Breakthroughs

    PubMed Central

    Razi Soofiyani, Saeideh; Baradaran, Behzad; Lotfipour, Farzaneh; Kazemi, Tohid; Mohammadnejad, Leila

    2013-01-01

    Gene therapy is one of the most attractive fields in medicine. The concept of gene delivery to tissues for clinical applications has been discussed around half a century, but scientist’s ability to manipulate genetic material via recombinant DNA technology made this purpose to reality. Various approaches, such as viral and non-viral vectors and physical methods, have been developed to make gene delivery safer and more efficient. While gene therapy initially conceived as a way to treat life-threatening disorders (inborn errors, cancers) refractory to conventional treatment, to date gene therapy is considered for many non–life-threatening conditions including those adversely influence on a patient’s quality of life. Gene therapy has made significant progress, including tangible success, although much slower than was initially predicted. Although, gene therapies still at a fairly primitive stage, it is firmly science based. There is justifiable hope that with enhanced pathobiological understanding and biotechnological improvements, gene therapy will be a standard part of clinical practice within 20 years. PMID:24312844

  20. Diagnostic Imaging for Dental Implant Therapy

    PubMed Central

    Nagarajan, Aishwarya; Perumalsamy, Rajapriya; Thyagarajan, Ramakrishnan; Namasivayam, Ambalavanan

    2014-01-01

    Dental implant is a device made of alloplastic (foreign) material implanted into the jaw bone beneath the mucosal layer to support a fixed or removable dental prosthesis. Dental implants are gaining immense popularity and wide acceptance because they not only replace lost teeth but also provide permanent restorations that do not interfere with oral function or speech or compromise the self-esteem of a patient. Appropriate treatment planning for replacement of lost teeth is required and imaging plays a pivotal role to ensure a satisfactory outcome. The development of pre-surgical imaging techniques and surgical templates helps the dentist place the implants with relative ease. This article focuses on various types of imaging modalities that have a pivotal role in implant therapy. PMID:25379354

  1. Bacteriophage-derived vectors for targeted cancer gene therapy.

    PubMed

    Pranjol, Md Zahidul Islam; Hajitou, Amin

    2015-01-01

    Cancer gene therapy expanded and reached its pinnacle in research in the last decade. Both viral and non-viral vectors have entered clinical trials, and significant successes have been achieved. However, a systemic administration of a vector, illustrating safe, efficient, and targeted gene delivery to solid tumors has proven to be a major challenge. In this review, we summarize the current progress and challenges in the targeted gene therapy of cancer. Moreover, we highlight the recent developments of bacteriophage-derived vectors and their contributions in targeting cancer with therapeutic genes following systemic administration. PMID:25606974

  2. Cystic Fibrosis Gene Therapy in the UK and Elsewhere

    PubMed Central

    Pytel, Kamila M.; Alton, Eric W.F.W.

    2015-01-01

    Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified in 1989. This opened the door for the development of cystic fibrosis (CF) gene therapy, which has been actively pursued for the last 20 years. Although 26 clinical trials involving approximately 450 patients have been carried out, the vast majority of these trials were short and included small numbers of patients; they were not designed to assess clinical benefit, but to establish safety and proof-of-concept for gene transfer using molecular end points such as the detection of recombinant mRNA or correction of the ion transport defect. The only currently published trial designed and powered to assess clinical efficacy (defined as improvement in lung function) administered AAV2-CFTR to the lungs of patients with CF. The U.K. Cystic Fibrosis Gene Therapy Consortium completed, in the autumn of 2014, the first nonviral gene therapy trial designed to answer whether repeated nonviral gene transfer (12 doses over 12 months) can lead to clinical benefit. The demonstration that the molecular defect in CFTR can be corrected with small-molecule drugs, and the success of gene therapy in other monogenic diseases, is boosting interest in CF gene therapy. Developments are discussed here. PMID:25838137

  3. Gene Therapy for Cystic Fibrosis Shows Some Promise in Study

    MedlinePLUS

    ... in tests of lung function compared with the placebo group, and there were no safety concerns," study ... either the gene therapy or a "dummy" saline placebo at monthly intervals. Alton's team evaluated their lung ...

  4. Feasibility of Gene Therapy for Late Neuronal Ceroid Lipofuscinosis

    Microsoft Academic Search

    Dolan Sondhi; Neil R. Hackett; Robin L. Apblett; Stephen M. Kaminsky; Robert G. Pergolizzi; Ronald G. Crystal

    2001-01-01

    ate infantile neuronal ceroid lipofuscinosis is a progressive childhood neurodegenerative disorder characterized by intracellular accumulation of autofluorescent material resem- bling lipofuscin in neuronal cells. This report summarizes the new therapies under con- sideration for late infantile neuronal ceroid lipofuscinosis, with a focus on strategies for in vivo gene therapy for the retinal and central nervous system manifestations of the disease.

  5. Progress and prospects: gene therapy for performance and appearance enhancement

    Microsoft Academic Search

    M Kiuru; R G Crystal

    2008-01-01

    While medical therapies aim at reversing, reducing or eliminating diseases, the goal of enhancements is to improve performance or appearance beyond normal levels. Distinction between the two interventions is not always clear as they often present as a continuum. Gene therapy typically aims at treating or preventing disease, but the technology can theoretically be employed for enhancement. Some of the

  6. Hypoxia as a target for tissue specific gene therapy.

    PubMed

    Rhim, Taiyoun; Lee, Dong Yun; Lee, Minhyung

    2013-12-10

    Hypoxia is a hallmark of various ischemic diseases such as ischemic heart disease, ischemic limb, ischemic stroke, and solid tumors. Gene therapies for these diseases have been developed with various therapeutic genes including growth factors, anti-apoptotic genes, and toxins. However, non-specific expression of these therapeutic genes may induce dangerous side effects in the normal tissues. To avoid the side effects, gene expression should be tightly regulated in an oxygen concentration dependent manner. The hypoxia inducible promoters and enhancers have been evaluated as a transcriptional regulation tool for hypoxia inducible gene therapy. The hypoxia inducible UTRs were also used in gene therapy for spinal cord injury as a translational regulation strategy. In addition to transcriptional and translational regulations, post-translational regulation strategies have been developed using the HIF-1? ODD domain. Hypoxia inducible transcriptional, translational, and post-translational regulations are useful for tissue specific gene therapy of ischemic diseases. In this review, hypoxia inducible gene expression systems are discussed and their applications are introduced. PMID:23742881

  7. Bioethical conflicts of gene therapy: a brief critical review.

    PubMed

    Freire, José Ednésio da Cruz; de Medeiros, Suelen Carneiro; Lopes Neto, Antônio Viana; Monteiro Júnior, José Edvar; Sousa, Antônio Juscelino Sudário; Rocha, Antônio José; de Menezes, Léa Maria Bezerra

    2014-01-01

    Methods and techniques employed in gene therapy are reviewed in parallel with pertinent ethical conflicts. Clinical interventions based on gene therapy techniques preferentially use vectors for the transportation of therapeutic genes, however little is known about the potential risks and damages to the patient. Thus, attending carefully to the clinical complications arising as well as to security is essential. Despite the scientific and technological advances, there are still many uncertainties about the side effects of gene therapy. Moreover, there is a need, above all, to understand the principles of bioethics as both science and ethics, in accordance with its socioecological responsibility, in order to prioritize the health and welfare of man and nature, using properly natural resources and technology. Therefore, it is hard to determine objective results and to which extent the insertion of genes can affect the organism, as well as the ethical implication. PMID:25650850

  8. 363. Gene Delivery to Human Sweat Glands: A Model for Cystic Fibrosis Gene Therapy

    Microsoft Academic Search

    Haeyul Lee; David R. Koehler; Cho Y. Pang; Ronald H. Levine; Philip Ng; Donna J. Palmer; Paul M. Quinton; Jim Hu

    2005-01-01

    Cystic fibrosis (CF) is considered a disease that could be treated by gene therapy, yet the results from past clinical trials showed only transient transgene expression. Gene therapy vectors are mostly studied in cultured cells, rodent models or non-human primates, but it is difficult to test them in human system prior to clinical studies. In this study, we investigated the

  9. 698. Towards Non-Invasive Assessment of CF Airway Gene Therapy: High Resolution Propogation-Based Imaging of Airway Surface Liquid Via Synchrotron Light

    Microsoft Academic Search

    David W. Parsons; Karen W. Siu; Jeffrey Crosbie; Ivan Williams; Boucher C. Richard; Kentaro Uesugi; Naoto Yagi

    2006-01-01

    Genetic and pharmaceutical treatments to deal with the ion-channel pathophysiology of cystic fibrosis attempt to increase the abnormally low depth of the thin (<10um) airway surface liquid. A practical therapeutic measurement of ASL depth must be non-invasive and repeatable. In this proof-of-concept study we examined whether Propagation-Based (phase-contrast) Imaging (PBI) could image the airway surface in live mice to resolve

  10. Coaxial electrospray for multimodal imaging and image-guided therapy

    NASA Astrophysics Data System (ADS)

    Si, Ting; Zhang, Leilei; Li, Guangbin; Roberts, Cynthia J.; Jia, Laibin; Yin, Xiezhen; Xu, Ronald

    2012-03-01

    Recent development in multimodal imaging and image-guided therapy requires multifunctional microparticles that encapsulate several imaging and therapeutic agents in the same carrier for simultaneous detection and treatment of the diseases. However, commonly used microfabrication processes for these microparticles have multiple limitations such as the low encapsulation efficiency and the loss of bioactivity for the encapsulated biological cargos. To overcome these limitations, we have carried out both the experimental and the theoretical studies on coaxial electrospray of poly(lactide-co-glycolide) PLGA microparticles. On the experimental side, a coaxial electrospray setup has been developed and tested. The setup consists of a customized coaxial needle assembly, two ring electrodes, two high-voltage power supplies, two syringe infusion pumps, a particle collection reservoir, and a process monitoring system. On the theoretical side, a classical normal mode method has been used for instability analysis of the coaxial electrified jet based on the experimental parameters. The effects of different dimensionless process parameters on the formation of different unstable modes have also been studied. The reported research represents the first step toward the quantitative control and optimization of the coaxial electrospray process for the fabrication of multifunctional microparticles in multimodal imaging and image-guided therapy.

  11. [CANCER RESEARCH 64, 13231330, February 15, 2004] Imaging Tri-Fusion Multimodality Reporter Gene Expression in Living Subjects

    E-print Network

    Tsien, Roger Y.

    to cancer research, gene therapy, and transgenic mod- els are rapidly expanding. We report construction[CANCER RESEARCH 64, 1323­1330, February 15, 2004] Imaging Tri-Fusion Multimodality Reporter Gene by the fusion gene in cell culture, we imaged living mice bearing 293T cells transiently expressing the hrl

  12. Development of gene and stem cell therapy for ocular neurodegeneration

    PubMed Central

    Zhang, Jing-Xue; Wang, Ning-Li; Lu, Qing-Jun

    2015-01-01

    Retinal degenerative diseases pose a serious threat to eye health, but there is currently no effective treatment available. Recent years have witnessed rapid development of several cutting-edge technologies, such as gene therapy, stem cell therapy, and tissue engineering. Due to the special features of ocular structure, some of these technologies have been translated into ophthalmological clinic practice with fruitful achievements, setting a good example for other fields. This paper reviews the development of the gene and stem cell therapies in ophthalmology. PMID:26086019

  13. Fetal and neonatal gene therapy: benefits and pitfalls

    Microsoft Academic Search

    SN Waddington; NL Kennea; SMK Buckley; LG Gregory; M Themis; C Coutelle

    2004-01-01

    The current approaches to gene therapy of monogenetic diseases into mature organisms are confronted with several problems including the following: (1) the underlying genetic defect may have already caused irreversible pathological changes; (2) the level of sufficient protein expression to ameliorate or prevent the disease requires prohibitively large amounts of gene delivery vector; (3) adult tissues may be poorly infected

  14. 77 FR 63840 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-17

    ...FDA-2012-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of...Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General...hear updates of research programs in the Gene Transfer and Immunogenicity Branch,...

  15. Recent advances in gene therapy for lysosomal storage disorders

    PubMed Central

    Rastall, David PW; Amalfitano, Andrea

    2015-01-01

    Lysosomal storage disorders (LSDs) are a group of genetic diseases that result in metabolic derangements of the lysosome. Most LSDs are due to the genetic absence of a single catabolic enzyme, causing accumulation of the enzyme’s substrate within the lysosome. Over time, tissue-specific substrate accumulations result in a spectrum of symptoms and disabilities that vary by LSD. LSDs are promising targets for gene therapy because delivery of a single gene into a small percentage of the appropriate target cells may be sufficient to impact the clinical course of the disease. Recently, there have been several significant advancements in the potential for gene therapy of these disorders, including the first human trials. Future clinical trials will build upon these initial attempts, with an improved understanding of immune system responses to gene therapy, the obstacle that the blood–brain barrier poses for neuropathic LSDs, as well other biological barriers that, when overcome, may facilitate gene therapy for LSDs. In this manuscript, we will highlight the recent innovations in gene therapy for LSDs and discuss the clinical limitations that remain to be overcome, with the goal of fostering an understanding and further development of this important field.

  16. Laboratory Investigation Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy

    E-print Network

    Terasaki, Mark

    Laboratory Investigation Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy radiation therapy, rats Summary Purpose: Microbeam radiation therapy (MRT), a novel experimental, d21). On d14, the remaining 62 rats were given deliberately suboptimal microbeam radiation therapy

  17. original article The American Society of Gene & Cell Therapy Molecular Therapy 1

    E-print Network

    Hemminki, Akseli

    original article© The American Society of Gene & Cell Therapy Molecular Therapy 1 Augmenting­macrophage colony­stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells was seen in 13/21 patients and 8/12 showed objective clinical benefit as evaluated by radiology

  18. Photoacoustic imaging and temperature measurement for photothermal cancer therapy

    PubMed Central

    Shah, Jignesh; Park, Suhyun; Aglyamov, Salavat; Larson, Timothy; Ma, Li; Sokolov, Konstantin; Johnston, Keith; Milner, Thomas; Emelianov, Stanislav Y.

    2009-01-01

    Photothermal therapy is a noninvasive, targeted, laser-based technique for cancer treatment. During photothermal therapy, light energy is converted to heat by tumor-specific photoabsorbers. The corresponding temperature rise causes localized cancer destruction. For effective treatment, however, the presence of photoabsorbers in the tumor must be ascertained before therapy and thermal imaging must be performed during therapy. This study investigates the feasibility of guiding photothermal therapy by using photoacoustic imaging to detect photoabsorbers and to monitor temperature elevation. Photothermal therapy is carried out by utilizing a continuous wave laser and metal nanocomposites broadly absorbing in the near-infrared optical range. A linear array-based ultrasound imaging system is interfaced with a nanosecond pulsed laser to image tissue-mimicking phantoms and ex-vivo animal tissue before and during photothermal therapy. Before commencing therapy, photoacoustic imaging identifies the presence and spatial location of nanoparticles. Thermal maps are computed by monitoring temperature-induced changes in the photoacoustic signal during the therapeutic procedure and are compared with temperature estimates obtained from ultrasound imaging. The results of our study suggest that photoacoustic imaging, augmented by ultrasound imaging, is a viable candidate to guide photoabsorber-enhanced photothermal therapy. PMID:18601569

  19. Gene therapy: a promising approach to treating spinal muscular atrophy.

    PubMed

    Mulcahy, Pádraig J; Iremonger, Kayleigh; Karyka, Evangelia; Herranz-Martín, Saúl; Shum, Ka-To; Tam, Janice Kal Van; Azzouz, Mimoun

    2014-07-01

    Spinal muscular atrophy (SMA) is a severe autosomal recessive disease caused by a genetic defect in the survival motor neuron 1 (SMN1) gene, which encodes SMN, a protein widely expressed in all eukaryotic cells. Depletion of the SMN protein causes muscle weakness and progressive loss of movement in SMA patients. The field of gene therapy has made major advances over the past decade, and gene delivery to the central nervous system (CNS) by in vivo or ex vivo techniques is a rapidly emerging field in neuroscience. Despite Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis being among the most common neurodegenerative diseases in humans and attractive targets for treatment development, their multifactorial origin and complicated genetics make them less amenable to gene therapy. Monogenic disorders resulting from modifications in a single gene, such as SMA, prove more favorable and have been at the fore of this evolution of potential gene therapies, and results to date have been promising at least. With the estimated number of monogenic diseases standing in the thousands, elucidating a therapeutic target for one could have major implications for many more. Recent progress has brought about the commercialization of the first gene therapies for diseases, such as pancreatitis in the form of Glybera, with the potential for other monogenic disease therapies to follow suit. While much research has been carried out, there are many limiting factors that can halt or impede translation of therapies from the bench to the clinic. This review will look at both recent advances and encountered impediments in terms of SMA and endeavor to highlight the promising results that may be applicable to various associated diseases and also discuss the potential to overcome present limitations. PMID:24845847

  20. Objective Assessment of Image Quality VI: Imaging in Radiation Therapy

    PubMed Central

    Barrett, Harrison H.; Kupinski, Matthew A.; Müeller, Stefan; Halpern, Howard J.; Morris, John C.; Dwyer, Roisin

    2015-01-01

    Earlier work on Objective Assessment of Image Quality (OAIQ) focused largely on estimation or classification tasks in which the desired outcome of imaging is accurate diagnosis. This paper develops a general framework for assessing imaging quality on the basis of therapeutic outcomes rather than diagnostic performance. By analogy to Receiver Operating Characteristic (ROC) curves and their variants as used in diagnostic OAIQ, the method proposed here utilizes the Therapy Operating Characteristic or TOC curves, which are plots of the probability of tumor control vs. the probability of normal-tissue complications as the overall dose level of a radiotherapy treatment is varied. The proposed figure of merit is the area under the TOC curve, denoted AUTOC. This paper reviews an earlier exposition of the theory of TOC and AUTOC, which was specific to the assessment of image-segmentation algorithms, and extends it to other applications of imaging in external-beam radiation treatment as well as in treatment with internal radioactive sources. For each application, a methodology for computing the TOC is presented. A key difference between ROC and TOC is that the latter can be defined for a single patient rather than a population of patients. PMID:24200954

  1. The challenge of liposomes in gene therapy

    Microsoft Academic Search

    Francis Martin; Teni Boulikas

    1998-01-01

    Summary Recently, liposomes have gained a special interest as gene delivery systems: over 30 human clinical trials for gene delivery using cationic liposomes have been approved; all these delivery methods use intratumoral, subcutaneous and other local delivery but not systemic delivery due to the toxicity of cationic lipids. Stealth liposomes (coated with polyethyleneglyc ol to camouflage the liposome and evade

  2. Radiolabeled regulatory peptides for imaging and therapy

    PubMed Central

    Nanda, Prasant K.; Lane, Stephanie R.; Retzloff, Lauren B.; Pandey, Usha S.; Smith, Charles Jeffrey

    2010-01-01

    Purpose of review The purpose of the present review is to describe new, innovative strategies of diagnosing and treating specific human cancers using a cadre of radiolabeled regulatory peptides. Recent findings Peptide receptor-targeted radionuclide therapy is a method of site-directed radiotherapy that specifically targets human cancers expressing a cognate receptor-subtype in very high numbers. Ideally, the procedure targets only the primary or metastatic disease and is minimally invasive, with little radiation damage to normal, collateral tissues. For treatment strategies of this type to be effective, it is critical to evaluate the toxicity of the treatment protocol, the radiation dosimetry of the therapeutic regimen, and the biological profile of the radiopharmaceutical, including biodistribution and pharmacokinetics of the drug. Site-directed molecular imaging procedures via ?-scintigraphy can address many of the critical issues associated with peptide receptor-targeted radionuclide therapy and it is, therefore, necessary to describe the effective balance between the clinical benefits and risks of this treatment strategy. Summary Continued development in the design or chemical structure of radiolabeled, biologically active peptides could do much to improve the targeting ability of these drugs, thereby creating new and innovative strategies for diagnosis or treatment of human cancers. PMID:19901831

  3. Deciphering Development: Quantifying Gene Expression through Imaging

    NSDL National Science Digital Library

    Melissa Lee Philips (; )

    2007-08-01

    This article from BioScience provides information on genetic tagging and how it can provide imaging in live animals. Scientists can now visualize developmental gene expression quantitatively in three dimensions and at single-cell resolution. Recent advances in optical microscopy and fluorescent genetic tags allow imaging of gene expression in live animals, as well. Eventually, researchers hope to construct virtual atlases of animal development.

  4. Macrophage mediated PCI enhanced gene-directed enzyme prodrug therapy

    NASA Astrophysics Data System (ADS)

    Christie, Catherine E.; Zamora, Genesis; Kwon, Young J.; Berg, Kristian; Madsen, Steen J.; Hirschberg, Henry

    2015-03-01

    Photochemical internalization (PCI) is a photodynamic therapy-based approach for improving the delivery of macromolecules and genes into the cell cytosol. Prodrug activating gene therapy (suicide gene therapy) employing the transduction of the E. coli cytosine deaminase (CD) gene into tumor cells, is a promising method. Expression of this gene within the target cell produces an enzyme that converts the nontoxic prodrug, 5-FC, to the toxic metabolite, 5-fluorouracil (5-FU). 5-FC may be particularly suitable for brain tumors, because it can readily cross the bloodbrain barrier (BBB). In addition the bystander effect, where activated drug is exported from the transfected cancer cells into the tumor microenvironment, plays an important role by inhibiting growth of adjacent tumor cells. Tumor-associated macrophages (TAMs) are frequently found in and around glioblastomas. Monocytes or macrophages (Ma) loaded with drugs, nanoparticles or photosensitizers could therefore be used to target tumors by local synthesis of chemo attractive factors. The basic concept is to combine PCI, to enhance the ex vivo transfection of a suicide gene into Ma, employing specially designed core/shell NP as gene carrier.

  5. Single stem cell gene therapy for genetic skin disease.

    PubMed

    Larsimont, Jean-Christophe; Blanpain, Cédric

    2015-04-01

    Stem cell gene therapy followed by transplantation into damaged regions of the skin has been successfully used to treat genetic skin blistering disorder. Usually, many stem cells are virally transduced to obtain a sufficient number of genetically corrected cells required for successful transplantation, as genetic insertion in every stem cell cannot be precisely defined. In this issue of EMBO Molecular Medicine, Droz-Georget Lathion et al developed a new strategy for ex vivo single cell gene therapy that allows extensive genomic and functional characterization of the genetically repaired individual cells before they can be used in clinical settings. PMID:25724199

  6. Endothelial progenitor cells for cancer gene therapy

    Microsoft Academic Search

    K-M Debatin; J Wei; C Beltinger

    2008-01-01

    Endothelial progenitor cells (EPCs) are promising for cancer therapy because they specifically target tumors. They have the capacity to home to, invade, migrate within and incorporate into tumor structures. They are easily expanded and can be armed with therapeutic payloads protected within the progenitor cells. Once in the tumor, armed EPCs can be triggered to induce cell death in surrounding

  7. Gene therapy: can neural stem cells deliver?

    Microsoft Academic Search

    Evan Y. Snyder; Jeanne F. Loring; Franz-Josef Müller

    2006-01-01

    Neural stem cells are a self-renewing population that generates the neurons and glia of the developing brain. They can be isolated, proliferated, genetically manipulated and differentiated in vitro and reintroduced into a developing, adult or pathologically altered CNS. Neural stem cells have been considered for use in cell replacement therapies in various neurodegenerative diseases, and an unexpected and potentially valuable

  8. Gene therapy for acute lung injury

    Microsoft Academic Search

    K. L. Brigham; A. A. Stecenko

    2000-01-01

    The remarkable transition of biological science into the age of molecular biology held great promise for development of new therapies for treatment of human disease. The fact that the technology exists for analyzing genetic material in exquisite detail and constructing DNA in virtually any desired form was the basis for promising rapid translation into clinical medicine and the final cure

  9. An Update on Gene Therapy in Parkinson’s Disease

    Microsoft Academic Search

    Jennifer Witt; William J. Marks Jr

    2011-01-01

    Gene therapy for Parkinson’s disease (PD) may offer an alternative to current pharmacologic and surgical treatments; the former\\u000a are limited by motor complications and non-motor adverse effects, and both by lack of neuroprotection. Three main strategies\\u000a under investigation using gene transfer for targeted protein expression include improving availability of dopamine to the\\u000a striatum with more continuous delivery, reducing activity in

  10. Combining radiation therapy with interleukin-3 gene immunotherapy

    Microsoft Academic Search

    Chi-Shiun Chiang; Ji-Hong Hong; Yuan Chou Wu; William H McBride; Graeme J Dougherty

    2000-01-01

    The goal of this study was to explore immunological strategies to increase local and systemic tumor control in patients receiving radiation therapy. In previous studies, interleukin-3 (IL-3) gene expression within murine tumors was shown to increase their response to irradiation through immune mechanisms. In this study, the efficacy of systemically administered IL-3 gene-transduced irradiated tumor cell vaccines was tested for

  11. Neural Stem Cell-based Gene Therapy for Brain Tumors

    Microsoft Academic Search

    Seung U. Kim

    2011-01-01

    Advances in gene-based medicine since 1990s have ushered in new therapeutic strategy of gene therapy for inborn error genetic\\u000a diseases and cancer. Malignant brain tumors such as glioblastoma multiforme and medulloblastoma remain virtually untreatable\\u000a and lethal. Currently available treatment for brain tumors including radical surgical resection followed by radiation and\\u000a chemotherapy, have substantially improved the survival rate in patients suffering

  12. Stem and progenitor cell-mediated tumor selective gene therapy

    Microsoft Academic Search

    K S Aboody; J Najbauer; M K Danks

    2008-01-01

    The poor prognosis for patients with aggressive or metastatic tumors and the toxic side effects of currently available treatments necessitate the development of more effective tumor-selective therapies. Stem\\/progenitor cells display inherent tumor-tropic properties that can be exploited for targeted delivery of anticancer genes to invasive and metastatic tumors. Therapeutic genes that have been inserted into stem cells and delivered to

  13. Gene-Based Intramuscular Interferon-? Therapy for Experimental Autoimmune Encephalomyelitis

    Microsoft Academic Search

    Ritika Jaini; Drew Hannaman; Justin M. Johnson; Robert M. Bernard; Cengiz Z. Altuntas; Maida M. de las Alas; Pavani Kesaraju; Claire F. Evans; Vincent K. Tuohy

    2006-01-01

    In contrast to serial injections of recombinant interferon-? (IFN-?) for long-term therapy of multiple sclerosis (MS), prolonged systemic delivery of proteins derived through in vivo gene transfer may provide a more clinically relevant alternative. Here we compare the therapeutic efficacies of electroporation (EP)-mediated intramuscular IFN-? gene transfer with repeated alternate-day injections of recombinant IFN-? after the onset of relapsing–remitting experimental

  14. Human Cone Visual Pigment Deletions Spare Sufficient Photoreceptors to Warrant Gene Therapy

    PubMed Central

    Cideciyan, Artur V.; Hufnagel, Robert B.; Carroll, Joseph; Sumaroka, Alexander; Luo, Xunda; Schwartz, Sharon B.; Dubra, Alfredo; Land, Megan; Michaelides, Michel; Gardner, Jessica C.; Hardcastle, Alison J.; Moore, Anthony T.; Sisk, Robert A.; Ahmed, Zubair M.; Kohl, Susanne

    2013-01-01

    Abstract Human X-linked blue-cone monochromacy (BCM), a disabling congenital visual disorder of cone photoreceptors, is a candidate disease for gene augmentation therapy. BCM is caused by either mutations in the red (OPN1LW) and green (OPN1MW) cone photoreceptor opsin gene array or large deletions encompassing portions of the gene array and upstream regulatory sequences that would predict a lack of red or green opsin expression. The fate of opsin-deficient cone cells is unknown. We know that rod opsin null mutant mice show rapid postnatal death of rod photoreceptors. Using in vivo histology with high-resolution retinal imaging, we studied a cohort of 20 BCM patients (age range 5–58) with large deletions in the red/green opsin gene array. Already in the first years of life, retinal structure was not normal: there was partial loss of photoreceptors across the central retina. Remaining cone cells had detectable outer segments that were abnormally shortened. Adaptive optics imaging confirmed the existence of inner segments at a spatial density greater than that expected for the residual blue cones. The evidence indicates that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM. PMID:24067079

  15. Targeting adipose tissue via systemic gene therapy

    PubMed Central

    O'Neill, Sean M.; Hinkle, Christine; Chen, Shu-Jen; Sandhu, Arbansjit; Hovhannisyan, Ruben; Stephan, Stephen; Lagor, William R.; Ahima, Rexford S.; Johnston, Julie C.; Reilly, Muredach P.

    2015-01-01

    Adipose tissue plays a critical role in energy and metabolic homeostasis, but it is challenging to adapt techniques to modulate adipose function in vivo. Here we develop an in vivo, systemic method of gene transfer specifically targeting adipose tissue using adeno-associated virus (AAV) vectors. We constructed AAV vectors containing CMV promoter regulated reporter genes, intravenously injected adult mice with vectors using multiple AAV serotypes, and determined that AAV2/8 best targeted adipose tissue. Altering vectors to contain adiponectin promoter/enhancer elements and liver specific microRNA-122 target sites restricted reporter gene expression to adipose tissue. As proof of efficacy, the leptin gene was incorporated into the adipose-targeted expression vector, package into AAV2/8, and administered intravenously to 9-10 week old ob/ob mice. Phenotypic changes were measured over an eight week period. Leptin mRNA and protein were expressed in adipose and leptin protein was secreted into plasma. Mice responded with reversal of weight gain, decreased hyperinsulinemia, and improved glucose tolerance. AAV2/8-mediated systemic delivery of an adipose-targeted expression vector can replace a gene lacking in adipose tissue and correct a mouse model of human disease, demonstrating experimental application and therapeutic potential in disorders of adipose. PMID:24830434

  16. Multi-gene targeted antiangiogenic therapies for experimental corneal neovascularization

    PubMed Central

    Chen, Peng; Yin, Hongmei; Wang, Yao; Mi, Jing; He, Wenxiao; Xie, Lixin

    2010-01-01

    Purpose To determine the effectiveness of multigene-based anti-angiogenic gene therapies for experimental murine corneal neovascularization (corneal NV). Methods Recombinant retroviral vectors encoding murine endostatin (mEndo), murine-soluble vascular endothelial growth factor receptor-2 (msFlk-1), or murine-soluble Tie2 (msTie2) were constructed and packaged in PT67 cells. Viral titers were determined by infection of NIH3T3 cells. Expressions of mEndo, msFlk-1, and msTie2 were confirmed by reverse transcription PCR. The 3-(4,5-Dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to estimate the effect of mEndo, msFlk-1, or msTie2 on the proliferation of human umbilical vein endothelial cells, and the scarification test was used to measure the migration of the cells. Seventy C57Bl/6 mice were subjected to the induction of chemical-burn corneal NV and tested for efficacy of gene therapy. Gene therapy was performed by subconjunctival injection of viral preparations and its effect was evaluated by scoring corneal NV. Results The recombinant virus-producing cell lines expressing mEndo, msFlk-1, and msTie2 were constructed successfully. Overexpression of these putative anti-angiogenic proteins inhibited the proliferation and migration of human umbilical vein endothelial cells in vitro. In the murine corneal NV model, subconjunctival injection of the retroviral particles of mEndo and msFlk-1 showed the most significant inhibition of corneal NV. Conclusions Gene therapy with the recombinant retroviral vector-hosted mEndo and msFlk-1 gene effectively inhibited corneal NV induced by alkaline burn. The combination of multiple anti-angiogenic genes might be necessary for effective therapy of corneal NV, although each of these pathways makes a potential target for the treatment of this disease. PMID:20208988

  17. original article The American Society of Gene Therapy Molecular Therapy vol. 17 no. 2, 389394 feb. 2009 389

    E-print Network

    Cai, Long

    in cancer cells, and are candidates for use as oncolytic therapy. This long-term report of a phase I trialoriginal article© The American Society of Gene Therapy Molecular Therapy vol. 17 no. 2, 389­394 feb examines vascular administration of HSV as therapy for cancer. Twelve subjects with metastatic colorectal

  18. Fusigenic Viral Liposome for Gene Therapy in Cardiovascular Diseases

    Microsoft Academic Search

    Victor J. Dzau; Michael J. Mann; Ryuichi Morishita; Yasufumi Kaneda

    1996-01-01

    To improve the efficiency of liposome-mediated DNA transfer as a tool for gene therapy, we have developed a fusigenic liposome vector based on principles of viral cell fusion. The fusion proteins of hemagglutinating virus of Japan (HVJ; also Sendai virus) are complexed with liposomes that encapsulate oligodeoxynucleotide or plasmid DNA. Subsequent fusion of HVJ-liposomes with plasma membranes introduces the DNA

  19. Gene therapy progress and prospects: synthetic polymer-based systems

    Microsoft Academic Search

    D Schaffert; E Wagner

    2008-01-01

    Low efficiency, significant toxicity, polymer polydispersity and poorly understood delivery mechanisms have initially plagued the field of polymer-based gene therapy. Numerous strategies have helped to improve polyplexes, including the development of biodegradable polymers with reduced toxicity, incorporation of cell targeting, surface shielding and additional transport domains for effective and specific delivery, or improved chemistry for syntheses of polymers with uniform

  20. Latest development in viral vectors for gene therapy

    Microsoft Academic Search

    Kenneth Lundstrom

    2003-01-01

    Gene therapy includes the application of various viral vectors, which represent most types and families of viruses, suitable for infection of mammalian host cells. Both hereditary diseases and acquired illnesses, such as cancer, can be targeted. Because of the various properties of each viral vector, the definition of their application range depends on factors such as packaging capacity, host range,

  1. Advances in Preclinical Investigation of Prostate Cancer Gene Therapy

    Microsoft Academic Search

    Marxa L Figueiredo; Chinghai Kao; Lily Wu

    2007-01-01

    Treating recurrent prostate cancer poses a great challenge to clinicians. Research efforts in the last decade have shown that adenoviral vector-based gene therapy is a promising approach that could expand the arsenal against prostate cancer. This maturing field is at the stage of being able to translate many preclinical discoveries into clinical practices. At this juncture, it is important to

  2. Future of gene therapies in high grade gliomas

    Microsoft Academic Search

    Deepak Kumar Gupta; Mattei Tobias Alecio; Ashok Kumar Mahapatra; Ramina Ricardo

    Summary High-grade gliomas are relatively frequent in adults, and consist of the most malignant kind of primary brain tumor. Being resistant to standard treatment modalities such as surgery, radiation, and chemotherapy, it is fatal within 1 to 2 years of onset of symptoms. Although several gene therapy systems proved to be efficient in controlling or eradicating these tumors in animal

  3. A model for the analysis of nonviral gene therapy

    Microsoft Academic Search

    G A Banks; R J Roselli; R Chen; T D Giorgio

    2003-01-01

    Further understanding of the mechanisms involved in cellular and intracellular delivery of transgene is needed to produce clinical applications of gene therapy. The compartmental and computational model designed in this work is integrated with data from previous experiments to quantitatively estimate rate constants of plasmid translocation across cellular barriers in transgene delivery in vitro. The experimental conditions between two cellular

  4. Adenoviral Gene Therapy for Pancreatic Cancer: Where Do We Stand?

    Microsoft Academic Search

    Koert F. D. Kuhlmann; Dirk J. Gouma; John G. Wesseling

    2008-01-01

    Background: The prognosis of patients with pancreatic cancer is poor. This is mainly caused by the late diagnosis, the aggressive biology and the lack of effective treatment modalities. Adenoviral gene therapy has the potential to selectively treat both primary tumor and (micro)metastatic tissue. Methods: This review provides an overview of what has been achieved so far in the field of

  5. Gene therapy of experimental brain tumors using neural progenitor cells

    Microsoft Academic Search

    Sara Benedetti; Barbara Pirola; Bianca Pollo; Lorenzo Magrassi; Maria Grazia Bruzzone; Dorotea Rigamonti; Rossella Galli; Silvia Selleri; Francesco Di Meco; Claudio De Fraja; Angelo Vescovi; Elena Cattaneo; Gaetano Finocchiaro

    2000-01-01

    Glioblastomas, the most frequent and malignant of primary brain tumors, have a very poor prognosis. Gene therapy of glioblastomas is limited by the short survival of viral vectors and by their difficulty in reaching glioblastoma cells infiltrating the brain parenchyma. Neural stem\\/progenitor cells can be engineered to produce therapeutic molecules and have the potential to overcome these limitations because they

  6. Gene Therapy: Approaches for the Treatment of Malignant Gliomas

    Microsoft Academic Search

    G. Schackert; St. Frank; H. K. Schackert

    1996-01-01

    Summary Gene therapy approaches for malignant brain tumors evolved from the need to develop new treatment modalities, increasing insights in the molecular basis of tumorigenesis and the advent of recombinant DNA technology. Immunotherapy of tumors growing in an immunologically privileged organ is a challeng ing task for researchers and clinicians. Both strategies, systemic immunization and local overexpression of cytokines in

  7. 889. Adeno-Associated Virus Gene Therapy of Feline Gangliosidosis

    Microsoft Academic Search

    Douglas R. Martin; Begona Cachon-Gonzalez; Miguel Sena-Esteves; Misako Hwang; Atoska S. Gentry; Nancy E. Morrison; Nancy R. Cox; Timothy M. Cox; Henry J. Baker

    2006-01-01

    Feline ganglioside storage diseases are authentic models of the human conditions and are valuable for development of gene therapy strategies for human patients. Deficiency of the lysosomal enzymes ?-galactosidase or ?-N-acetylhexosaminidase causes continuous cumulation of GM1 or GM2 ganglioside, respectively, resulting in disease manifestations nd death. There is no reliable treatment for human gangliosidoses, although knockout mouse models have been

  8. RNA interference based gene therapy for neurological disease

    Microsoft Academic Search

    Aarti Jagannath; Matthew Wood

    2007-01-01

    Neurodegenerative disorders represent a major class of disorders for which thus far any effective small molecule drug therapy has failed to emerge. RNA interference (RNAi), by which disease genes such as those identified for spino-cerebellar ataxia and Huntington's disease can be specifically silenced, has great potential in becoming a successful therapeutic strategy for these diseases. RNAi has shown therapeutic value

  9. Celiac Disease: a model autoimmune disease with gene therapy applications

    Microsoft Academic Search

    M Londei; S Quaratino; L Maiuri

    2003-01-01

    Gene therapy (GT) is still at the ‘experimental’ stage and some recent setbacks have cooled the potential use of this therapeutic tool even in life-threatening conditions. However, this therapeutic approach has a potential, which is not limited to disease for which we have not other option. There are increasing evidence that GT will be soon used in diseases that are

  10. Gene targeting: Roadmap to future therapies

    Microsoft Academic Search

    Lars C. Huber; Thomas Pap; Ulf Müller-Ladner; Renate E. Gay; Steffen Gay

    2004-01-01

    Conclusions  It can be stated that the complexity of the mechanisms involved in the pathogenesis of RA requires a multifaceted approach\\u000a that targets several pathways. Generally, gene targeting should be considered as powerful means to elucidate the pathogenic\\u000a function of key molecules and, in terms of \\

  11. 77 FR 73472 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-10

    ...Administration [Docket No. FDA-2012-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting AGENCY: Food...closed to the public. Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General Function of the...

  12. 76 FR 64951 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-19

    ...Administration [Docket No. FDA-2011-N-0002] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting AGENCY: Food...open to the public. Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General Function of the...

  13. 78 FR 15726 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-12

    ...Administration [Docket No. FDA-2013-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting AGENCY: Food...closed to the public. Name of Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General Function of the...

  14. 76 FR 18768 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-05

    ...Docket No. FDA-2011-N-0002] Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting AGENCY: Food...closed to the public. Name of Committee: Cellular, Tissue, and Gene Therapies Advisory Committee. General Function of the...

  15. 76 FR 49774 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-11

    ...Cellular, Tissue and Gene Therapies Advisory Committee...Cellular, Tissue and Gene Therapies Advisory Committee...thalassemia, Hurler syndrome, Krabbe disease, and...default.htm. Scroll down to the appropriate...

  16. Molecular Imaging in Stem Cell Therapy for Spinal Cord Injury

    PubMed Central

    Tian, Mei; Zhang, Hong

    2014-01-01

    Spinal cord injury (SCI) is a serious disease of the center nervous system (CNS). It is a devastating injury with sudden loss of motor, sensory, and autonomic function distal to the level of trauma and produces great personal and societal costs. Currently, there are no remarkable effective therapies for the treatment of SCI. Compared to traditional treatment methods, stem cell transplantation therapy holds potential for repair and functional plasticity after SCI. However, the mechanism of stem cell therapy for SCI remains largely unknown and obscure partly due to the lack of efficient stem cell trafficking methods. Molecular imaging technology including positron emission tomography (PET), magnetic resonance imaging (MRI), optical imaging (i.e., bioluminescence imaging (BLI)) gives the hope to complete the knowledge concerning basic stem cell biology survival, migration, differentiation, and integration in real time when transplanted into damaged spinal cord. In this paper, we mainly review the molecular imaging technology in stem cell therapy for SCI. PMID:24701583

  17. MEN1 gene replacement therapy reduces proliferation rates in a mouse model of pituitary adenomas

    PubMed Central

    Walls, Gerard V.; Lemos, Manuel C; Javid, Mahsa; Bazan-Peregrino, Miriam; Jeyabalan, Jeshmi; Reed, Anita A. C.; Harding, Brian; Tyler, Damian J.; Stuckey, Daniel J.; Piret, Sian; Christie, Paul T.; Ansorge, Olaf; Clarke, Kieran; Seymour, Len; Thakker, Rajesh V.

    2012-01-01

    Multiple endocrine neoplasia type 1 (MEN1) is characterized by the combined occurrence of pituitary, pancreatic and parathyroid tumors showing loss of heterozygosity in the putative tumor suppressor gene MEN1. This gene encodes the protein menin, the overexpression of which inhibits cell proliferation in vitro. In this study, we conducted a preclinical evaluation of MEN1 gene therapy in pituitary tumors of Men1+/? mice, using a recombinant non-replicating adenoviral serotype 5 vector that contained the murine Men1 cDNA under control of a cytomegalovirus promoter (Men1.rAd5). Pituitary tumours in 55 Men1+/? female mice received a transauricular, intratumoral injection of Men1.rAd5 or control treatments, followed by 5-bromo-2-deoxyuridine (BrdU) in drinking water for four weeks before magnetic resonance imaging (MRI) and immunohistochemical analysis. Immediate procedure-related and four-week mortalities were similar in all groups, indicating that the adenoviral gene therapy was not associated with a higher mortality. Menin expression was higher in the Men1.rAd5-treated mice when compared to other groups. Daily proliferation rates assessed by BrdU incorporation were reduced significantly in Men1.rAd5-injected tumors relative to control treated tumors. In contrast, apoptotic rates, immune T cell response and tumor volumes remained similar in all groups. Our findings establish that MEN1 gene replacement therapy can generate menin expression in pituitary tumors, and significantly reduce tumor cell proliferation. PMID:22915754

  18. Gene therapy of chronic granulomatous disease

    Microsoft Academic Search

    M Grez; S Becker; S Saulnier; H Knö?; MG Ott; A Maurer; MC Dinauer; D Hoelzer; R Seger; JP Hossle

    2000-01-01

    Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder which results from absence or malfunction of the respiratory burst oxidase normally expressed in neutrophils and other phagocytic leukocytes. Two-thirds of the patients are males hemizygous for mutations in the X-linked gene coding for gp91-phox. As a therapeutic approach towards the X-linked form of CGD bicistronic retroviral vectors containing the gp91-phox

  19. Positive selection of gene-modified cells increases the efficacy of pancreatic cancer suicide gene therapy.

    PubMed

    Martinez-Quintanilla, Jordi; Cascallo, Manel; Gros, Alena; Fillat, Cristina; Alemany, Ramon

    2009-11-01

    Thymidine kinase (TK)-mediated suicide gene therapy has been considered for the treatment of pancreatic cancer. However, despite a bystander effect, the proportion of transduced tumor cells has proven too low to result in efficacy. We propose the use of a drug-selectable marker (MDR1) to enrich TK-expressing cells using chemotherapy. This enrichment or positive selection phase may increase the efficacy of suicide gene therapy. To test this strategy, we generated stable NP18MDR/TK-GFP transfectants and showed docetaxel resistance in vivo. Mixed tumors of MDR/TK-expressing cells and parental NP18 cells were established and docetaxel was used to increase the proportion of TK-expressing cells. After this positive selection phase, suicide gene therapy with ganciclovir was applied. Upon positive selection, the proportion of TK-expressing cells increased from 4% to 22%. Subsequent suicide gene therapy was more effective compared with a control group without positive selection. Starting with 10% of TK-expressing cells the positive-negative selection strategy completely inhibited tumor growth. Taken together, these results suggest that a positive-negative selection strategy based on MDR and TK genes represents an efficient way to increase the proportion of TK-expressing cells in the tumor and the efficacy of TK-mediated suicide gene therapy. PMID:19887556

  20. Nanogels for delivery, imaging and therapy.

    PubMed

    Sivaram, Amal J; Rajitha, P; Maya, S; Jayakumar, R; Sabitha, M

    2015-07-01

    Nanogels are hydrogels having size in nanoregime, which is composed of cross-linked polymer networks. The advantages of nanogels include stimuli-responsive nature, easy drug loading, and higher drug-loading capacity, physical stability, versatility in design, stability of entrapped drug, and controlled release of the anti-inflammatory, antimicrobial, protein, peptide and anticancer drugs. Stimuli-responsive nature of nanogel is of particular importance in anticancer and anti-inflammatory drug delivery, as cancer and inflammation are associated with acidic pH, heat generation, and change in ionic content. Nanogels composed of muco-adhesive polymers provide prolonged residence time and increase the ocular availability of loaded drugs. By forming suitably sized complex with proteins or by acting as artificial chaperones, they thus help to keep the proteins and enzymes in proper confirmation necessary for exerting biological activity; nanogels can increase the stability and activity of protein/peptide drugs. Better drug penetrations achieved by prolonged contact with skin contribute much in transdermal drug delivery. When it comes to cancer drug delivery, the presence of multiple interactive functional groups in nanogels different targeting agents can be conjugated for delivery of the selective drugs. This review focuses on applications of nanogels in cancer drug delivery and imaging, anti-inflammatory, anti-psoriatic, transdermal, ocular and protein/peptide drug delivery and therapy. WIREs Nanomed Nanobiotechnol 2015, 7:509-533. doi: 10.1002/wnan.1328 For further resources related to this article, please visit the WIREs website. PMID:25581024

  1. Pseudo-Fovea Formation After Gene Therapy for RPE65-LCA

    PubMed Central

    Cideciyan, Artur V.; Aguirre, Geoffrey K.; Jacobson, Samuel G.; Butt, Omar H.; Schwartz, Sharon B.; Swider, Malgorzata; Roman, Alejandro J.; Sadigh, Sam; Hauswirth, William W.

    2015-01-01

    Purpose. The purpose of this study was to evaluate fixation location and oculomotor characteristics of 15 patients with Leber congenital amaurosis (LCA) caused by RPE65 mutations (RPE65-LCA) who underwent retinal gene therapy. Methods. Eye movements were quantified under infrared imaging of the retina while the subject fixated on a stationary target. In a subset of patients, letter recognition under retinal imaging was performed. Cortical responses to visual stimulation were measured using functional magnetic resonance imaging (fMRI) in two patients before and after therapy. Results. All patients were able to fixate on a 1° diameter visible target in the dark. The preferred retinal locus of fixation was either at the anatomical fovea or at an extrafoveal locus. There were a wide range of oculomotor abnormalities. Natural history showed little change in oculomotor abnormalities if target illuminance was increased to maintain target visibility as the disease progressed. Eleven of 15 study eyes treated with gene therapy showed no differences from baseline fixation locations or instability over an average of follow-up of 3.5 years. Four of 15 eyes developed new pseudo-foveas in the treated retinal regions 9 to 12 months after therapy that persisted for up to 6 years; patients used their pseudo-foveas for letter identification. fMRI studies demonstrated that preservation of light sensitivity was restricted to the cortical projection zone of the pseudo-foveas. Conclusions. The slow emergence of pseudo-foveas many months after the initial increases in light sensitivity points to a substantial plasticity of the adult visual system and a complex interaction between it and the progression of underlying retinal disease. The visual significance of pseudo-foveas suggests careful consideration of treatment zones for future gene therapy trials. (ClinicalTrials.gov number, NCT00481546.) PMID:25537204

  2. Current Status of Gene Delivery and Gene Therapy in Lacrimal Gland using Viral Vectors

    PubMed Central

    Selvam, Shivaram; Thomas, Padmaja B.; Hamm-Alvarez, Sarah F.; Schechter, Joel E.; Stevenson, Douglas; Mircheff, Austin K.; Trousdale*, Melvin D.

    2006-01-01

    Gene delivery is one of the biggest challenges in the field of gene therapy. It involves the efficient transfer of transgenes into somatic cells for therapeutic purposes. A few major drawbacks in gene delivery include inefficient gene transfer and lack of sustained transgene expression. However, the classical method of using viral vectors for gene transfer has circumvented some of these issues. Several kinds of viruses, including retrovirus, adenovirus, adeno-associated virus, and herpes simplex virus, have been manipulated for use in gene transfer and gene therapy applications. The transfer of genetic material into lacrimal epithelial cells and tissues, both in vitro and in vivo, has been critical for the study of tear secretory mechanisms and autoimmunity of the lacrimal gland. These studies will help in the development of therapeutic interventions for autoimmune disorders such as Sjögren’s syndrome and dry eye syndromes which are associated with lacrimal dysfunction. These studies are also critical for future endeavors which utilize the lacrimal gland as a reservoir for the production of therapeutic factors which can be released in tears, providing treatment for diseases of the cornea and posterior segment. This review will discuss the developments related to gene delivery and gene therapy in the lacrimal gland using several viral vector systems. PMID:17056149

  3. Gene therapy of the rheumatic diseases: 1998 to 2008

    PubMed Central

    Evans, Christopher H; Ghivizzani, Steven C; Robbins, Paul D

    2009-01-01

    During the decade since the launch of Arthritis Research, the application of gene therapy to the rheumatic diseases has experienced the same vicissitudes as the field of gene therapy as a whole. There have been conceptual and technological advances and an increase in the number of clinical trials. However, funding has been unreliable and a small number of high-profile deaths in human trials, including one in an arthritis gene therapy trial, have provided ammunition to skeptics. Nevertheless, steady progress has been made in a number of applications, including rheumatoid arthritis and osteoarthritis, Sjögren syndrome, and lupus. Clinical trials in rheumatoid arthritis have progressed to phase II and have provided the first glimpses of possible efficacy. Two phase I protocols for osteoarthritis are under way. Proof of principle has been demonstrated in animal models of Sjögren syndrome and lupus. For certain indications, the major technological barriers to the development of genetic therapies seem to have been largely overcome. The translational research necessary to turn these advances into effective genetic medicines requires sustained funding and continuity of effort. PMID:19232068

  4. IL-12 based gene therapy in veterinary medicine

    PubMed Central

    2012-01-01

    The use of large animals as an experimental model for novel treatment techniques has many advantages over the use of laboratory animals, so veterinary medicine is becoming an increasingly important translational bridge between preclinical studies and human medicine. The results of preclinical studies show that gene therapy with therapeutic gene encoding interleukin-12 (IL-12) displays pronounced antitumor effects in various tumor models. A number of different studies employing this therapeutic plasmid, delivered by either viral or non-viral methods, have also been undertaken in veterinary oncology. In cats, adenoviral delivery into soft tissue sarcomas has been employed. In horses, naked plasmid DNA has been delivered by direct intratumoral injection into nodules of metastatic melanoma. In dogs, various types of tumors have been treated with either local or systemic IL-12 electrogene therapy. The results of these studies show that IL-12 based gene therapy elicits a good antitumor effect on spontaneously occurring tumors in large animals, while being safe and well tolerated by the animals. Hopefully, such results will lead to further investigation of this therapy in veterinary medicine and successful translation into human clinical trials. PMID:23171444

  5. MOLECULAR THERAPY Vol. 1, No. 6, June 2000 Copyright The American Society of Gene Therapy

    E-print Network

    Ford, James

    Hemophilia B is a bleeding disorder that results from a deficiency of factor IX in plasma. It is an X for treatment of hemophilia [reviewed in (2)]. Retroviral vectors have been used successfully to accomplish long of transgene expression in the liver for effective gene therapy of hemophilia. As a first step toward producing

  6. Integrin-mediated vectors for gene transfer and therapy.

    PubMed

    Hart, S L

    1999-04-01

    Gene therapy offers the possibility of new therapeutic strategies for diseases for which at present no cure exists. Current gene delivery systems, however, both viral and non-viral, have so far proven to be inadequate in one way or another and new efficient vector systems are required if gene therapy is to fulfill its clinical potential. The prospect of targeting integrins to improve vector efficiency is attractive since integrin-mediated internalization is exploited by bacterial and viral intracellular pathogens. Viral and synthetic vectors that incorporate peptide ligands for integrins have been exploited in the development of targeted vectors. This has generated enhanced efficiencies of transfection by synthetic vectors and transduction by adenoviral vectors, as well as extending the tropism of adenoviral vectors. The technology of phage display of random peptide libraries provides an approach to the selection of high-affinity peptide ligands, while the identification of integrin-binding motifs from natural protein ligands for integrins provides another source of peptides. Investigations into integrin receptors themselves, their activation and the signal transduction pathways they invoke may lead to further improvements in the design of integrin-targeted vectors and extensions to their potential applications in gene therapy. PMID:11715943

  7. Cellular unfolded protein response against viruses used in gene therapy

    PubMed Central

    Sen, Dwaipayan; Balakrishnan, Balaji; Jayandharan, Giridhara R.

    2014-01-01

    Viruses are excellent vehicles for gene therapy due to their natural ability to infect and deliver the cargo to specific tissues with high efficiency. Although such vectors are usually “gutted” and are replication defective, they are subjected to clearance by the host cells by immune recognition and destruction. Unfolded protein response (UPR) is a naturally evolved cyto-protective signaling pathway which is triggered due to endoplasmic reticulum (ER) stress caused by accumulation of unfolded/misfolded proteins in its lumen. The UPR signaling consists of three signaling pathways, namely PKR-like ER kinase, activating transcription factor 6, and inositol-requiring protein-1. Once activated, UPR triggers the production of ER molecular chaperones and stress response proteins to help reduce the protein load within the ER. This occurs by degradation of the misfolded proteins and ensues in the arrest of protein translation machinery. If the burden of protein load in ER is beyond its processing capacity, UPR can activate pro-apoptotic pathways or autophagy leading to cell death. Viruses are naturally evolved in hijacking the host cellular translation machinery to generate a large amount of proteins. This phenomenon disrupts ER homeostasis and leads to ER stress. Alternatively, in the case of gutted vectors used in gene therapy, the excess load of recombinant vectors administered and encountered by the cell can trigger UPR. Thus, in the context of gene therapy, UPR becomes a major roadblock that can potentially trigger inflammatory responses against the vectors and reduce the efficiency of gene transfer. PMID:24904562

  8. Rhodamine based plasmid DNA nanoparticles for mitochondrial gene therapy.

    PubMed

    Santos, João; Sousa, Fani; Queiroz, João; Costa, Diana

    2014-09-01

    Conventional treatments for patients suffering from mitochondrial cytopathies are, in most of the cases, inefficient and there is, until now, no effective cure. Mitochondrial gene therapy can be seen as a valuable approach to reestablish normal metabolic function, adding a new perspective of treatment for mitochondrial-related diseases. We developed novel mitochondrial-targeted plasmid DNA nanoparticles by incorporation of rhodamine 123, a fluorescent amphiphile with mitochondria affinity. These nanocarriers have suitable sizes for gene therapy purposes, are biocompatible and are able to protect the encapsulated pDNA from nucleases digestion. Furthermore, the pDNA vectors were easily internalized intodifferent cell linesand targeted delivery to mitochondria was confirmed by fluorescence confocal microscopy. In addition, p53 protein inexpression, mediated by rhodamine nanoparticles, demonstrates the ability of the proposed system to target mitochondria; due to the different genetic code in mitochondria, p53 protein cannot be expressed. Overall, the presented model pDNA constructs possess interesting properties as gene delivery systems and their mitochondrial target ability might have a profound relevance for further engineering of adequate vectors to be applied in mitochondrial gene therapy field. PMID:24967548

  9. Gene mutations and molecularly targeted therapies in acute myeloid leukemia

    PubMed Central

    Hatzimichael, Eleftheria; Georgiou, Georgios; Benetatos, Leonidas; Briasoulis, Evangelos

    2013-01-01

    Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period of time. However, over the last 30 years fine-tuning of therapeutics have increased the rates of remission and cure. Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3, JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in clinical development. For loss-of-function gene mutations, which are mostly biomarkers of favorable prognosis, combined therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products, proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their biological functions and clinical significance and present small molecule compounds in clinical development, which are expected to have a role in treating AML subtypes with characteristic molecular alterations. PMID:23358589

  10. Large deformation three-dimensional image registration in image-guided radiation therapy

    Microsoft Academic Search

    Mark Foskey; Brad Davis; Lav Goyal; Sha Chang; Ed Chaney; Nathalie Strehl; Sandrine Tomei; Julian Rosenman; Sarang Joshi

    2005-01-01

    In this paper, we present and validate a framework, based on deformable image registration, for automatic processing of serial three-dimensional CT images used in image-guided radiation therapy. A major assumption in deformable image registration has been that, if two images are being registered, every point of one image corresponds appropriately to some point in the other. For intra-treatment images of

  11. Experimental studies on PNP suicide gene therapy of hepatoma.

    PubMed

    Cai, Xiaokun; Zhou, Junli; Lin, Jusheng; Sun, Xuemei; Xue, Xiulan; Li, Chao

    2005-01-01

    To investigate the killing effect of PNP/MeP-dR suicide gene system on hepatoma cells, pcDNA3.0/PNP, an eukaryotic expression vector harboring E. coli PNP gene, was transfected into human hepatoma HepG2 cells by liposome-mediated method. A HepG2 cell line with stable PNP gene expression, HepG2/PNP, was established with presence of G418 selection. The cell growth curves were determined with trypan blue staining. The sensitivity of HepG2/PNP to MeP-dR and bystander effects were assayed by MTT and FCM methods. The enzymatic activity of the product of PNP gene was determined by HPLC method. The cytotoxic effects of MeP-dR on HepG2/PNP cells were obvious (IC50 = 4.5 micromol/L) and all HepG2/PNP cells were killed 4 days after the treatment with 100 micromol/L MeP-dR. In mixed cultures containing increasing percentages of HepG2/PNP cells, total population killing was demonstrated when HepG2/PNP cells accounted for as few as 5% of all HepG2 cells 8 days after the treatment with 100 micromol MeP-dR. High-pressure liquid chromatography (HPLC) demonstrated that the PNP enzyme could convert MeP-dR into 6-MP. PNP/MeP-dR suicide gene system had an advantage over traditional suicide gene systems for hepatoma gene therapy. Our e results suggest that high-level bystander effects of this system result in significant anti-tumor responses to hepatoma gene therapy, especially in vivo. PMID:16116966

  12. Engineering adeno-associated viruses for clinical gene therapy

    PubMed Central

    Kotterman, Melissa A.; Schaffer, David V.

    2015-01-01

    Clinical gene therapy has been increasingly successful, due both to an enhanced molecular understanding of human disease and to progressively improving gene delivery technologies. Among the latter, delivery vectors based on adeno-associated virus (AAV) have emerged as safe and effective – in one recent case leading to regulatory approval. Although shortcomings in viral vector properties will render extension of such successes to many other human diseases challenging, new approaches to engineer and improve AAV vectors and their genetic cargo are increasingly helping to overcome these barriers. PMID:24840552

  13. GENE AND CELL-MEDIATED THERAPIES FOR MUSCULAR DYSTROPHY

    PubMed Central

    Konieczny, Patryk; Swiderski, Kristy; Chamberlain, Jeffrey S.

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a devastating muscle disorder that affects 1 in 3500 boys. Despite years of research and considerable progress in understanding the molecular mechanism of the disease and advancement of therapeutic approaches, there is no cure for DMD. The current treatment options are limited to physiotherapy and corticosteroids, and although they provide a substantial improvement in affected children, they only slow the course of the disorder. On a more optimistic note, the most recent approaches either significantly alleviate or eliminate muscular dystrophy in murine and canine models of DMD and importantly, many of them are being tested in early phase human clinical trials. This review summarizes advancements that have been made in viral and non-viral gene therapy as well as stem cell therapy for DMD with a focus on the replacement and repair of the affected dystrophin gene. PMID:23553671

  14. Imaging Molecular Pathways: Reporter Genes

    PubMed Central

    Brogan, John; Li, Fang; Li, Wenrong; He, Zhimin; Huang, Qian; Li, Chuan-Yuan

    2012-01-01

    Molecular imaging is a rapidly advancing field that allows cancer biologists to look deeper into the complex inner workings of tumor cells, or whole tumors, in a non-invasive manner. In this review, we will summarize some recent advances that enable investigators to study various important biological processes in tumors in vivo. We will discuss novel imaging approaches that allow investigators to visualize and quantify molecular pathways, such as receptor tyrosine kinase activation, hypoxia signal transduction, apoptosis, and DNA double-strand breaks. Select examples of these applications will be discussed. Because of the limited scope of this review, we will only focus on natural reporters, such as bioluminescence and fluorescent proteins. PMID:22348248

  15. Lentiviral-mediated gene therapy for murine mucopolysaccharidosis type IIIA

    Microsoft Academic Search

    Chantelle McIntyre; Ainslie Lauren Derrick Roberts; Enzo Ranieri; Peter Roy Clements; Sharon Byers; Donald S. Anson

    2008-01-01

    Mucopolysaccharidosis type IIIA (MPS IIIA) is a heritable glycosaminoglycan (GAG) storage disorder which is characterised by lysosomal accumulation of heparan sulphate, secondary to a deficiency of sulphamidase (heparan-N-sulphatase, N-sulphoglucosamine sulphohydrolase, EC No. 3.10.1.1.). There is currently no treatment for affected individuals who experience progressive CNS deterioration prior to an early death.As a first step towards developing gene therapy as a

  16. Mobile genetic elements and cancer. From mutations to gene therapy.

    PubMed

    Kozeretska, I A; Demydov, S V; Ostapchenko, L I

    2011-12-01

    In the present review, an association between cancer and the activity of the non-LTR retroelements L1, Alu, and SVA, as well as endogenous retroviruses, in the human genome, is analyzed. Data suggesting that transposons have been involved in embryogenesis and malignization processes, are presented. Events that lead to the activation of mobile elements in mammalian somatic cells, as well as the use of mobile elements in genetic screening and cancer gene therapy, are reviewed. PMID:22217707

  17. Pleiotrophin gene therapy for peripheral ischemia: evaluation of full-length and truncated gene variants.

    PubMed

    Fang, Qizhi; Mok, Pamela Y; Thomas, Anila E; Haddad, Daniel J; Saini, Shereen A; Clifford, Brian T; Kapasi, Neel K; Danforth, Olivia M; Usui, Minako; Ye, Weisheng; Luu, Emmy; Sharma, Rikki; Bartel, Maya J; Pathmanabhan, Jeremy A; Ang, Andrew A S; Sievers, Richard E; Lee, Randall J; Springer, Matthew L

    2013-01-01

    Pleiotrophin (PTN) is a growth factor with both pro-angiogenic and limited pro-tumorigenic activity. We evaluated the potential for PTN to be used for safe angiogenic gene therapy using the full length gene and a truncated gene variant lacking the domain implicated in tumorigenesis. Mouse myoblasts were transduced to express full length or truncated PTN (PTN or T-PTN), along with a LacZ reporter gene, and injected into mouse limb muscle and myocardium. In cultured myoblasts, PTN was expressed and secreted via the Golgi apparatus, but T-PTN was not properly secreted. Nonetheless, no evidence of uncontrolled growth was observed in cells expressing either form of PTN. PTN gene delivery to myocardium, and non-ischemic skeletal muscle, did not result in a detectable change in vascularity or function. In ischemic hindlimb at 14 days post-implantation, intramuscular injection with PTN-expressing myoblasts led to a significant increase in skin perfusion and muscle arteriole density. We conclude that (1) delivery of the full length PTN gene to muscle can be accomplished without tumorigenesis, (2) the truncated PTN gene may be difficult to use in a gene therapy context due to inefficient secretion, (3) PTN gene delivery leads to functional benefit in the mouse acute ischemic hindlimb model. PMID:23630585

  18. Neurotrophic gene polymorphisms and response to psychological therapy.

    PubMed

    Lester, K J; Hudson, J L; Tropeano, M; Creswell, C; Collier, D A; Farmer, A; Lyneham, H J; Rapee, R M; Eley, T C

    2012-01-01

    Therapygenetics, the study of genetic determinants of response to psychological therapies, is in its infancy. Here, we investigate whether single-nucleotide polymorphisms in nerve growth factor (NGF) (rs6330) and brain-derived neutrotrophic factor (BDNF) (rs6265) genes predict the response to cognitive behaviour therapy (CBT). Neurotrophic genes represent plausible candidate genes: they are implicated in synaptic plasticity, response to stress, and are widely expressed in brain areas involved in mood and cognition. Allelic variation at both loci has shown associations with anxiety-related phenotypes. A sample of 374 anxiety-disordered children with white European ancestry was recruited from clinics in Reading, UK, and in Sydney, Australia. Participants received manualised CBT treatment and DNA was collected from buccal cells using cheek swabs. Treatment response was assessed at post-treatment and follow-up time points. We report first evidence that children with one or more copies of the T allele of NGF rs6330 were significantly more likely to be free of their primary anxiety diagnosis at follow-up (OR = 0.60 (0.42-0.85), P = 0.005). These effects remained even when other clinically relevant covariates were accounted for (OR = 0.62 (0.41-0.92), P = 0.019). No significant associations were observed between BDNF rs6265 and response to psychological therapy. These findings demonstrate that knowledge of genetic markers has the potential to inform clinical treatment decisions for psychotherapeutic interventions. PMID:22832952

  19. review The American Society of Gene & Cell Therapy Molecular Therapy vol. 17 no. 10, 16771682 oct. 2009 1677

    E-print Network

    Cai, Long

    follow- ing treatment with surgery, chemotherapy, radiation therapy, and some of the newer targetedreview© The American Society of Gene & Cell Therapy Molecular Therapy vol. 17 no. 10, 1677­1682 oct and improved survival for many patients with cancer. Unfortunately, even for patients who achieve remission

  20. original article The American Society of Gene Therapy Molecular Therapy vol. 17 no. 1, 5156 jan. 2009 51

    E-print Network

    Cai, Long

    dropped to 2.5% during 4 hours/day of hyperbaric chamber treatment. Each tumor-oxygenating maneuveroriginal article© The American Society of Gene Therapy Molecular Therapy vol. 17 no. 1, 51­56 jan. 2009 51 Hypoxia contributes to the resistance of tumors to con- ventional therapies. We hypothesized

  1. Image-Guided Photodynamic Cancer Therapy

    Microsoft Academic Search

    Zheng-Rong Lu; Anagha Vaidya

    Photodynamic therapy is a therapeutic modality with a long history. It has been historically known in ancient India and China\\u000a for the treatment of skin disorders. In Western medicine, the first experimental evidence of photodynamic therapy was reported\\u000a by Raab et al. who observed the lethality of acridine dyes to paramecium in the presence of light [1]. The photodynamic effect

  2. 923. Combining In Situ Gene Therapy with Radiotherapy and Hormonal Therapy in the Treatment of Stage D1 Prostate Cancer

    Microsoft Academic Search

    Tetsuo Fujita; Bin S. Teh; Terry L. Timme; Gustavo Ayala; Wei-Yuan Mai; Takefumi Satoh; Nobuyuki Kusaka; Koji Naruishi; Ken-ichi Tabata; Estuardo Aguilar-Cordova; Thomas Wheeler; E. Brian Butler; Timothy C. Thompson

    2006-01-01

    Introduction: Clinical trial of combination adenoviral vector mediated Herpes Simplex Virus-thymidine kinase (HSV-tk) + valacyclovir (VCV) in situ gene therapy with radiotherapy (RT) and hormonal therapy was conducted for Stage D1 prostate cancer. We now report the safety, efficacy, and immune responses using this approach.Methods: Five patients with Stage D1 prostate cancer were treated as follows: Gene therapy: 3 separate

  3. Immobilization of gene vector on polyurethane surface using monoclonal antibody for site-specific gene therapy

    Microsoft Academic Search

    Cunxian Song; Manyan Wang; R. J. Levy

    2005-01-01

    Conventional strategies of gene therapy using viral vectors result in suboptimal localization and potentially dangerous distal spread of vector. We hypothesized that site-specific delivery of adenoviral gene vectors could be achieved from a polyurethane (PU) film through a mechanism involving anti-viral antibody tethering. PU films were formulated with a collagen coating. Anti-adenoviral monoclonal antibodies were covalently bound to the collagen

  4. Role of sonographic imaging in occupational therapy practice.

    PubMed

    Roll, Shawn C

    2015-01-01

    Occupational therapy practice is grounded in the delivery of occupation-centered, patient-driven treatments that engage clients in the process of doing to improve health. As emerging technologies, such as medical imaging, find their way into rehabilitation practice, it is imperative that occupational therapy practitioners assess whether and how these tools can be incorporated into treatment regimens that are dually responsive to the medical model of health care and to the profession's foundation in occupation. Most medical imaging modalities have a discrete place in occupation-based intervention as outcome measures or for patient education; however, sonographic imaging has the potential to blend multiple occupational therapy practice forms to document treatment outcomes, inform clinical reasoning, and facilitate improved functional performance when used as an accessory tool in direct intervention. Use of medical imaging is discussed as it relates to occupational foundations and the professional role within the context of providing efficient, effective patient-centered rehabilitative care. PMID:25871607

  5. Role of Sonographic Imaging in Occupational Therapy Practice

    PubMed Central

    2015-01-01

    Occupational therapy practice is grounded in the delivery of occupation-centered, patient-driven treatments that engage clients in the process of doing to improve health. As emerging technologies, such as medical imaging, find their way into rehabilitation practice, it is imperative that occupational therapy practitioners assess whether and how these tools can be incorporated into treatment regimens that are dually responsive to the medical model of health care and to the profession’s foundation in occupation. Most medical imaging modalities have a discrete place in occupation-based intervention as outcome measures or for patient education; however, sonographic imaging has the potential to blend multiple occupational therapy practice forms to document treatment outcomes, inform clinical reasoning, and facilitate improved functional performance when used as an accessory tool in direct intervention. Use of medical imaging is discussed as it relates to occupational foundations and the professional role within the context of providing efficient, effective patient-centered rehabilitative care. PMID:25871607

  6. Gene network analysis: from heart development to cardiac therapy.

    PubMed

    Ferrazzi, Fulvia; Bellazzi, Riccardo; Engel, Felix B

    2015-03-01

    Networks offer a flexible framework to represent and analyse the complex interactions between components of cellular systems. In particular gene networks inferred from expression data can support the identification of novel hypotheses on regulatory processes. In this review we focus on the use of gene network analysis in the study of heart development. Understanding heart development will promote the elucidation of the aetiology of congenital heart disease and thus possibly improve diagnostics. Moreover, it will help to establish cardiac therapies. For example, understanding cardiac differentiation during development will help to guide stem cell differentiation required for cardiac tissue engineering or to enhance endogenous repair mechanisms. We introduce different methodological frameworks to infer networks from expression data such as Boolean and Bayesian networks. Then we present currently available temporal expression data in heart development and discuss the use of network-based approaches in published studies. Collectively, our literature-based analysis indicates that gene network analysis constitutes a promising opportunity to infer therapy-relevant regulatory processes in heart development. However, the use of network-based approaches has so far been limited by the small amount of samples in available datasets. Thus, we propose to acquire high-resolution temporal expression data to improve the mathematical descriptions of regulatory processes obtained with gene network inference methodologies. Especially probabilistic methods that accommodate the intrinsic variability of biological systems have the potential to contribute to a deeper understanding of heart development. PMID:25231088

  7. Liver-targeted gene therapy: Approaches and challenges.

    PubMed

    Aravalli, Rajagopal N; Belcher, John D; Steer, Clifford J

    2015-06-01

    The liver plays a major role in many inherited and acquired genetic disorders. It is also the site for the treatment of certain inborn errors of metabolism that do not directly cause injury to the liver. The advancement of nucleic acid-based therapies for liver maladies has been severely limited because of the myriad untoward side effects and methodological limitations. To address these issues, research efforts in recent years have been intensified toward the development of targeted gene approaches using novel genetic tools, such as zinc-finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats as well as various nonviral vectors such as Sleeping Beauty transposons, PiggyBac transposons, and PhiC31 integrase. Although each of these methods uses a distinct mechanism of gene modification, all of them are dependent on the efficient delivery of DNA and RNA molecules into the cell. This review provides an overview of current and emerging therapeutic strategies for liver-targeted gene therapy and gene repair. Liver Transpl 21:718-737, 2015. © 2015 AASLD. PMID:25824605

  8. Targeting Gene-Viro-Therapy with AFP driving Apoptin gene shows potent antitumor effect in hepatocarcinoma

    PubMed Central

    2012-01-01

    Background Gene therapy and viral therapy are used for cancer therapy for many years, but the results are less than satisfactory. Our aim was to construct a new recombinant adenovirus which is more efficient to kill hepatocarcinoma cells but more safe to normal cells. Methods By using the Cancer Targeting Gene-Viro-Therapy strategy, Apoptin, a promising cancer therapeutic gene was inserted into the double-regulated oncolytic adenovirus AD55 in which E1A gene was driven by alpha fetoprotein promoter along with a 55 kDa deletion in E1B gene to form AD55-Apoptin. The anti-tumor effects and safety were examined by western blotting, virus yield assay, real time polymerase chain reaction, 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, Hoechst33342 staining, Fluorescence-activated cell sorting, xenograft tumor model, Immunohistochemical assay, liver function analysis and Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling assay. Results The recombinant virus AD55-Apoptin has more significant antitumor effect for hepatocelluar carcinoma cell lines (in vitro) than that of AD55 and even ONYX-015 but no or little impair on normal cell lines. Furthermore, it also shows an obvious in vivo antitumor effect on the Huh-7 liver carcinoma xenograft in nude mice with bigger beginning tumor volume till about 425 mm3 but has no any damage on the function of liver. The induction of apoptosis is involved in AD55-Apoptin induced antitumor effects. Conclusion The AD55-Apoptin can be a potential anti-hepatoma agent with remarkable antitumor efficacy as well as higher safety in cancer targeting gene-viro-therapy system. PMID:22321574

  9. Neuronal dysfunction and medical therapy in heart failure: can an imaging biomarker help to "personalize" therapy?

    PubMed

    Wessler, Benjamin S; Udelson, James E

    2015-06-01

    (123)I-metaiodobenzylguanidine ((123)I-MIBG) imaging is a tool for evaluating one of the fundamental pathophysiologic abnormalities seen in heart failure (HF), that of an upregulated sympathetic nervous system and its effect on the myocardium. Although this imaging technique offers information about prognosis for patients treated with contemporary guideline-based HF therapies and improves risk stratification, there are neither rigorous nor sufficient outcome data to suggest that this imaging tool can guide therapeutic decision making or better target subsets of patients with HF for particular therapies. PMID:26033899

  10. Image-guided thermal therapy of uterine fibroids

    PubMed Central

    Shen, Shu-Huei; Fennessy, Fiona; McDannold, Nathan; Jolesz, Ferenc; Tempany, Clare

    2009-01-01

    Thermal ablation is an established treatment for tumor. The merging of newly developed imaging techniques has allowed precise targeting and real-time thermal mapping. This article provides an overview of the image-guided thermal ablation techniques in the treatment of uterine fibroids. Background on uterine fibroids, including epidemiology, histology, symptoms, imaging findings and current treatment options, is first outlined. After describing the principle of magnetic resonance thermal imaging, we introduce the applications of image-guided thermal therapies, including laser ablation, radiofrequency ablation, cryotherapy and particularly the newest, magnetic resonance-guided focused ultrasound surgery, and how they apply to uterine fibroid treatment. PMID:19358440

  11. Phase contrast portal imaging for image-guided microbeam radiation therapy

    NASA Astrophysics Data System (ADS)

    Umetani, Keiji; Kondoh, Takeshi

    2014-03-01

    High-dose synchrotron microbeam radiation therapy is a unique treatment technique used to destroy tumors without severely affecting circumjacent healthy tissue. We applied a phase contrast technique to portal imaging in preclinical microbeam radiation therapy experiments. Phase contrast portal imaging is expected to enable us to obtain higherresolution X-ray images at therapeutic X-ray energies compared to conventional portal imaging. Frontal view images of a mouse head sample were acquired in propagation-based phase contrast imaging. The phase contrast images depicted edge-enhanced fine structures of the parietal bones surrounding the cerebrum. The phase contrast technique is expected to be effective in bony-landmark-based verification for image-guided radiation therapy.

  12. Image-guided focal therapy for prostate cancer

    PubMed Central

    Sankineni, Sandeep; Wood, Bradford J.; Rais-Bahrami, Soroush; Diaz, Annerleim Walton; Hoang, Anthony N.; Pinto, Peter A.; Choyke, Peter L.; Türkbey, Bar??

    2014-01-01

    The adoption of routine prostate specific antigen screening has led to the discovery of many small and low-grade prostate cancers which have a low probability of causing mortality. These cancers, however, are often treated with radical therapies resulting in long-term side effects. There has been increasing interest in minimally invasive focal therapies to treat these tumors. While imaging modalities have improved rapidly over the past decade, similar advances in image-guided therapy are now starting to emerge—potentially achieving equivalent oncologic efficacy while avoiding the side effects of conventional radical surgery. The purpose of this article is to review the existing literature regarding the basis of various focal therapy techniques such as cryotherapy, microwave, laser, and high intensity focused ultrasound, and to discuss the results of recent clinical trials that demonstrate early outcomes in patients with prostate cancer. PMID:25205025

  13. Heme oxygenase -1 gene therapy: recent advances and therapeutic applications.

    PubMed

    Abraham, Nader G; Asija, Amit; Drummond, George; Peterson, Stephen

    2007-04-01

    Heme oxygenase-1 (HO-1) is regarded as a sensitive and reliable indicator of cellular oxidative stress. Studies on carbon monoxide (CO) and bilirubin, two of the three (iron is the third) end products of heme degradation have improved the understanding of the protective role of HO against oxidative injury. CO is a vasoactive molecule and bilirubin is an antioxidant, and an increase in their production through an increase in HO activity assists other antioxidant systems in attenuating the overall production of reactive oxygen species (ROS), thus facilitating cellular resistance to oxidative injury. Gene transfer is used to insert specific genes into cells that are either otherwise deficient in or that underexpress the gene. Successful HO gene transfer requires two essential elements to produce functional HO activity. Firstly, the HO gene must be delivered in a safe vector, e.g., adenoviral, retroviral or leptosome based vectors, currently being used in clinical trials. Secondly, with the exception of HO gene delivery to either ocular or cardiovascular tissue via catheter-based delivery systems, HO delivery must be site and organ specific. This has been achieved in rabbit ocular tissues, rat liver, kidney and vasculature, SHR kidney, and endothelial cells [Abraham et al., 1995a; Abraham et al., 1995b; Abraham et al., 2002c; Quan et al., 2004; Sabaawy et al., 2000; Sabaawy et al., 2001; Yang et al., 2004]. In this review, we discuss the functional significance of the HO system in various pathophysiological conditions and the beneficial therapeutic applications of human HO gene transfer and gene therapy in a variety of clinical circumstances. PMID:17430129

  14. Imaging Cardiac Stem Cell Therapy: Translations to Human Clinical Studies

    Microsoft Academic Search

    Wendy Y. Zhang; Antje D. Ebert; Jagat Narula; Joseph C. Wu

    Stem cell therapy promises to open exciting new options in the treatment of cardiovascular diseases. Although feasible and\\u000a clinically safe, the in vivo behavior and integration of stem cell transplants still remain largely unknown. Thus, the development\\u000a of innovative non-invasive imaging techniques capable of effectively tracking such therapy in vivo is vital for a more in-depth\\u000a investigation into future clinical

  15. Eukaryotic expression vectors bearing genes encoding cytotoxic proteins for cancer gene therapy.

    PubMed

    Glinka, Elena M

    2012-09-01

    Cancer gene therapy is a promising direction for the treatment of cancer patients. A primary goal of all cancer therapies is to selectively target and kill tumour cells. Such therapies are administered via different approaches, including both viral and non-viral delivery; however, both methods have advantages and disadvantages. Transcriptional targeting enables genes encoding toxic proteins to be expressed directly in cancer cells. Numerous vectors have been created with the purpose of killing cancer cells, and some have successfully suppressed malignant tumours. Data concerning the function of vectors bearing genes that encode cytotoxic proteins under the control of different promoters, including tissue/tumour specific and constitutive promoters, is summarised here. This review focuses on vectors that bear genes encoding diphtheria toxin, Pseudomonas exotoxin A, caspases, gef, streptolysin, and melittin. Data describing the efficacy of such vectors have been summarised. Notably, there are vectors that killed cancer cell lines originating from the same type of cancer with differential efficiency. Thus, there is differential inhibition of cancer cell growth dependent on the cell line. In this review, the constructs employing genes whose expression induces cell death and the efficiency with which they suppress cancer cell growth will be summarised. PMID:22613563

  16. Immune GeneViral Therapy with Triplex Efficacy Mediated by Oncolytic Adenovirus Carrying an

    E-print Network

    Tian, Weidong

    in the prospects for cancer gene therapy [1­3]. Although a few achievements have recently been made in the field of cancer gene therapy, great effort is still needed to select effective transgenes with multiple efficacy against cancers and to design specific gene vectors selectively targeting cancer cells. Approaches

  17. Promises of gene therapy, Mario CapecchiSite: DNA Interactive (www.dnai.org)

    NSDL National Science Digital Library

    2008-03-26

    Interviewee: Mario Capecchi DNAi Location: Applications>Genes and Medicine>Gene targeting>Possibilities Possibilities for new therapies Mario Capecchi talks about the possible use of embryonic stem cells and gene targeting techniques to develop new therapies for for diabetes and Parkinson's.

  18. HUMAN GENE THERAPY 16:126131 (January 2005) Mary Ann Liebert, Inc.

    E-print Network

    Kay, Mark A.

    126 HUMAN GENE THERAPY 16:126­131 (January 2005) © Mary Ann Liebert, Inc. Technical Report Improved containing an inducible phage C31 integrase gene and a therapeutic expression cassette flanked with att these vectors viable for gene therapy applications. OVERVIEW SUMMARY Minicircle DNAs devoid of plasmid bacterial

  19. Gap junctions in human glioblastomas: implications for suicide gene therapy.

    PubMed

    Cottin, S; Gould, P V; Cantin, L; Caruso, M

    2011-09-01

    Glioblastoma is a very aggressive astrocytic tumor and most patients have 1-year survival time after diagnosis. A promising therapeutic strategy is the local delivery of the herpes simplex virus thymidine kinase gene in the tumor bed followed by ganciclovir treatment. The presence of functional gap junctions is highly relevant for the success of suicide gene therapy. Connexins are expressed in practically all tissues and form gap junctions that allow intercellular communication. Connexin 43 (Cx43) is the major connexin member being expressed in astrocytes but its status in glioblastoma is not well defined. We have investigated by immunofluorescence the presence of Cx43 in 74 human glioblastoma samples; its expression was detected in 77% of the samples analyzed. We report here that glioblastoma is a heterogenous disease as regards Cx43 expression with presentations, in which Cx43 expression is unaltered, reduced or totally lost. A predominant Cx43 cytoplasmic localization was observed in four out of eight primary glioblastoma cultures that we have established. This aberrant localization reduced gap junctionnal intercellular communication by 50 to 75% as compared with primary cell cultures displaying gap junctional plaques. However, the bystander effect evaluated after lentiviral delivery of the herpes simplex virus thymidine kinase gene and ganciclovir treatment was detected in all Cx43-positive primary cell cultures, and it was independant of the Cx43 localization. These findings may have important clinical implications for the design of anticancer cytotoxic therapies that rely on the gap junction-mediated bystander effect for their success. PMID:21779029

  20. Cationic Polyene Phospholipids as DNA Carriers for Ocular Gene Therapy

    PubMed Central

    Machado, Susana; Calado, Sofia; Bitoque, Diogo; Oliveira, Ana Vanessa; Øpstad, Christer L.; Zeeshan, Muhammad; Sliwka, Hans-Richard; Partali, Vassilia; Pungente, Michael D.; Silva, Gabriela A.

    2014-01-01

    Recent success in the treatment of congenital blindness demonstrates the potential of ocular gene therapy as a therapeutic approach. The eye is a good target due to its small size, minimal diffusion of therapeutic agent to the systemic circulation, and low immune and inflammatory responses. Currently, most approaches are based on viral vectors, but efforts continue towards the synthesis and evaluation of new nonviral carriers to improve nucleic acid delivery. Our objective is to evaluate the efficiency of novel cationic retinoic and carotenoic glycol phospholipids, designated C20-18, C20-20, and C30-20, to deliver DNA to human retinal pigmented epithelium (RPE) cells. Liposomes were produced by solvent evaporation of ethanolic mixtures of the polyene compounds and coformulated with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) or cholesterol (Chol). Addition of DNA to the liposomes formed lipoplexes, which were characterized for binding, size, biocompatibility, and transgene efficiency. Lipoplex formulations of suitable size and biocompatibility were assayed for DNA delivery, both qualitatively and quantitatively, using RPE cells and a GFP-encoding plasmid. The retinoic lipoplex formulation with DOPE revealed a transfection efficiency comparable to the known lipid references 3?-[N-(N?,N?-dimethylaminoethane)-carbamoyl]-cholesterol (DC-Chol) and 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (EPC) and GeneJuice. The results demonstrate that cationic polyene phospholipids have potential as DNA carriers for ocular gene therapy. PMID:25147812

  1. Autologous stem cell transplant with gene therapy for Friedreich ataxia.

    PubMed

    Tajiri, Naoki; Staples, Meaghan; Kaneko, Yuji; Kim, Seung U; Zesiewicz, Theresa A; Borlongan, Cesar V

    2014-09-01

    We advance the overarching hypothesis that stem cell therapy is a potent treatment for Friedreich's ataxia (FRDA). Here, we discuss the feasibility of autologous transplantation in FRDA, highlighting the need for the successful isolation of the FRDA patient's bone marrow-derived mesenchymal stem cells, followed by characterization that these cells maintain the GAA repeat expansion and the reduced FXN mRNA expression, both hallmark features of FRDA. Next, we discuss the need for assessment of the proliferative capability and pluripotency of FRDA patient's bone marrow-derived mesenchymal stem cells. In particular, we view the need for characterizing the in vitro differentiation of bone marrow-derived mesenchymal stem cells into the two cell types primarily affected in FRDA, peripheral neurons and cardiomyocytes. Finally, we discuss the need to test the application of bone marrow-derived mesenchymal stem cells as potent autologous donor cells for FRDA. The demonstration of the functional correction of the mutated gene in these cells will be a critical endpoint of determining the potential of stem cell therapy in FRDA. We envision a gene-based cell transplant strategy as a likely therapeutic approach for FRDA, involving stable insertion of functional human bacterial artificial chromosomes or BACs containing the intact FXN gene into stem cells, thereafter leading to the expression of frataxin protein in differentiated neurons/cardiomyocytes. PMID:24962209

  2. Stem and progenitor cell-mediated tumor selective gene therapy.

    PubMed

    Aboody, K S; Najbauer, J; Danks, M K

    2008-05-01

    The poor prognosis for patients with aggressive or metastatic tumors and the toxic side effects of currently available treatments necessitate the development of more effective tumor-selective therapies. Stem/progenitor cells display inherent tumor-tropic properties that can be exploited for targeted delivery of anticancer genes to invasive and metastatic tumors. Therapeutic genes that have been inserted into stem cells and delivered to tumors with high selectivity include prodrug-activating enzymes (cytosine deaminase, carboxylesterase, thymidine kinase), interleukins (IL-2, IL-4, IL-12, IL-23), interferon-beta, apoptosis-promoting genes (tumor necrosis factor-related apoptosis-inducing ligand) and metalloproteinases (PEX). We and others have demonstrated that neural and mesenchymal stem cells can deliver therapeutic genes to elicit a significant antitumor response in animal models of intracranial glioma, medulloblastoma, melanoma brain metastasis, disseminated neuroblastoma and breast cancer lung metastasis. Most studies reported reduction in tumor volume (up to 90%) and increased survival of tumor-bearing animals. Complete cures have also been achieved (90% disease-free survival for >1 year of mice bearing disseminated neuroblastoma tumors). As we learn more about the biology of stem cells and the molecular mechanisms that mediate their tumor-tropism and we identify efficacious gene products for specific tumor types, the clinical utility of cell-based delivery strategies becomes increasingly evident. PMID:18369324

  3. Glial cells metabolically cooperate: a potential requirement for gene replacement therapy.

    PubMed Central

    Gruber, H E; Koenker, R; Luchtman, L A; Willis, R C; Seegmiller, J E

    1985-01-01

    Immunofluorescently labeled glial cells are shown by radioautography to metabolically cooperate with hypoxanthine phosphoribosyltransferase-deficient fibroblasts. The observations of cooperation without cell contact and of incorporation gradients around the glial cells suggest that cooperation occurs through extracellular transport of radiolabeled purine compounds. The transfer of radiolabeled adenine, adenosine, or methylthioadeninosine is supported by the quantitative loss of cooperation when the recipient cell is also deficient in enzymes required for adenine or adenosine salvage. The demonstration of glial cell cooperation provides impetus for current research toward gene replacement therapy for the neurologic symptoms of the Lesch-Nyhan syndrome. Images PMID:2995977

  4. Gene therapy for muscular dystrophy: moving the field forward.

    PubMed

    Al-Zaidy, Samiah; Rodino-Klapac, Louise; Mendell, Jerry R

    2014-11-01

    Gene therapy for the muscular dystrophies has evolved as a promising treatment for this progressive group of disorders. Although corticosteroids and/or supportive treatments remain the standard of care for Duchenne muscular dystrophy, loss of ambulation, respiratory failure, and compromised cardiac function is the inevitable outcome. Recent developments in genetically mediated therapies have allowed for personalized treatments that strategically target individual muscular dystrophy subtypes based on disease pathomechanism and phenotype. In this review, we highlight the therapeutic progress with emphasis on evolving preclinical data and our own experience in completed clinical trials and others currently underway. We also discuss the lessons we have learned along the way and the strategies developed to overcome limitations and obstacles in this field. PMID:25439576

  5. [Expressing foreign genes by Newcastle disease virus for cancer therapy].

    PubMed

    Bai, F L; Tian, H; Yu, Q Z; Renl, G P; Li, D S

    2015-01-01

    An interesting aspect of Newcastle disease virus (NDV) is the ability to selectively replicate in tumor cells. Recently, using reverse genetics technology to enhance the oncolytic properties and therapeutic potential of NDV for tumor therapy has become popular in immunocompetent carcinoma tumor models. Expressing foreign genes by recombinant NDV (rNDV-FG) has been shown to be more effective in cancer therapy in preclinical studies. This paper provides an overview of the current studies on the cytotoxic and anti-cancer effects of rNDV-FG via direct oncolysis and immune stimulation. Safety of rNDV-FG as a therapeutic agent for cancer immunotherapy and virotherapy is also discussed. PMID:26065249

  6. Tissue-Engineered Skeletal Muscle Organoids for Reversible Gene Therapy

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman; DelTatto, Michael; Shansky, Janet; Lemaire, Julie; Chang, Albert; Payumo, Francis; Lee, Peter; Goodyear, Amy; Raven, Latasha

    1996-01-01

    Genetically modified murine skeletal myoblasts were tissue engineered in vitro into organ-like structures (organoids) containing only postmitotic myofibers secreting pharmacological levels of recombinant human growth hormone (rhGH). Subcutaneous organoid Implantation under tension led to the rapid and stable appearance of physiological sera levels of rhGH for up to 12 weeks, whereas surgical removal led to its rapid disappearance. Reversible delivery of bioactive compounds from postimtotic cells in tissue engineered organs has several advantages over other forms of muscle gene therapy.

  7. Tissue-Engineered Skeletal Muscle Organoids for Reversible Gene Therapy

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman; DelTatto, Michael; Shansky, Janet; Lemaire, Julie; Chang, Albert; Payumo, Francis; Lee, Peter; Goodyear, Amy; Raven, Latasha

    1996-01-01

    Genetically modified murine skeletal myoblasts were tissue engineered in vitro into organ-like structures (organoids) containing only postmitotic myoribers secreting pharmacological levels of recombinant human growth hormone (rhGH). Subcutaneous organoid implantation under tension led to the rapid and stable appearance of physiological sera levels of rhGH for up to 12 weeks, whereas surgical removal led to its rapid disappearance. Reversible delivery of bioactive compounds from postmitotic cells in tissue engineered organs has several advantages over other forms of muscle gene therapy.

  8. Image-Guidance for Stereotactic Body Radiation Therapy

    SciTech Connect

    Fuss, Martin [Department of Radiation Medicine, Oregon Health and Science University, Portland, OR (United States) and Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX (United States) and Cancer Therapy and Research Center, San Antonio, TX (United States)]. E-mail: fussm@ohsu.edu; Boda-Heggemann, Judit [Department of Radiation Oncology, Mannheim Medical Center, University of Heidelberg, Mannheim (Germany); Papanikolau, Nikos [Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX (United States); Cancer Therapy and Research Center, San Antonio, TX (United States); Salter, Bill J. [Department of Radiation Oncology, University of Utah, Salt Lake City, UT (United States); Huntsman Cancer Institute, Salt Lake City, UT (United States)

    2007-07-01

    The term stereotactic body radiation therapy (SBRT) describes a recently introduced external beam radiation paradigm by which small lesions outside the brain are treated under stereotactic conditions, in a single or few fractions of high-dose radiation delivery. Similar to the treatment planning and delivery process for cranial radiosurgery, the emphasis is on sparing of adjacent normal tissues through the creation of steep dose gradients. Thus, advanced methods for assuring an accurate relationship between the target volume position and radiation beam geometry, immediately prior to radiation delivery, must be implemented. Such methods can employ imaging techniques such as planar (e.g., x-ray) or volumetric (e.g., computed tomography [CT]) approaches and are commonly summarized under the general term image-guided radiation therapy (IGRT). This review summarizes clinical experience with volumetric and ultrasound based image-guidance for SBRT. Additionally, challenges and potential limitations of pre-treatment image-guidance are presented and discussed.

  9. Compact Gamma-Ray Imager for In-Vivo Gene Imaging

    SciTech Connect

    Greenwald, A. C.

    2000-06-01

    A compact, low-cost, gamma-ray imaging system is needed to study gene expression in small animals. State-of-the-art electronic imaging systems have insufficient resolution and animals must be sacrificed for detailed imaging that precludes time evolution studies. With improved electronics radioactive tracers attached to gene markers can be used to track the absorption and mobility of gene therapy medications in live animals. Other instrumentation being developed for medical applications does not have the response to match the radiation source for this work. The objective of this research was to develop thick film (Cd,Zn)Te detectors matched to the gamma ray energy of {sup 129}I. The detector would be a direct readout device using p-i-n diodes formed from the high Z material absorbing the radiation, with separate readout. Higher quality semiconducting material was expected from epitaxial growth on GaAs, a near lattice matched substrate. In practice, it was difficult to obtain material with high resistance and low leakage current. Spire Corporation achieved the goal of fabricating working detectors in (Cd,Zn)Te deposited on GaAs. The spectra of an alpha emitter ({sup 225}Am) was adequately resolved in thin film devices. Thick p-i-n diodes were fabricated but other processing problems prevented full demonstration of a gamma ray detector.

  10. Gene and Cell Therapies for the Failing Heart to Prevent Sudden Arrhythmic Death

    PubMed Central

    Sovari, Ali A.; Dudley, Samuel C.

    2013-01-01

    Current therapies for treatment and prevention of sudden cardiac death have certain limitations, and a search for new therapeutic approaches is desirable to reduce the burden of sudden arrhythmic death. Gene therapy and stem cell therapy have been investigated as new, valuable tools in treating cardiac diseases such as arrhythmias. In this review, the basics of each modality, important related experimental and clinical studies, and potential advantages and limitations of these treatments will be discussed. The future success of gene and cell therapy to become practical clinical tools greatly depends on our understanding of the mechanisms of ventricular arrhythmia and the mechanisms of action of gene and cell therapy. PMID:22858914

  11. Optoacoustic Imaging for Guiding and Monitoring HIFU Therapy

    NASA Astrophysics Data System (ADS)

    Chitnis, Parag V.; Brecht, Hans P.; Su, Richard; Oraevsky, Alexander A.

    2011-09-01

    Although high-intensity focused ultrasound (HIFU) has exciting potential for noninvasively treating tumors and cardiac diseases, its clinical acceptance is hindered by the lack of a reliable and cost-effective method of noninvasively guiding and monitoring the treatment. The present study investigated the feasibility of employing optoacoustic imaging (OAI) for guiding and monitoring HIFU therapy. OAI combines molecular specificity provided by optical imaging and the resolution provided by diagnostic ultrasound. A 3-D optoacoustic imaging system was used to visualize thermal lesions produced in excised tissue specimens and in vivo mice using high intensity focused ultrasound (HIFU). A 7.5 MHz surgical, focused transducer with a radius of curvature of 35 mm and an aperture of 23 mm generated HIFU. A pulsed laser, which could operate at 755 nm and 1064 nm, illuminated the specimens. Tomographic images were obtained using a 64 element curved array while the specimens were rotated incrementally. Images were acquired before and after HIFU exposure. The images were then combined to reconstruct 3-D volume images (voxel resolution 0.5 mm). Optoacoustic images using 1064-nm illumination provided visualization of HIFU lesions. The location and the extent of the lesions were confirmed upon dissection. These preliminary results demonstrate the potential of optoacoustic imaging to assess and monitor HIFU therapy.

  12. [Collaborative study on regulatory science for facilitating clinical development of gene therapy products for genetic diseases].

    PubMed

    Uchida, Eriko; Igarashi, Yuka; Sato, Yoji

    2014-01-01

    Gene therapy products are expected as innovative medicinal products for intractable diseases such as life-threatening genetic diseases and cancer. Recently, clinical developments by pharmaceutical companies are accelerated in Europe and the United States, and the first gene therapy product in advanced countries was approved for marketing authorization by the European Commission in 2012. On the other hand, more than 40 clinical studies for gene therapy have been completed or ongoing in Japan, most of them are conducted as clinical researches by academic institutes, and few clinical trials have been conducted for approval of gene therapy products. In order to promote the development of gene therapy products, revision of the current guideline and/or preparation of concept paper to address the evaluation of the quality and safety of gene therapy products are necessary and desired to clearly show what data should be submitted before First-in-Human clinical trials of novel gene therapy products. We started collaborative study with academia and regulatory agency to promote regulatory science toward clinical development of gene therapy products for genetic diseases based on lentivirus and adeno-associated virus vectors; National Center for Child Health and Development (NCCHD), Nippon Medical School and PMDA have been joined in the task force. At first, we are preparing pre-draft of the revision of the current gene therapy guidelines in this project. PMID:25707196

  13. Towards gene therapy based on femtosecond optical transfection

    NASA Astrophysics Data System (ADS)

    Antkowiak, M.; Torres-Mapa, M. L.; McGinty, J.; Chahine, M.; Bugeon, L.; Rose, A.; Finn, A.; Moleirinho, S.; Okuse, K.; Dallman, M.; French, P.; Harding, S. E.; Reynolds, P.; Gunn-Moore, F.; Dholakia, K.

    2012-06-01

    Gene therapy poses a great promise in treatment and prevention of a variety of diseases. However, crucial to studying and the development of this therapeutic approach is a reliable and efficient technique of gene and drug delivery into primary cell types. These cells, freshly derived from an organ or tissue, mimic more closely the in vivo state and present more physiologically relevant information compared to cultured cell lines. However, primary cells are known to be difficult to transfect and are typically transfected using viral methods, which are not only questionable in the context of an in vivo application but rely on time consuming vector construction and may also result in cell de-differentiation and loss of functionality. At the same time, well established non-viral methods do not guarantee satisfactory efficiency and viability. Recently, optical laser mediated poration of cell membrane has received interest as a viable gene and drug delivery technique. It has been shown to deliver a variety of biomolecules and genes into cultured mammalian cells; however, its applicability to primary cells remains to be proven. We demonstrate how optical transfection can be an enabling technique in research areas, such as neuropathic pain, neurodegenerative diseases, heart failure and immune or inflammatory-related diseases. Several primary cell types are used in this study, namely cardiomyocytes, dendritic cells, and neurons. We present our recent progress in optimizing this technique's efficiency and post-treatment cell viability for these types of cells and discuss future directions towards in vivo applications.

  14. Towards magnetic resonance imaging guided radiation therapy (MRIgRT)

    Microsoft Academic Search

    Teodor Marius Stanescu

    2008-01-01

    The goal of this work is to address key aspects of the magnetic resonance imaging guided radiation therapy (MRIgRT) process of cancer sites. MRIgRT is implemented by using a system comprised of a magnetic resonance imaging (MRI) scanner coupled with a radiation source, in our case a radiotherapy accelerator (Linac). The potential benefits of MRIgRT are the real-time tracking of

  15. Lung gene therapy—How to capture illumination from the light already present in the tunnel

    PubMed Central

    Xia, Emily; Munegowda, Manjunatha Ankathatti; Cao, Huibi; Hu, Jim

    2015-01-01

    Gene therapy has been considered as the most ideal medical intervention for genetic diseases because it is intended to target the cause of diseases instead of disease symptoms. Availability of techniques for identification of genetic mutations and for in vitro manipulation of genes makes it practical and attractive. After the initial hype in 1990s and later disappointments in clinical trials for more than a decade, light has finally come into the tunnel in recent years, especially in the field of eye gene therapy where it has taken big strides. Clinical trials in gene therapy for retinal degenerative diseases such as Leber’s congenital amaurosis (LCA) and choroideremia demonstrated clear therapeutic efficacies without apparent side effects. Although these successful examples are still rare and sporadic in the field, they provide the proof of concept for harnessing the power of gene therapy to treat genetic diseases and to modernize our medication. In addition, those success stories illuminate the path for the development of gene therapy treating other genetic diseases. Because of the differences in target organs and cells, distinct barriers to gene delivery exist in gene therapy for each genetic disease. It is not feasible for authors to review the current development in the entire field. Thus, in this article, we will focus on what we can learn from the current success in gene therapy for retinal degenerative diseases to speed up the gene therapy development for lung diseases, such as cystic fibrosis.

  16. Physiologic and metabolic safety of butyrylcholinesterase gene therapy in mice

    PubMed Central

    Murthy, Vishakantha; Gao, Yang; Geng, Liyi; LeBrasseur, Nathan; White, Tom; Parks, Robin J; Brimijoin, Stephen

    2014-01-01

    In continuing efforts to develop gene transfer of human butyrylcholinesterase (BChE) as therapy for cocaine addiction, we conducted wide-ranging studies of physiological and metabolic safety. For that purpose, mice were given injections of adeno-associated virus (AAV) vector or helper-dependent adenoviral (hdAD) vector encoding human or mouse BChE mutated for optimal cocaine hydrolysis. Age-matched controls received saline or AAV-luciferase control vector. At times when transduced BChE was abundant, physiologic and metabolic parameters in conscious animals were evaluated by non-invasive Echo-MRI and an automated “Comprehensive Laboratory Animal Monitoring System” (CLAMS). Despite high vector doses (up to 1013 particles per mouse) and high levels of transgene protein in the plasma (~ 1500-fold above baseline), the CLAMS apparatus revealed no adverse physiologic or metabolic effects. Likewise, body composition determined by Echo-MRI, and glucose tolerance remained normal. A CLAMS study of vector-treated mice given 40 mg/kg cocaine showed none of the physiologic and metabolic fluctuations exhibited in controls. We conclude that neither the tested vectors nor great excesses of circulating BChE affect general physiology directly, while they protect mice from disturbance by cocaine. Hence, viral gene transfer of BChE appears benign and worth exploring as a therapy for cocaine abuse and possibly other disorders as well. PMID:24892251

  17. Cell and gene therapy for Friedreich ataxia: progress to date.

    PubMed

    Evans-Galea, Marguerite V; Pébay, Alice; Dottori, Mirella; Corben, Louise A; Ong, Sze Hwee; Lockhart, Paul J; Delatycki, Martin B

    2014-08-01

    Neurodegenerative disorders such as Friedreich ataxia (FRDA) present significant challenges in developing effective therapeutic intervention. Current treatments aim to manage symptoms and thus improve quality of life, but none can cure, nor are proven to slow, the neurodegeneration inherent to this disease. The primary clinical features of FRDA include progressive ataxia and shortened life span, with complications of cardiomyopathy being the major cause of death. FRDA is most commonly caused by an expanded GAA trinucleotide repeat in the first intron of FXN that leads to reduced levels of frataxin, a mitochondrial protein important for iron metabolism. The GAA expansion in FRDA does not alter the coding sequence of FXN. It results in reduced production of structurally normal frataxin, and hence any increase in protein level is expected to be therapeutically beneficial. Recently, there has been increased interest in developing novel therapeutic applications like cell and/or gene therapies, and these cutting-edge applications could provide effective treatment options for FRDA. Importantly, since individuals with FRDA produce frataxin at low levels, increased expression should not elicit an immune response. Here we review the advances to date and highlight the future potential for cell and gene therapy to treat this debilitating disease. PMID:24749505

  18. Cancer targeting Gene-Viro-Therapy of liver carcinoma by dual-regulated oncolytic adenovirus armed with TRAIL gene

    Microsoft Academic Search

    X Cao; M Yang; R-C Wei; Y Zeng; J-F Gu; W-D Huang; D-Q Yang; H-L Li; M Ding; N Wei; K-J Zhang; B Xu; X-R Liu; Q-J Qian; X-Y Liu

    2011-01-01

    Liver cancer is a common and aggressive malignancy, but available treatment approaches remain suboptimal. Cancer targeting Gene-Viro-Therapy (CTGVT) has shown excellent anti-tumor effects in a preclinical study. CTGVT takes advantage of both gene therapy and virotherapy by incorporating an anti-tumor gene into an oncolytic virus vector. Potent anti-tumor activity is achieved by virus replication and exogenous expression of the anti-tumor

  19. The investigation of controlled release microchips, nanoparticles, and sirna for gene therapy in tissue engineering applications

    E-print Network

    Chern, Christina

    2009-05-15

    The study of drug delivery for the treatment of illnesses and injuries is an important area of pharmaceutical technology. A relatively new area of drug delivery being explored is gene therapy, which utilizes the idea that genes can be used...

  20. Hybrid Segmentation Framework for Tissue Images Containing Gene Expression Data

    E-print Network

    Ju, Tao

    Hybrid Segmentation Framework for Tissue Images Containing Gene Expression Data Musodiq Bello 1 that characterize the distribu- tion of gene expression in relation to a standard anatomical model are required. In this work, we propose a new automatic method that results in the segmentation of gene expression images

  1. Issues in image-guided therapy [A Look at . . .

    Microsoft Academic Search

    P. Haigron; Limin Luo; J.-L. Coatrieux

    2009-01-01

    M edical robotics, computer- assisted surgery (CAS), image-guided therapy (IGT), and the like emerged more than 20 years ago, and many advances have been made since. Conferences and workshops have been organized; scientific contributions, position papers, and patents have been published; new academic societies have been launched; and companies were created all over the world to propose methods, devices, and

  2. Optoacoustic Imaging for Guiding and Monitoring HIFU Therapy

    Microsoft Academic Search

    Parag V. Chitnis; Hans P. Brecht; Richard Su; Alexander A. Oraevsky

    2011-01-01

    Although high-intensity focused ultrasound (HIFU) has exciting potential for noninvasively treating tumors and cardiac diseases, its clinical acceptance is hindered by the lack of a reliable and cost-effective method of noninvasively guiding and monitoring the treatment. The present study investigated the feasibility of employing optoacoustic imaging (OAI) for guiding and monitoring HIFU therapy. OAI combines molecular specificity provided by optical

  3. Roadmap: Radiologic Imaging Sciences -Radiation Therapy (with AAS Radiologic Technology)

    E-print Network

    Sheridan, Scott

    Roadmap: Radiologic Imaging Sciences - Radiation Therapy (with AAS Radiologic Technology Social Sciences and domestic diversity; see note 1 US 10097 Destination Kent State: First Year Experience note 1; See Kent Core Summary Semester One: [15 Credit Hours] COMM 15000 Introduction to Human

  4. Roadmap: Radiologic Imaging Sciences -Radiation Therapy (with AAS Radiologic Technology)

    E-print Network

    Sheridan, Scott

    Roadmap: Radiologic Imaging Sciences - Radiation Therapy (with AAS Radiologic Technology Experience 1 Not required of transfer students with 25 credits; see note 1 Kent Core Requirements 6-8 See note 1; See Kent Core Summary Semester One: [18 Credit Hours] COMM 15000 Introduction to Human

  5. Gene transfer in human vestibular epithelia and the prospects for inner ear gene therapy.

    PubMed

    Kesser, Bradley W; Hashisaki, George T; Holt, Jeffrey R

    2008-05-01

    Transfer of exogenous genetic material into the mammalian inner ear using viral vectors has been characterized over the last decade. A number of different viral vectors have been shown to transfect the varying cell types of the nonprimate mammalian inner ear. Several routes of delivery have been identified for introduction of vectors into the inner ear while minimizing injury to existing structures and at the same time ensuring widespread distribution of the agent throughout the cochlea and the rest of the inner ear. These studies raise the possibility that gene transfer may be developed as a potential strategy for treating inner ear dysfunction in humans. Furthermore, a recent report showing successful transfection of excised human vestibular epithelia offers proof of principle that viral gene transfer is a viable strategy for introduction and expression of exogenous genetic material to restore function to the inner ear. Human vestibular epithelia were harvested from patients undergoing labyrinthectomy, either for intractable Ménière's disease or vestibular schwannoma resection, and cultured for as long as 5 days. In those experiments, recombinant, multiply-deleted, replication-deficient adenoviral vectors were used to transfect and express a reporter gene as well as the functionally relevant gene, wild-type KCNQ4, a potassium channel gene that when mutated causes the autosomal dominant HL DFNA2.Here, we review the current state of viral-mediated gene transfer in the inner ear and discuss different viral vectors, routes of delivery, and potential applications of gene therapy. Emphasis is placed on experiments demonstrating viral transfection of human inner ear tissue and implications of these findings and for the future of gene therapy in the human inner ear. PMID:18300702

  6. Gene transfer to sperm and testis: future prospects of gene therapy for male infertility.

    PubMed

    Kojima, Yoshiyuki; Kurokawa, Satoshi; Mizuno, Kentaro; Umemoto, Yukihiro; Sasaki, Shoichi; Hayashi, Yutaro; Kohri, Kenjiro

    2008-04-01

    Male infertility has been considered a major contributory factor to infertility. The causes of spermatogenetic failure found in most cases of male infertility remain largely idiopathic. Unfortunately, there is no effective treatment to improve spermatogenesis for idiopathic male infertility patients. Intracytoplasmic sperm injection (ICSI) is the current treatment of choice for severe male infertility and has brought the joy of childbearing to couples for whom it was previously impossible; however, several problems exist with this treatment. In addition, if there are no spermatozoa in the testis of these patients, they do not have paternity potential even if ICSI is conducted. Ultimately, fertilization is better in vivo than in vitro. Recently, on the other hand, gene transfer to sperm and testis has been developed to find more effective and simple methods to obtain transgenic animals. This technique has the potential to be the most useful approach for the future treatment of male infertility. In this review, we will give an overview of the recent advanced technique of gene transfer to sperm and testis, and discuss the future prospects of gene therapy for the treatment of male infertility. In conclusion, although more investigations on the mechanism of spermatogenesis and male infertility and the establishment of techniques for more efficient and safer gene transfer to the sperm and testis will be needed, gene therapy will enable a revolutionary advance for reproductive treatment and provide great benefit for patients with male infertility in the future. PMID:18393832

  7. Recent Development of Silica Nanoparticles as Delivery Vectors for Cancer Imaging and Therapy

    PubMed Central

    Wu, Xu; Wu, Min; Xiaojun Zhao, Julia

    2013-01-01

    In spite of significant advances in early detection and combined treatments, a number of cancers are often diagnosed at advanced stages and thereby carry a poor prognosis. Developing novel prognostic biomarkers and targeted therapies may offer alternatives for cancer diagnosis and treatment. Recent rapid development of nanomaterials, such as silica based nanoparticles (SiNPs), can just render such a promise. In this article, we attempt to summarize the recent progress of SiNPs in tumor research as a novel delivery vector. SiNP-assisted imaging techniques are used in cancer diagnosis both in vitro and in vivo. Meanwhile, SiNP-mediated drug delivery can efficiently treat tumor by carrying chemotherapeutic agents, photosensitizers, photothermal agents, siRNA, and gene therapeutic agents. Finally, SiNPs that contain at least two different functional agents may be more powerful for both tumor imaging and therapy. PMID:24028896

  8. Imaging and imaging-guided therapy in severe acute pancreatitis

    Microsoft Academic Search

    Kenneth D. Carpenter; Patrick C. Freeny

    1996-01-01

    Effective utilization of imaging in patients with severe acute pancreatitis requires an understanding of the subtypes and\\u000a complications of pancreatitis. Imaging, particularly computed tomography, can confirm the diagnosis of pancreatitis, identify\\u000a local complications, offer prognostic information, and guide therapeutic interventions. Conventional radiography, ultrasound,\\u000a endoscopic retrograde cholangiopancreatography, and magnetic resonance imaging have important adjunctive roles in the evaluation\\u000a and treatment of

  9. Near-infrared dye bound albumin with separated imaging and therapy wavelength channels for imaging-guided photothermal therapy.

    PubMed

    Chen, Qian; Wang, Chao; Zhan, Zhixiong; He, Weiwei; Cheng, Zhenping; Li, Youyong; Liu, Zhuang

    2014-09-01

    Development of theranostic agent for imaging-guided photothermal therapy has been of great interest in the field of nanomedicine. However, if fluorescent imaging and photothermal ablation are conducted with the same wavelength of light, the requirements of the agent's quantum yield (QY) for imaging and therapy are controversial. In this work, our synthesized near-infrared dye, IR825, is bound with human serum albumin (HSA), forming a HSA-IR825 complex with greatly enhanced fluorescence under 600 nm excitation by as much as 100 folds compared to that of free IR825, together with a rather high absorbance but low fluorescence QY at 808 nm. Since high QY that is required for fluorescence imaging would result in reduced photothermal conversion efficiency, the unique optical behavior of HSA-IR825 enables imaging and photothermal therapy at separated wavelengths both with optimized performances. We thus use HSA-IR825 for imaging-guided photothermal therapy in an animal tumor model. As revealed by in vivo fluorescence imaging, HSA-IR825 upon intravenous injection shows high tumor uptake likely owing to the enhanced permeability and retention effect, together with low levels of retentions in other organs. While HSA is an abundant protein in human serum, IR825 is able to be excreted by renal excretion as evidenced by high-performance liquid chromatography (HPLC). In vivo tumor treatment experiment is finally carried out with HSA-IR825, achieving 100% of tumor ablation in mice using a rather low dose of IR825. Our work presents a safe, simple, yet imageable photothermal nanoprobe, promising for future clinical translation in cancer treatment. PMID:24957292

  10. Morphological restoration of gonadotrope population by thymulin gene therapy in nude mice

    PubMed Central

    Reggiani, Paula; Martines, Eliana; Ferese, Celia; Goya, Rodolfo; Cónsole, Gloria

    2009-01-01

    Summary The integrity of the thymus during the first week of life is necessary for a proper maturation of the pituitary-gonadal axis as revealed by the significantly reduced levels of circulating gonadotropins in congenitally athymic (nude) mice. In the present work we studied the impact of athymia and the effect of neonatal thymulin gene therapy on the pituitaries of adult nude mice. Also circulating thymulin and gonadotropin levels were evaluated. We used an adenoviral vector expressing a synthetic gene for the thymic peptide thymulin (metFTS) termed RAd-FTS. On postnatal day 1, each experimental heterozygous (nu/+) and homozygous (nu/nu) pup of both sexes received a single bilateral i.m. injection of RAd-FTS or RAd-GFP/TK, a control vector expressing green fluorescent protein. On postnatal days 51-52, mice were bled and sacrificed, their pituitaries were immediately dissected, fixed and immunostained. Morphometry was performed by means of an image analysis system. The following parameters were calculated: volume density (VD: cell area/reference area), cell density (CD: number of cells/reference area), and cell size (expressed in ?m2). Serum thymulin levels were measured by a bioassay and gonadotropin levels were assayed by RIA. It was observed that neonatal thymulin gene therapy in the athymic mice restored their serum thymulin levels and prevented the reduction in circulating gonadotropin levels. The histometrical analysis revealed that the treatment prevented the reduction in gonadotrope CD and the VD in athymic mice. Our data suggest that thymulin gene therapy may be an effective strategy to approach reproductive deficits associated with endocrine thymus dysfunction. PMID:19337971

  11. original article The American Society of Gene Therapy Molecular Therapy vol. 16 no. 9, 16371642 sep. 2008 1637

    E-print Network

    Cai, Long

    inactivation results in cancer cell selectivity; cellular thymidine kinase is an E2F- responsive geneoriginal article© The American Society of Gene Therapy Molecular Therapy vol. 16 no. 9, 1637 cancer cells having cell-cycle defects, through replication, cell lysis, and spread within tumors

  12. Optical Imaging, Photodynamic Therapy and Optically Triggered Combination Treatments.

    PubMed

    Mallidi, Srivalleesha; Spring, Bryan Q; Chang, Sung; Vakoc, Benjamin; Hasan, Tayyaba

    2015-01-01

    Optical imaging is becoming increasingly promising for real-time image-guided resections, and combined with photodynamic therapy (PDT), a photochemistry-based treatment modality, optical approaches can be intrinsically "theranostic." Challenges in PDT include precise light delivery, dosimetry, and photosensitizer tumor localization to establish tumor selectivity, and like all other modalities, incomplete treatment and subsequent activation of molecular escape pathways are often attributable to tumor heterogeneity. Key advances in molecular imaging, target-activatable photosensitizers, and optically active nanoparticles that provide both cytotoxicity and a drug release mechanism have opened exciting avenues to meet these challenges. The focus of the review is optical imaging in the context of PDT, but the general principles presented are applicable to many of the conventional approaches to cancer management. We highlight the role of optical imaging in providing structural, functional, and molecular information regarding photodynamic mechanisms of action, thereby advancing PDT and PDT-based combination therapies of cancer. These advances represent a PDT renaissance with increasing applications of clinical PDT as a frontline cancer therapy working in concert with fluorescence-guided surgery, chemotherapy, and radiation. PMID:26049699

  13. Transposons: cut-and-paste gene delivery From mutagenesis to gene therapy for hemophilia, transposonsmobile genetic elementshave proven

    E-print Network

    Cai, Long

    Transposons: cut-and-paste gene delivery From mutagenesis to gene therapy for hemophilia Smith takes a look at some present offerings of transposon products and the promise of applications genetic elements called transposons. Transposons, also known as jumping genes, are sequences of DNA

  14. Tmc gene therapy restores auditory function in deaf mice.

    PubMed

    Askew, Charles; Rochat, Cylia; Pan, Bifeng; Asai, Yukako; Ahmed, Hena; Child, Erin; Schneider, Bernard L; Aebischer, Patrick; Holt, Jeffrey R

    2015-07-01

    Genetic hearing loss accounts for up to 50% of prelingual deafness worldwide, yet there are no biologic treatments currently available. To investigate gene therapy as a potential biologic strategy for restoration of auditory function in patients with genetic hearing loss, we tested a gene augmentation approach in mouse models of genetic deafness. We focused on DFNB7/11 and DFNA36, which are autosomal recessive and dominant deafnesses, respectively, caused by mutations in transmembrane channel-like 1 (TMC1). Mice that carry targeted deletion of Tmc1 or a dominant Tmc1 point mutation, known as Beethoven, are good models for human DFNB7/11 and DFNA36. We screened several adeno-associated viral (AAV) serotypes and promoters and identified AAV2/1 and the chicken ?-actin (Cba) promoter as an efficient combination for driving the expression of exogenous Tmc1 in inner hair cells in vivo. Exogenous Tmc1 or its closely related ortholog, Tmc2, were capable of restoring sensory transduction, auditory brainstem responses, and acoustic startle reflexes in otherwise deaf mice, suggesting that gene augmentation with Tmc1 or Tmc2 is well suited for further development as a strategy for restoration of auditory function in deaf patients who carry TMC1 mutations. PMID:26157030

  15. Systematic measurements of whole-body imaging dose distributions in image-guided radiation therapy

    SciTech Connect

    Haelg, Roger A.; Besserer, Juergen; Schneider, Uwe [Radiotherapie Hirslanden AG, Institute for Radiotherapy, Aarau 5000 (Switzerland); Vetsuisse Faculty, University of Zurich, Zurich 8057 (Switzerland) and Radiotherapie Hirslanden AG, Institute for Radiotherapy, Aarau 5000 (Switzerland)

    2012-12-15

    Purpose: The full benefit of the increased precision of contemporary treatment techniques can only be exploited if the accuracy of the patient positioning is guaranteed. Therefore, more and more imaging modalities are used in the process of the patient setup in clinical routine of radiation therapy. The improved accuracy in patient positioning, however, results in additional dose contributions to the integral patient dose. To quantify this, absorbed dose measurements from typical imaging procedures involved in an image-guided radiation therapy treatment were measured in an anthropomorphic phantom for a complete course of treatment. The experimental setup, including the measurement positions in the phantom, was exactly the same as in a preceding study of radiotherapy stray dose measurements. This allows a direct combination of imaging dose distributions with the therapy dose distribution. Methods: Individually calibrated thermoluminescent dosimeters were used to measure absorbed dose in an anthropomorphic phantom at 184 locations. The dose distributions from imaging devices used with treatment machines from the manufacturers Accuray, Elekta, Siemens, and Varian and from computed tomography scanners from GE Healthcare were determined and the resulting effective dose was calculated. The list of investigated imaging techniques consisted of cone beam computed tomography (kilo- and megavoltage), megavoltage fan beam computed tomography, kilo- and megavoltage planar imaging, planning computed tomography with and without gating methods and planar scout views. Results: A conventional 3D planning CT resulted in an effective dose additional to the treatment stray dose of less than 1 mSv outside of the treated volume, whereas a 4D planning CT resulted in a 10 times larger dose. For a daily setup of the patient with two planar kilovoltage images or with a fan beam CT at the TomoTherapy unit, an additional effective dose outside of the treated volume of less than 0.4 mSv and 1.4 mSv was measured, respectively. Using kilovoltage or megavoltage radiation to obtain cone beam computed tomography scans led to an additional dose of 8-46 mSv. For treatment verification images performed once per week using double exposure technique, an additional effective dose of up to 18 mSv was measured. Conclusions: Daily setup imaging using kilovoltage planar images or TomoTherapy megavoltage fan beam CT imaging can be used as a standard procedure in clinical routine. Daily kilovoltage and megavoltage cone beam computed tomography setup imaging should be applied on an individual or indication based protocol. Depending on the imaging scheme applied, image-guided radiation therapy can be administered without increasing the dose outside of the treated volume compared to therapies without image guidance.

  16. Gene therapy in liver diseases: state-of-the-art and future perspectives.

    PubMed

    Domvri, Kalliopi; Zarogoulidis, Paul; Porpodis, Konstantinos; Koffa, Maria; Lambropoulou, Maria; Kakolyris, Stylianos; Kolios, George; Zarogoulidis, Konstantinos; Chatzaki, Ekaterini

    2012-12-01

    Gene therapy is a fundamentally novel therapeutic approach that involves introducing genetic material into target cells in order to fight or prevent disease. A number of different strategies of gene therapy are tested at experimental and clinical levels, including: a) replacing a mutated gene that causes disease with a healthy copy of the gene, b) inactivating a mutated gene that its improper function causes pathogenesis, c) introducing a new gene coding a therapeutic compound to fight a disease, d) introducing to the target organ an enzyme converting an inactive pro-drug to its cytotoxic metabolite. In gene therapy, the transcriptional machinery of the patient is used to produce the active factor that exerts the intended therapeutic effect, ideally in a permanent, tissue-specific and manageable way. The liver is a major target for gene therapy, presenting inherited metabolic defects of single-gene etiology, but also severe multifactorial pathologies with limited therapeutic options such as hepatocellular carcinoma. The initial promising results from gene therapy strategies in liver diseases were followed by skepticism on the actual clinical value due to specificity, efficacy, toxicity and immune limitations, but are recently re-evaluated due to progress in vector technology and monitoring techniques. The significant amount of experimental data along with the available information from clinical trials are systematically reviewed here and presented per pathological entity. Finally, future perspectives of gene therapy protocols in hepatology are summarized. PMID:22845887

  17. Progress and prospects: Immunobiology of gene therapy for neurodegenerative disease: prospects and risks

    Microsoft Academic Search

    M M McMenamin; M J A Wood; MJA Wood

    2010-01-01

    Gene therapy for neurological, and in particular neurodegenerative, disease is now a reality. A number of early phase clinical trials have been completed and several are currently in progress. In view of this, it is critically important to evaluate the immunological risk associated with neurological gene therapy, which has clear implications for trial safety and efficacy. Moreover, it is imperative

  18. Intratumoral gene therapy for non-small cell lung cancer: current status and future directions

    Microsoft Academic Search

    B. Neyns; M. Noppen

    2003-01-01

    Intratumoral gene therapy for non-small cell lung cancer: current status and future directions. B. Neyns, M. Noppen. Major advances in the field of molecular genetics and cancer biology have allowed for the development of ratio- nally designed anti-cancer strategies. When genetic mate- rial (DNA or RNA) is used for this purpose, this approach is called gene therapy. Cancer cells are

  19. HUMAN GENE THERAPY 17:10771094 (November 2006) Mary Ann Liebert, Inc.

    E-print Network

    Kay, Mark A.

    HUMAN GENE THERAPY 17:1077­1094 (November 2006) © Mary Ann Liebert, Inc. Molecular Analysis to integration of gene therapy vectors into the host genome have raised concerns about the genetic manipulation of somatic cells. Previously, it was demonstrated that integrase C31 derived from a Streptomyces phage

  20. Hum Gene Ther . Author manuscript Developing cell therapy techniques for respiratory disease: intratracheal

    E-print Network

    Paris-Sud XI, Université de

    Hum Gene Ther . Author manuscript Page /1 15 Developing cell therapy techniques for respiratory , Universit de Nantesé , Nantes,FR In-Cell-Art3 44000 Nantes,FR Service d Anatomo-Pathologie4 ' CHU Nantes, in a murine model of acute epithelial airway injury already used in gene therapy experiments on cystic

  1. Gene Therapy for Brain Cancer: Combination Therapies Provide Enhanced Efficacy and Safety

    PubMed Central

    Candolfi, Marianela; Kroeger, Kurt M.; Muhammad, A.K.M.G.; Yagiz, Kader; Farrokhi, Catherine; Pechnick, Robert N.; Lowenstein, Pedro R.; Castro, Maria G.

    2009-01-01

    Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive nature, the proximity of the tumor to vital brain structures often preventing total resection, and the resistance of recurrent GBM to conventional radiotherapy and chemotherapy. Gene therapy has been proposed as a useful adjuvant for GBM, to be used in conjunction with current treatment. Work from our laboratory has shown that combination of conditional cytotoxic with immunotherapeutic approaches for the treatment of GBM elicits regression of large intracranial tumor masses and anti-tumor immunological memory in syngeneic rodent models of GBM. In this review we examined the currently available animal models for GBM, including rodent transplantable models, endogenous rodent tumor models and spontaneous GBM in dogs. We discuss non-invasive surrogate end points to assess tumor progression and therapeutic efficacy, such as behavioral tests and circulating biomarkers. Growing preclinical and clinical data contradict the old dogma that cytotoxic anti-cancer therapy would lead to an immune-suppression that would impair the ability of the immune system to mount an anti-tumor response. The implications of the findings reviewed indicate that combination of cytotoxic therapy with immunotherapy will lead to synergistic antitumor efficacy with reduced neurotoxicity and supports the clinical implementation of combined cytotoxic-immunotherapeutic strategies for the treatment of patients with GBM. PMID:19860655

  2. [Novel therapy for malignant lymphoma: adoptive immuno-gene therapy using chimeric antigen receptor(CAR)-expressing T lymphocytes].

    PubMed

    Ozawa, Keiya

    2014-03-01

    Adoptive T-cell therapy using chimeric antigen receptor (CAR) technology is a novel approach to cancer immuno-gene therapy. CARs are hybrid proteins consisting of target-antigen-specific single-chain antibody fragment fused to intracellular T-cell activation domains (CD28 or CD137/CD3 zeta receptor). CAR-expressing engineered T lymphocytes can directly recognize and kill tumor cells in an HLA independent manner. In the United States, promising results have been obtained in the clinical trials of adoptive immuno-gene therapy using CD19-CAR-T lymphocytes for the treatment of refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL). In this review article, CD19-CAR-T gene therapy for refractory B-cell non-Hodgkin lymphoma is discussed. PMID:24724418

  3. Cell and Gene Therapy Approaches for Cardiac Vascularization

    PubMed Central

    Melly, Ludovic; Boccardo, Stefano; Eckstein, Friedrich; Banfi, Andrea; Marsano, Anna

    2012-01-01

    Despite encouraging preclinical results for therapeutic angiogenesis in ischemia, a suitable approach providing sustained, safe and efficacious vascular growth in the heart is still lacking. Vascular Endothelial Growth Factor (VEGF) is the master regulator of angiogenesis, but it also can easily induce aberrant and dysfunctional vascular growth if its expression is not tightly controlled. Control of the released level in the microenvironment around each cell in vivo and its distribution in tissue are critical to induce stable and functional vessels for therapeutic angiogenesis. The present review discusses the limitations and perspectives of VEGF gene therapy and of different cell-based approaches for the implementation of therapeutic angiogenesis in the treatment of cardiac ischemia. PMID:24710537

  4. Rapamycin Enhances Adenovirus-Mediated Cancer Imaging and Therapy in Pre-Immunized Murine Hosts

    PubMed Central

    Jiang, Ziyue Karen; Johnson, Mai; Moughon, Diana L.; Kuo, Jennifer; Sato, Makoto; Wu, Lily

    2013-01-01

    Tumor-specific adenoviral vectors comprise a fruitful gene-based diagnostic imaging and therapy research area for advanced stage of cancer, including metastatic disease. However, clinical translation of viral vectors has encountered considerable obstacles, largely due to host immune responses against the virus. Here, we explored the utilization of an immunosuppressant, rapamycin, to circumvent the anti-adenovirus immunity in immunocompetent murine prostate cancer models. Rapamycin diminished adenoviral-induced acute immune response by inhibiting NF-?B activation; it also reduced the scale and delayed the onset of inflammatory cytokine secretion. Further, we found that rapamycin abrogated anti-adenovirus antibody production and retarded the function of myeloid cells and lymphocytes that were activated upon viral administration in pre-immunized hosts. Thus, the co-administration of rapamycin prolonged and enhanced adenovirus-delivered transgene expression in vivo, and thereby augmented the imaging capability of adenoviral vectors in both bioluminescent and positron emission tomography modalities. Furthermore, we showed that despite an excellent response of cancer cells to a cytotoxic gene therapeutic vector in vitro, only minimal therapeutic effects were observed in vivo in pre-immunized mice. However, when we combined gene therapy with transient immunosuppression, complete tumor growth arrest was achieved. Overall, transient immunosuppression by rapamycin was able to boost the diagnostic utility and therapeutic potentials of adenoviral vectors. PMID:24023896

  5. An overview of the Tenth International Conference on Cancer Gene Therapy.

    PubMed

    Scanlon, K J

    2001-11-01

    Dr. Scanlon, the new president (2001-2002) of the International Society of Cancer Gene Therapy, gave the conference summary and an overview of gene therapy in the new millennium. The conference reflected the progress made in the development of new promoters and improved delivery systems for gene therapy. Many presentations and posters focused on the progress in these areas. These scientific findings in the field of gene therapy may ultimately be exploited in the future developments of stem cell research. Conversely, challenges still remain before gene therapy will significantly impact cancer. The basic science of the cancer model systems lacked the ability to reflect the clinical reality of patient treatment. This places the burden on the physicians to be more vigilant to subtle changes in patient response that were not observed in the preclinical models. The bystander effect has yet to be fully understood and needs further clinical validation. Systemic delivery needs to be further addressed before a marketable product can be developed. The delivery systems discussed at the conference lack the ability to achieve pharmacological doses of therapeutic genes in the target tissue. Until these challenges are addressed, gene therapy will remain on the sidelines as a cancer modality. Yet, the field should be optimistic with the current progress. The future influences of the digital and genomic revolution in the health care industry will certainly impact the design of products for gene therapy. Dr. Scanlon concluded that the education of scientists would cross over into diverse disciplines so that novel observations will be exploited for new therapies. This gene therapy series will continue with the International Conference on the Gene Therapy of Cancer, scheduled for December 13-15, 2001, in San Diego, CA. PMID:11773981

  6. Feasibility of a predictive model of Hsp70b-activated gene therapy protein expression during ultrasound hyperthermia

    E-print Network

    Silcox, Christina Elise

    2014-01-01

    Gene therapy has been heralded as a possible approach to a variety of diseases and conditions, ranging from cancer and heart disease to blindness and neurodegenerative diseases. However, progress in gene therapy requires ...

  7. Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy

    PubMed Central

    Yu, Mi Kyung; Park, Jinho; Jon, Sangyong

    2012-01-01

    Nanomaterials offer new opportunities for cancer diagnosis and treatment. Multifunctional nanoparticles harboring various functions including targeting, imaging, therapy, and etc have been intensively studied aiming to overcome limitations associated with conventional cancer diagnosis and therapy. Of various nanoparticles, magnetic iron oxide nanoparticles with superparamagnetic property have shown potential as multifunctional nanoparticles for clinical translation because they have been used asmagnetic resonance imaging (MRI) constrast agents in clinic and their features could be easily tailored by including targeting moieties, fluorescence dyes, or therapeutic agents. This review summarizes targeting strategies for construction of multifunctional nanoparticles including magnetic nanoparticles-based theranostic systems, and the various surface engineering strategies of nanoparticles for in vivo applications. PMID:22272217

  8. Functionalized Gold Nanorods for Tumor Imaging and Targeted Therapy

    PubMed Central

    Gui, Chen; Cui, Da-xiang

    2012-01-01

    Gold nanorods, as an emerging noble metal nanomaterial with unique properties, have become the new exciting focus of theoretical and experimental studies in the past few years. The structure and function of gold nanorods, especially their biocompatibility, optical property, and photothermal effects, have been attracting more and more attention. Gold nanorods exhibit great potential in applications such as tumor molecular imaging and photothermal therapy. In this article, we review some of the main advances made over the past few years in the application of gold nanorods in surface functionalization, molecular imaging, and photothermal therapy. We also explore other prospective applications and discuss the corresponding concepts, issues, approaches, and challenges, with the aim of stimulating broader interest in gold nanorod-based nanotechnology and improving its practical application. PMID:23691482

  9. Imaging across the Life Span: Innovations in Imaging and Therapy for Gynecologic Cancer

    PubMed Central

    Xu-Welliver, Meng; Yuh, William T. C.; Fielding, Julia R.; Macura, Katarzyna J.; Huang, Zhibin; Ayan, Ahmet S.; Backes, Floor J.; Jia, Guang; Moshiri, Mariam; Zhang, Jun

    2014-01-01

    The focus of this article is radiation therapy for gynecologic cancers, with emphasis on imaging-based treatment planning and delivery. For the various gynecologic cancers, radiation oncologists rely on essential clinical information to triage treatment options, and various imaging studies are performed for treatment planning and radiation therapy delivery. A practical approach is provided to help radiologists tailor their reports for the needs of their radiation oncology and gynecologic oncology colleagues, to optimize multidisciplinary care for patients with gynecologic cancer. Template radiology reports are proposed to address the specific information needs of oncologists at each phase—before, during, and after treatment. Fueled by the rapid progress in engineering and computer sciences during the past 2 decades, remarkable advances have been made in anatomic, functional, and molecular imaging and in radiation treatment planning and delivery in patients with gynecologic cancer. Radiation therapy has evolved from a nontargeted approach to a precisely targeted, highly conformal treatment modality, to further improve treatment outcomes and reduce morbidity. High-quality imaging has become essential for staging of the disease, delineation of tumor extent for treatment planning and delivery, and monitoring therapy response. Anatomic and functional imaging has also been shown to provide prognostic information that allows clinicians to tailor therapy on the basis of personalized patient information. This field is an area of active research, and future clinical trials are warranted to validate preliminary results in the field. ©RSNA, 2014 PMID:25019442

  10. Lentiviral Vectors in Gene Therapy: Their Current Status and Future Potential

    Microsoft Academic Search

    David Escors; Karine Breckpot

    2010-01-01

    The concept of gene therapy originated in the mid twentieth century and was perceived as a revolutionary technology with the\\u000a promise to cure almost any disease of which the molecular basis was understood. Since then, several gene vectors have been\\u000a developed and the feasibility of gene therapy has been shown in many animal models of human disease. However, clinical efficacy

  11. A gene therapy approach to accelerating bone healingEvaluation of gene expression in a New Zealand white rabbit model

    Microsoft Academic Search

    Axel W. A. Baltzer; Christian Lattermann; Janey D. Whalen; Stefan Braunstein; Paul D. Robbins; Christopher H. Evans

    1999-01-01

    It has been demonstrated that BMPs, IGFs, and TGF?s improve the process of bone healing in vivo. We have suggested the use\\u000a of gene therapy as a possible way to deliver growth factors to fracture sites in order to improve repair. The aim of this\\u000a study was to develop a minimally invasive gene therapy approach to treat bone injuries locally

  12. Combinatorial gene therapy renders increased survival in cirrhotic rats

    PubMed Central

    2010-01-01

    Background Liver fibrosis ranks as the second cause of death in México's productive-age population. This pathology is characterized by acummulation of fibrillar proteins in hepatic parenchyma causing synthetic and metabolic disfunction. Remotion of excessive fibrous proteins might result in benefit for subjects increasing survival index. The goal of this work was to find whether the already known therapeutical effect of human urokinase Plasminogen Activator and human Matrix Metalloprotease 8 extends survival index in cirrhotic animals. Methods Wistar rats (80 g) underwent chronic intoxication with CCl4: mineral oil for 8 weeks. Cirrhotic animals were injected with a combined dose of Ad-delta-huPA plus Ad-MMP8 (3 × 1011 and 1.5 × 1011 vp/Kg, respectively) or with Ad-beta-Gal (4.5 × 1011) and were killed after 2, 4, 6, 8 and 10 days. Then, liver and serum were collected. An additional set of cirrhotic animals injected with combined gene therapy was also monitored for their probability of survival. Results Only the cirrhotic animals treated with therapeutical genes (Ad-delta-huPA+Ad-MMP-8) showed improvement in liver fibrosis. These results correlated with hydroxyproline determinations. A significant decrement in alpha-SMA and TGF-beta1 gene expression was also observed. Cirrhotic rats treated with Ad-delta-huPA plus Ad-MMP8 had a higher probability of survival at 60 days with respect to Ad-beta-Gal-injected animals. Conclusion A single administration of Ad-delta-huPA plus Ad-MMP-8 is efficient to induce fibrosis regression and increase survival in experimental liver fibrosis. PMID:20509929

  13. Gene and cell therapy for children--new medicines, new challenges?

    PubMed

    Buckland, Karen F; Bobby Gaspar, H

    2014-06-01

    The range of possible gene and cell therapy applications is expanding at an extremely rapid rate and advanced therapy medicinal products (ATMPs) are currently the hottest topic in novel medicines, particularly for inherited diseases. Paediatric patients stand to gain enormously from these novel therapies as it now seems plausible to develop a gene or cell therapy for a vast number of inherited diseases. There are a wide variety of potential gene and cell therapies in various stages of development. Patients who received first gene therapy treatments for primary immune deficiencies (PIDs) are reaching 10 and 15 years post-treatment, with robust and sustained immune recovery. Cell therapy clinical trials are underway for a variety of tissues including corneal, retinal and muscle repair and islet cell transplantation. Various cell therapy approaches are also being trialled to enhance the safety of bone marrow transplants, which should improve survival rates in childhood cancers and PIDs. Progress in genetic engineering of lymphocyte populations to target and kill cancerous cells is also described. If successful these ATMPs may enhance or replace the existing chemo-ablative therapy for several paediatric cancers. Emerging applications of gene therapy now include skin and neurological disorders such as epidermolysis bullosa, epilepsy and leukodystrophy. Gene therapy trials for haemophilia, muscular dystrophy and a range of metabolic disorders are underway. There is a vast array of potential advanced therapy medicinal products (ATMPs), and these are likely to be more cost effective than existing medicines. However, the first clinical trials have not been without setbacks and some of the key adverse events are discussed. Furthermore, the arrival of this novel class of therapies brings many new challenges for the healthcare industry. We present a summary of the key non-clinical factors required for successful delivery of these potential treatments. Technological advances are needed in vector design, raw material manufacture, cell culture and transduction methodology, and particularly in making all these technologies readily scalable. PMID:24583376

  14. GINI: From ISH Images to Gene Interaction Networks

    PubMed Central

    Puniyani, Kriti; Xing, Eric P.

    2013-01-01

    Accurate inference of molecular and functional interactions among genes, especially in multicellular organisms such as Drosophila, often requires statistical analysis of correlations not only between the magnitudes of gene expressions, but also between their temporal-spatial patterns. The ISH (in-situ-hybridization)-based gene expression micro-imaging technology offers an effective approach to perform large-scale spatial-temporal profiling of whole-body mRNA abundance. However, analytical tools for discovering gene interactions from such data remain an open challenge due to various reasons, including difficulties in extracting canonical representations of gene activities from images, and in inference of statistically meaningful networks from such representations. In this paper, we present GINI, a machine learning system for inferring gene interaction networks from Drosophila embryonic ISH images. GINI builds on a computer-vision-inspired vector-space representation of the spatial pattern of gene expression in ISH images, enabled by our recently developed system; and a new multi-instance-kernel algorithm that learns a sparse Markov network model, in which, every gene (i.e., node) in the network is represented by a vector-valued spatial pattern rather than a scalar-valued gene intensity as in conventional approaches such as a Gaussian graphical model. By capturing the notion of spatial similarity of gene expression, and at the same time properly taking into account the presence of multiple images per gene via multi-instance kernels, GINI is well-positioned to infer statistically sound, and biologically meaningful gene interaction networks from image data. Using both synthetic data and a small manually curated data set, we demonstrate the effectiveness of our approach in network building. Furthermore, we report results on a large publicly available collection of Drosophila embryonic ISH images from the Berkeley Drosophila Genome Project, where GINI makes novel and interesting predictions of gene interactions. Software for GINI is available at http://sailing.cs.cmu.edu/Drosophila_ISH_images/ PMID:24130465

  15. Chimeric adeno-associated virus and bacteriophage: a potential targeted gene therapy vector for malignant glioma.

    PubMed

    Asavarut, Paladd; O'Neill, Kevin; Syed, Nelofer; Hajitou, Amin

    2014-09-01

    The incipient development of gene therapy for cancer has fuelled its progression from bench to bedside in mere decades. Of all malignancies that exist, gliomas are the largest class of brain tumors, and are renowned for their aggressiveness and resistance to therapy. In order for gene therapy to achieve clinical success, a multitude of barriers ranging from glioma tumor physiology to vector biology must be overcome. Many viral gene delivery systems have been subjected to clinical investigation; however, with highly limited success. In this review, the current progress and challenges of gene therapy for malignant glioma are discussed. Moreover, we highlight the hybrid adeno-associated virus and bacteriophage vector as a potential candidate for targeted gene delivery to brain tumors. PMID:25375341

  16. Intratumoral gene therapy versus intravenous gene therapy for distant metastasis control with 2-diethylaminoethyl-dextran methyl methacrylate copolymer non-viral vector-p53.

    PubMed

    Baliaka, A; Zarogoulidis, P; Domvri, K; Hohenforst-Schmidt, W; Sakkas, A; Huang, H; Le Pivert, P; Koliakos, G; Koliakou, E; Kouzi-Koliakos, K; Tsakiridis, K; Chioti, A; Siotou, E; Cheva, A; Zarogoulidis, K; Sakkas, L

    2014-02-01

    Lung cancer still remains to be challenged by novel treatment modalities. Novel locally targeted routes of administration are a methodology to enhance treatment and reduce side effects. Intratumoral gene therapy is a method for local treatment and could be used either in early-stage lung cancer before surgery or at advanced stages as palliative care. Novel non-viral vectors are also in demand for efficient gene transfection to target local cancer tissue and at the same time protect the normal tissue. In the current study, C57BL/6 mice were divided into three groups: (a) control, (b) intravenous and (c) intatumoral gene therapy. The novel 2-Diethylaminoethyl-Dextran Methyl Methacrylate Copolymer Non-Viral Vector (Ryujyu Science Corporation) was conjugated with plasmid pSicop53 from the company Addgene for the first time. The aim of the study was to evaluate the safety and efficacy of targeted gene therapy in a Lewis lung cancer model. Indeed, although the pharmacokinetics of the different administration modalities differs, the intratumoral administration presented increased survival and decreased distant metastasis. Intratumoral gene therapy could be considered as an efficient local therapy for lung cancer. PMID:24285215

  17. Radioisotope Concentrator Gene Therapy Using the Sodium\\/Iodide Symporter Gene

    Microsoft Academic Search

    Robert B. Mandell; Leisa Z. Mandell; Charles J. Link

    1999-01-01

    We demonstrate a novel method of concentrating radiation for tumor imaging or killing. The rat sodium\\/iodide symporter gene (rNIS) was cloned into a retroviral vector for transfer into cancer cells to mimic the iodide uptake of thyroid follicular cells. In vitro iodide transport shows that the symporter functions similarly in rNIS-transduced tumor cells and rat thyroid follicular cells. rNIS-transduced and

  18. Small Multifunctional Nanoclusters (Nanoroses) for Targeted Cellular Imaging and Therapy

    PubMed Central

    Ma, Li Leo; Feldman, Marc D.; Tam, Jasmine M.; Paranjape, Amit S.; Cheruku, Kiran K.; Larson, Timothy A.; Tam, Justina O.; Ingram, Davis R.; Paramita, Vidia; Villard, Joseph W.; Jenkins, James T.; Wang, Tianyi; Clarke, Geoffrey D.; Asmis, Reto; Sokolov, Konstantin; Chandrasekar, Bysani; Milner, Thomas E.; Johnston, Keith P.

    2010-01-01

    The ability of 20–50 nm nanoparticles to target and modulate the biology of specific types of cells will enable major advancements in cellular imaging and therapy in cancer and atherosclerosis. A key challenge is to load an extremely high degree of targeting, imaging, and therapeutic functionality into small, yet stable particles. Herein we report ~30 nm stable uniformly sized near-infrared (NIR) active, superparamagnetic nanoclusters formed by kinetically controlled self-assembly of gold-coated iron oxide nanoparticles. The controlled assembly of nanocomposite particles into clusters with small primary particle spacings produces collective responses of the electrons that shift the absorbance into the NIR region. The nanoclusters of ~70 iron oxide primary particles with thin gold coatings display intense NIR (700–850 nm) absorbance with a cross section of ~10?14 m2. Because of the thin gold shells with an average thickness of only 2 nm, the r2 spin–spin magnetic relaxivity is 219 mM?1 s?1, an order of magnitude larger than observed for typical iron oxide particles with thicker gold shells. Despite only 12% by weight polymeric stabilizer, the particle size and NIR absorbance change very little in deionized water over 8 months. High uptake of the nanoclusters by macrophages is facilitated by the dextran coating, producing intense NIR contrast in dark field and hyperspectral microscopy, both in cell culture and an in vivo rabbit model of atherosclerosis. Small nanoclusters with optical, magnetic, and therapeutic functionality, designed by assembly of nanoparticle building blocks, offer broad opportunities for targeted cellular imaging, therapy, and combined imaging and therapy. PMID:19711944

  19. Additive Fuzzy Enhancement and an Associative Memory for Feature Tracking in Radiation Therapy Images

    Microsoft Academic Search

    Hamid R. Tizhoosh; Gerald Krell; Bernd Michaelis

    1997-01-01

    Medical images in radiation therapy, especially electronic portal images, are often very poor in quality because of imaging physics. For a reliable patient set-up verification by tracking of relevant features, better in-treatment images are necessary. In this work, we present the prototype of an additive fuzzy system for a locally adaptive image enhancement and a modified associative memory for image

  20. Mechanisms of natural gene therapy in dystrophic epidermolysis bullosa.

    PubMed

    Kiritsi, Dimitra; Garcia, Marta; Brander, Renske; Has, Cristina; Meijer, Rowdy; Jose Escámez, Maria; Kohlhase, Jürgen; van den Akker, Peter C; Scheffer, Hans; Jonkman, Marcel F; del Rio, Marcela; Bruckner-Tuderman, Leena; Pasmooij, Anna M G

    2014-08-01

    Revertant mosaicism has been reported in several inherited diseases, including the genetic skin fragility disorder epidermolysis bullosa (EB). Here, we describe the largest cohort of seven patients with revertant mosaicism and dystrophic EB (DEB), associated with mutations in the COL7A1 gene, and determine the underlying molecular mechanisms. We show that revertant mosaicism occurs both in autosomal dominantly and recessively inherited DEB. We found that null mutations resulting in complete loss of collagen VII and severe disease, as well as missense or splice-site mutations associated with some preserved collagen VII function and a milder phenotype, were corrected by revertant mosaicism. The mutation, subtype, and severity of the disease are thus not decisive for the presence of revertant mosaicism. Although collagen VII is synthesized and secreted by both keratinocytes and fibroblasts, evidence for reversion was only found in keratinocytes. The reversion mechanisms included back mutations/mitotic recombinations in 70% of the cases and second-site mutations affecting splicing in 30%. We conclude that revertant mosaicism is more common than previously assumed in patients with DEB, and our findings will have implications for future therapeutic strategies using the patient's naturally corrected cells as a source for cell-based therapies. PMID:24577406

  1. N3-substituted thymidine bioconjugates for cancer therapy and imaging

    PubMed Central

    Khalil, Ahmed; Ishita, Keisuke; Ali, Tehane; Tjarks, Werner

    2013-01-01

    The compound class of 3-carboranyl thymidine analogues (3CTAs) are boron delivery agents for boron neutron capture therapy (BNCT), a binary treatment modality for cancer. Presumably, these compounds accumulate selectively in tumor cells via intracellular trapping, which is mediated by hTK1. Favorable in vivo biodistribution profiles of 3CTAs led to promising results in preclinical BNCT of rats with intracerebral brain tumors. This review presents an overview on the design, synthesis, and biological evaluation of first- and second-generation 3CTAs. Boronated nucleosides developed prior to 3CTAs for BNCT and non-boronated N3-substituted thymidine conjugates for other areas of cancer therapy and imaging are also described. In addition, basic features of carborane clusters, which are used as boron moieties in the design and synthesis of 3CTAs, and the biological and structural features of TK1-like enzymes, which are the molecular targets of 3CTAs, are discussed. PMID:23617430

  2. New approaches for imaging and therapy of solid cancer.

    PubMed

    Sollini, M; Boni, R; Traino, A C; Lazzeri, E; Pasqualetti, F; Modeo, L; Mariani, G; Petrini, M; Erba, P A

    2015-06-01

    Radionuclide therapy is a systemic treatment that aims to deliver cytotoxic radiation to cancer cells. Due to their properties, antibodies have been considered as suitable agent for the delivery of therapeutic radioisotopes, radioimmunotherapy (RIT). This article gives an overview of new approaches for imaging and therapy of solid cancer with particular attention to strategies to enhance treatment success. Examples of increased antibody uptake by targeting stromal constituent of tumor microenvironment such as fibronectin (FN) an important tumor-associated angiogenesis targeting agent, with specifically designed antibody format will be provided. Strategies oriented to identify patients most likely to benefit from RIT including identification of radiosensitivity profiles, in vivo target identification by teragnostic approach and better prediction of dosimetric estimates would be presents. Combination regimens such as with chemo-radiotherapy and immunotherapy would be also discussed as an approach to enhance RIT success. PMID:25693421

  3. Towards image-guided photodynamic therapy of Glioblastoma

    NASA Astrophysics Data System (ADS)

    Mallidi, Srivalleesha; Huang, Huang-Chiao; Liu, Joyce; Mai, Zhiming; Hasan, Tayyaba

    2013-03-01

    Glioblastoma (GBM) is an aggressive cancer with dismal survival rates and few new treatment options. Fluorescence guided resection of GBM followed by photodynamic therapy (PDT) has shown promise in several chemo- or radiotherapy non-responsive GBM treatments clinically. PDT is an emerging light and photosensitizer (PS) mediated cytotoxic method. However, as with other therapeutic modalities, the outcomes are variable largely due to the nonpersonalization of dose parameters. The variability can be attributed to the differences in heterogeneous photosensitizer accumulation in tumors. Building upon our previous findings on utilizing PS fluorescence for designing tumor-specific PDT dose, we explore the use of photoacoustic imaging, a technique that provides contrast based on the tissue optical absorption properties, to obtain 3D information on the tumoral photosensitizer accumulation. The findings of this study will form the basis for customized photodynamic therapy for glioblastoma and have the potential to serve as a platform for treatment of other cancers.

  4. Prospective on the potential of imaging gene expression

    SciTech Connect

    Taylor, Scott E; Budinger, Thomas F.

    2000-06-01

    The feasibility of the non-invasive imaging of gene expression is explored. Calculations of the possibility of the direct imaging of specific messenger RNA with radiolabeled antisense are discussed. In addition, possible mechanism for the amplification of the biological signal to enhance image detection are discussed.

  5. Plasticity of the human visual system after retinal gene therapy in patients with Leber's congenital amaurosis.

    PubMed

    Ashtari, Manzar; Zhang, Hui; Cook, Philip A; Cyckowski, Laura L; Shindler, Kenneth S; Marshall, Kathleen A; Aravand, Puya; Vossough, Arastoo; Gee, James C; Maguire, Albert M; Baker, Chris I; Bennett, Jean

    2015-07-15

    Much of our knowledge of the mechanisms underlying plasticity in the visual cortex in response to visual impairment, vision restoration, and environmental interactions comes from animal studies. We evaluated human brain plasticity in a group of patients with Leber's congenital amaurosis (LCA), who regained vision through gene therapy. Using non-invasive multimodal neuroimaging methods, we demonstrated that reversing blindness with gene therapy promoted long-term structural plasticity in the visual pathways emanating from the treated retina of LCA patients. The data revealed improvements and normalization along the visual fibers corresponding to the site of retinal injection of the gene therapy vector carrying the therapeutic gene in the treated eye compared to the visual pathway for the untreated eye of LCA patients. After gene therapy, the primary visual pathways (for example, geniculostriate fibers) in the treated retina were similar to those of sighted control subjects, whereas the primary visual pathways of the untreated retina continued to deteriorate. Our results suggest that visual experience, enhanced by gene therapy, may be responsible for the reorganization and maturation of synaptic connectivity in the visual pathways of the treated eye in LCA patients. The interactions between the eye and the brain enabled improved and sustained long-term visual function in patients with LCA after gene therapy. PMID:26180100

  6. A promising gene delivery system developed from PEGylated MoS2 nanosheets for gene therapy

    PubMed Central

    2014-01-01

    A new class of two-dimensional (2D) nanomaterial, transition metal dichalcogenides (TMDCs) such as MoS2, MoSe2, WS2, and WSe2 which have fantastic physical and chemical properties, has drawn tremendous attention in different fields recently. Herein, we for the first time take advantage of the great potential of MoS2 with well-engineered surface as a novel type of 2D nanocarriers for gene delivery and therapy of cancer. In our system, positively charged MoS2-PEG-PEI is synthesized with lipoic acid-modified polyethylene glycol (LA-PEG) and branched polyethylenimine (PEI). The amino end of positively charged nanomaterials can bind to the negatively charged small interfering RNA (siRNA). After detection of physical and chemical characteristics of the nanomaterial, cell toxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Polo-like kinase 1 (PLK1) was investigated as a well-known oncogene, which was a critical regulator of cell cycle transmission at multiple levels. Through knockdown of PLK1 with siRNA carried by novel nanovector, qPCR and Western blot were used to measure the interfering efficiency; apoptosis assay was used to detect the transfection effect of PLK1. All results showed that the novel nanocarrier revealed good biocompatibility, reduced cytotoxicity, as well as high gene-carrying ability without serum interference, thus would have great potential for gene delivery and therapy. PMID:25386104

  7. Gene and cell therapy based treatment strategies for inflammatory bowel diseases

    PubMed Central

    van der Marel, Sander; Majowicz, Anna; van Deventer, Sander; Petry, Harald; Hommes, Daniel W; Ferreira, Valerie

    2011-01-01

    Inflammatory bowel diseases (IBD) are a group of chronic inflammatory disorders most commonly affecting young adults. Currently available therapies can result in induction and maintenance of remission, but are not curative and have sometimes important side effects. Advances in basic research in IBD have provided new therapeutic opportunities to target the inflammatory process involved. Gene and cell therapy approaches are suitable to prevent inflammation in the gastrointestinal tract and show therefore potential in the treatment of IBD. In this review, we present the current progress in the field of both gene and cell therapy and future prospects in the context of IBD. Regarding gene therapy, we focus on viral vectors and their applications in preclinical models. The focus for cell therapy is on regulatory T lymphocytes and mesenchymal stromal cells, their potential for the treatment of IBD and the progress made in both preclinical models and clinical trials. PMID:22180846

  8. Radiation Therapy Alone for Imaging-Defined Meningiomas

    SciTech Connect

    Korah, Mariam P., E-mail: mariam@radonc.emory.or [Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA (United States); Nowlan, Adam W. [Department of Radiation Oncology, Piedmont Hospital, Atlanta, GA (United States); Johnstone, Peter A.S. [Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN (United States); Crocker, Ian R. [Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA (United States)

    2010-01-15

    Purpose: To assess local control and treatment-related toxicity of single-modality radiation therapy (RT) in the treatment of imaging-defined meningiomas. Methods and Materials: The records of Emory University School of Medicine, Atlanta, GA, were reviewed between 1985 and 2003. We identified 41 patients with 42 meningiomas treated with RT alone for lesions diagnosed on imaging alone. No patients received a histologic diagnosis. Patients in whom there was uniform agreement that the tumor represented a meningioma were accepted for therapy. Of the patients, 22 were treated with stereotactic radiosurgery (SRS), 11 with fractionated stereotactic radiotherapy (FSR), and 9 with three-dimensional conformal therapy (3DCRT). The median doses of SRS, FSR, and 3DCRT were 14 Gy, 50.4 Gy, and 52.2 Gy, respectively. Results: Median follow-up was 60 months. Of 42 meningiomas, 39 were locally controlled. The 8-year actuarial local control rate by Kaplan-Meier methods was 94%. One failure occurred 6 months after 3DCRT, a second at 34 months after FSR, and a third at 125 months after SRS. A temporary symptomatic radiation-related neurologic sequela developed in 1 patient treated with SRS. No fatal treatment complications occurred. The 8-year rate for actuarial freedom from complication survival by Kaplan-Meier methods was 97%. Conclusions: RT alone is an attractive alternative to surgery for imaging-defined meningiomas without significant mass effect. It offers local control comparable to surgical resection with minimal morbidity. RT should be considered as a viable alternative to surgery for tumors in various locations.

  9. Roadmap: Radiologic Imaging Sciences Radiation Therapy (Freshman or AS degree) Bachelor of Radiologic Imaging Sciences Technology

    E-print Network

    Sheridan, Scott

    Roadmap: Radiologic Imaging Sciences ­ Radiation Therapy (Freshman or AS degree) ­ Bachelor diversity US 10097 Destination Kent State: First Year Experience 1 Not required of transfer students with 25 Not required for AS degree holders Semester Four: [13 Credit Hours] COMM 15000 Introduction to Human

  10. Neonatal thymulin gene therapy in nude mice: Effects on the morphology of the pituitary corticotrope population.

    PubMed

    Martines, Eliana; Reggiani, Paula C; Schwerdt, José I; Goya, Rodolfo G; Cónsole, Gloria

    2011-04-01

    The integrity of the thymus during early life is necessary for a proper maturation of the neuroendocrine system, including the adrenal axis. The thymic metallopeptide thymulin seems to be a central physiologic mediator of thymus-pituitary communication. Furthermore, neonatal thymulin gene therapy has been shown to prevent the typical alterations of gonadotrophic cell number and morphology and serum gonadotropin levels in nude female mice. In the present study we assessed the impact of athymia and the effect of neonatal thymulin gene therapy on the corticotropic cell population in nude mice. The effect of thymulin administration to adult nudes on their hypothalamic content of corticotropin-releasing hormone (CRH) and the adrenal content of corticosterone was also determined. We used an adenoviral vector expressing a synthetic gene for the thymic peptide thymulin (metFTS) termed RAd-FTS. On postnatal day 1 or 2, heterozygous (nu/+) and homozygous (nu/nu) pups of both sexes received a single bilateral i.m. injection of RAd-FTS or RAd-GFP, a control vector. On postnatal day 71, mice were bled and sacrificed, and their pituitaries were immediately dissected, fixed and immunostained for corticotropin. Morphometry was performed by means of an image-analysis system. The following parameters were calculated: volume density (VD: ? cell area/reference area), cell density (CD: number of cells/reference area), and cell surface (CS: expressed in ?m²). Serum thymulin levels were measured by a bioassay, and CRH as well as corticosterone were determined by IRMA and RIA, respectively. Neonatal thymulin gene therapy in the athymic mice restored their serum thymulin levels and increased corticotrope CD, VD and CS in both control and athymic mice. Athymic mice showed only a marginal reduction in corticotrope CD, VD and CS. In these mutants hypothalamic CRH content was slightly increased, whereas adrenal corticosterone tended to be lower. Thymulin administration to adult mice tended to reverse these changes. Our results suggest a possible modulating effect of thymulin on the corticotrope population and the adrenal gland, confirming the existence of a bidirectional thymus-pituitary-adrenal axis. PMID:21360440

  11. Multiscale registration of planning CT and daily cone beam CT images for adaptive radiation therapy

    E-print Network

    Levy, Doron

    therapy ART is the incorporation of daily images in the radiotherapy treatment process soMultiscale registration of planning CT and daily cone beam CT images for adaptive radiation therapy images is thus an important component of ART. In this article, the authors report their research

  12. Moral obligation and the human germ-line gene therapy debate 

    E-print Network

    Clark, Alan B

    1998-01-01

    genetic engineering, there are few arguments made for a positive moral obligation to genetic intervention. This is especially so with respect to human germ-line gene therapy. Burke. K. Zimmerman makes one of the few arguments that society...

  13. Therapeutic Levels of Functional Human Factor X in Rats After Retroviral-Mediated Hepatic Gene Therapy

    E-print Network

    Ponder, Katherine P.

    patients with hemophilia A or B, for which safe preparations of purified factors arepriate coagulation hours) or FVIII (10their synthesis and has direct contact with the blood. Gene therapy for hemophilia

  14. Non-replicating expression vectors: applications in vaccine development and gene therapy

    PubMed Central

    Limbach, K. J.; Paoletti, E.

    1996-01-01

    This review presents experimental, preclinical and clinical data illustrating the multiple uses of recombinant non-replicating virus vectors in the fields of immunoprophylaxis and gene therapy. PMID:8666067

  15. Moral obligation and the human germ-line gene therapy debate

    E-print Network

    Clark, Alan B

    1998-01-01

    genetic engineering, there are few arguments made for a positive moral obligation to genetic intervention. This is especially so with respect to human germ-line gene therapy. Burke. K. Zimmerman makes one of the few arguments that society...

  16. Chemiluminescent Nanomicelles for Imaging Hydrogen Peroxide and Self-Therapy in Photodynamic Therapy

    PubMed Central

    Chen, Rui; Zhang, Luzhong; Gao, Jian; Wu, Wei; Hu, Yong; Jiang, Xiqun

    2011-01-01

    Hydrogen peroxide is a signal molecule of the tumor, and its overproduction makes a higher concentration in tumor tissue compared to normal tissue. Based on the fact that peroxalates can make chemiluminescence with a high efficiency in the presence of hydrogen peroxide, we developed nanomicelles composed of peroxalate ester oligomers and fluorescent dyes, called peroxalate nanomicelles (POMs), which could image hydrogen peroxide with high sensitivity and stability. The potential application of the POMs in photodynamic therapy (PDT) for cancer was also investigated. It was found that the PDT-drug-loaded POMs were sensitive to hydrogen peroxide, and the PDT drug could be stimulated by the chemiluminescence from the reaction between POMs and hydrogen peroxide, which carried on a self-therapy of the tumor without the additional laser light resource. PMID:21765637

  17. Dynamic optical breast imaging for neoadjuvant therapy monitoring

    NASA Astrophysics Data System (ADS)

    Sajjadi, Amir Y.; Wanyo, Christy M.; Fang, Qianqian; Boas, David A.; Isakoff, Steven J.; Carp, Stefan A.

    2013-03-01

    Near-infrared optical measurements have been shown to offer a promising non-invasive way for monitoring breast neoadjuvant chemotherapy (NAC) and predicting outcome. In this study, we extend optical measurements to capture additional hemodynamic and metabolic biomarkers revealed by dynamically imaging breast tissue during fractional mammographic compression. We are obtaining pre-treatment, day 7 and optional monthly scans in breast cancer patients undergoing NAC. The difference in hemodynamic response to compression between healthy and tumor-bearing breast decreases over the course of neoadjuvant therapy in responders compared to nearly no change in patients not responding to the chemotherapy.

  18. Tumoral calcinosis: Serial images to monitor successful dietary therapy

    SciTech Connect

    Manaster, B.J.; McDowell Anderson, T. Jr.

    1982-05-01

    Tumoral calcinosis involves formation of periarticular calcified soft tissue masses. Experimental evidence suggests a metabolic etiology with dietary restriction of calcium and phosphorus as beneficial therapy. We prospectively monitored serum levels of calcium, phosphorous, alkaline phosphatase, and erythrocyte sedimentation rate (ESR) while successfully treating a patient with tumoral calcinosis. The values were compared with changes on serial radiographic and radionuclide bone and gallium images. Our work suggests using serial serum phosphate levels and the ESR as the most sensitive indications of progress in dietary treatment of tumoral calcinosis.

  19. Gene Therapy in Large Animal Models of Human Cardiovascular Genetic Disease

    Microsoft Academic Search

    Meg M. Sleeper; Lawrence T. Bish; H. Lee Sweeney

    2009-01-01

    Several naturally occurring animal models for human genetic heart diseases offer an excellent opportunity to evaluate poten- tial novel therapies, including gene therapy. Some of these diseases—especially those that result in a structural defect during development (e.g., patent ductus arteriosus, pulmonic stenosis)—would likely be diffi cult to treat with a therapeutic gene transfer approach. However, the ability to transduce a

  20. Success for gene therapy: render unto Caesar that which is Caesar's

    PubMed Central

    Qiao, Jian; Diaz, Rosa Maria; Vile, Richard G

    2004-01-01

    Reports that two young children developed leukemia after being treated for immunodeficiency with their own retrovirally modified bone-marrow cells delivered a severe blow to confidence in gene therapy as a treatment. Two reports, published since the trial was initiated, now take away some of the mystery as to why these events happened and allay fears for the safety of gene therapy across all therapeutic applications. PMID:15287968

  1. The state of the art of adeno-associated virus-based vectors in gene therapy

    Microsoft Academic Search

    Renata dos Santos Coura; Nance Beyer Nardi

    2007-01-01

    The adeno-associated virus (AAV) has rapidly gained popularity in gene therapy since the establishment of the first AAV2 infectious clone, in 1982, due to some of their distinguishing characteristics such as lack of pathogenicity, wide range of infectivity, and ability to establish long-term transgene expression. Notably over the past decade, this virus has attracted considerable interest as a gene therapy

  2. Clinical trials of gene therapy, virotherapy, and immunotherapy for malignant gliomas

    Microsoft Academic Search

    L Barzon; M Zanusso; F Colombo; G Palù

    2006-01-01

    Despite advances in surgical and adjuvant therapy, the prognosis for malignant gliomas remains dismal. This gloomy scenario has been recently brightened by the increasing understanding of the genetic and biological mechanisms at the basis of brain tumor development. These findings are being translated into innovative therapeutic approaches, including gene therapy, virotherapy, and vaccination, some of which have already been experimented

  3. Perfluorocarbon Nanoparticles for Physiological and Molecular Imaging and Therapy

    PubMed Central

    Chen, Junjie; Pan, Hua; Lanza, Gregory M.; Wickline, Samuel A.

    2014-01-01

    Herein we review the use of non-nephrotoxic perfluorocarbon nanoparticles (PFC NP) for noninvasive detection and therapy of kidney diseases, and provide a synopsis of other related literature pertinent to anticipated clinical application. Recent reports indicate that PFC NP allow quantitative mapping of kidney perfusion, and oxygenation after ischemia-reperfusion injury with the use of a novel multi-nuclear 1H/19F magnetic resonance imaging (MRI) approach,. Furthermore, when conjugated with targeting ligands, the functionalized PFC NP offer unique and quantitative capabilities for imaging inflammation in the kidney of atherosclerotic ApoE-null mice. Additionally, PFC NP can facilitate drug delivery for treatment of inflammation, thrombosis, and angiogenesis in selected conditions that are comorbidities for to kidney failure. The excellent safety profile of PFC NP with respect to kidney injury positions these nanomedicine approaches as promising diagnostic and therapeutic candidates for treating and following acute and chronic kidney diseases. PMID:24206599

  4. Molecular targeting of the lymphovascular system for imaging and therapy.

    PubMed

    Schöder, Heiko; Glass, Edwin C; Pecking, Alain P; Harness, Jay K; Wallace, Anne M; Hirnle, Peter; Alberini, Jean L; Vilain, Didier; Larson, Steven M; Hoh, Carl K; Vera, David R

    2006-06-01

    Progress toward targeting cancer cells is a multi-disciplinary endeavor. In addition to the surgical and oncology specialties, radiologists collaborate with mathematicians, computer scientists, and physicists, in a constant effort to incrementally improve upon the current imaging modalities. Recently, radiologists have formed collaborations with molecular biologists and chemists in order to develop molecular agents that target cancer cells via receptor-substrate or specific physiochemical interactions. In this review, we summarize selected efforts toward molecular targeting of the lymphovascular system. Standard imaging modalities, positron emission tomography, single photon emission tomography, and ultrasound, are reviewed as well as, the targeted introduction of substances for endolymphatic therapy. We also review the current status of sentinel lymph node mapping with radiocolloids and the application of molecular targeting for the development of a radiopharmaceutical specifically designed for sentinel lymph node mapping. PMID:16770532

  5. Calcium phosphosilicate nanoparticles for imaging and photodynamic therapy of cancer.

    PubMed

    Tacelosky, Diana M; Creecy, Amy E; Shanmugavelandy, Sriram S; Smith, Jill P; Claxton, David F; Adair, James H; Kester, Mark; Barth, Brian M

    2012-04-01

    Photodynamic therapy (PDT) has emerged as an alternative modality for cancer treatment. PDT works by initiating damaging oxidation or redox-sensitive pathways to trigger cell death. PDT can also regulate tumor angiogenesis and modulate systemic antitumor immunity. The drawbacks to PDT--photosensitizer toxicity, a lack of selectivity and efficacy of photosensitizers, and a limited penetrance of light through deep tissues--are the same pitfalls associated with diagnostic imaging. Developments in the field of nanotechnology have generated novel platforms for optimizing the advantages while minimizing the disadvantages of PDT. Calcium phosphosilicate nanoparticles (CPSNPs) represent an optimal nano-system for both diagnostic imaging and PDT. In this review, we will discuss how CPSNPs can enhance optical agents and serve as selective, non-toxic, and functionally stable photosensitizers for PDT. We will also examine novel applications of CPSNPs and PDT for the treatment of leukemia to illustrate their potential utility in cancer therapeutics. PMID:22541615

  6. Gold Nanoconstructs for Multimodal Diagnostic Imaging and Photothermal Cancer Therapy

    NASA Astrophysics Data System (ADS)

    Coughlin, Andrew James

    Cancer accounts for nearly 1 out of every 4 deaths in the United States, and because conventional treatments are limited by morbidity and off-target toxicities, improvements in cancer management are needed. This thesis further develops nanoparticle-assisted photothermal therapy (NAPT) as a viable treatment option for cancer patients. NAPT enables localized ablation of disease because heat generation only occurs where tissue permissive near-infrared (NIR) light and absorbing nanoparticles are combined, leaving surrounding normal tissue unharmed. Two principle approaches were investigated to improve the specificity of this technique: multimodal imaging and molecular targeting. Multimodal imaging affords the ability to guide NIR laser application for site-specific NAPT and more holistic characterization of disease by combining the advantages of several diagnostic technologies. Towards the goal of image-guided NAPT, gadolinium-conjugated gold-silica nanoshells were engineered and demonstrated to enhance imaging contrast across a range of diagnostic modes, including T1-weighted magnetic resonance imaging, X-Ray, optical coherence tomography, reflective confocal microscopy, and two-photon luminescence in vitro as well as within an animal tumor model. Additionally, the nanoparticle conjugates were shown to effectively convert NIR light to heat for applications in photothermal therapy. Therefore, the broad utility of gadolinium-nanoshells for anatomic localization of tissue lesions, molecular characterization of malignancy, and mediators of ablation was established. Molecular targeting strategies may also improve NAPT by promoting nanoparticle uptake and retention within tumors and enhancing specificity when malignant and normal tissue interdigitate. Here, ephrinA1 protein ligands were conjugated to nanoshell surfaces for particle homing to overexpressed EphA2 receptors on prostate cancer cells. In vitro, successful targeting and subsequent photothermal ablation of prostate cancer cells was achieved with negligible nanoshell binding to normal cells. In vivo however, ephrinA1-nanoshells did not promote enhanced therapeutic outcomes in mice bearing subcutaneous prostate cancer tumors treated with NAPT compared to nontargeted particles. Nonetheless, both treatment groups demonstrated effective ablation of prostate tumors, as evidenced by tumor tissue regression. Further investigation is warranted to overcome probable protein immunogenicity that offsets ephrinA1 targeting in vivo. With future study, photothermal therapy with multimodal gadolinium-conjugated and molecularly targeted nanoshells may offer a viable treatment option for cancer patients in the clinic.

  7. The MDS1–EVI1 Gene Complex as a Retrovirus Integration Site: Impact on Behavior of Hematopoietic Cells and Implications for Gene Therapy

    Microsoft Academic Search

    Jean-Yves Métais; Cynthia E Dunbar

    2008-01-01

    Gene therapy trials have been performed with virus-based vectors that have the ability to integrate permanently into genomic DNA and thus allow prolonged expression of corrective genes after transduction of hematopoietic stem and progenitor cells. Adverse events observed during the X-linked severe combined immunodeficiency gene therapy trial revealed a significant risk of genotoxicity related to retrovirus vector integration and activation

  8. Recombinant adenovirus deleted of all viral genes for gene therapy of cystic fibrosis.

    PubMed

    Fisher, K J; Choi, H; Burda, J; Chen, S J; Wilson, J M

    1996-03-01

    Recombinant adenoviruses are being developed for gene therapy of inherited disorders such as cystic fibrosis because they efficiently transduce recombinant genes into nondividing cells in vivo. First generation recombinant adenoviruses, rendered defective by deletion of sequences spanning E1a and E1b, express low levels of early and late viral genes that activate destructive cellular immune responses. Current strategies for improving recombinant adenoviruses attempt to inactivate other essential genes through deletion and growth in new packaging cell lines or incorporation of temperature sensitive mutations which allow propagation of the virus in available packaging cell lines at permissive temperatures. We describe in this report a new type of recombinant adenovirus that is deleted of all viral open reading frames. This recombinant (called delta-rAd), which contains only the essential cis elements (i.e., ITRs and contiguous packaging sequence), is propagated in 293 cells in the presence of E1-deleted helper virus. Concatamers of the monomeric vector genome were passaged and capable of transduction. The delta-rAd genome is packaged into virions that sediment at a lower density than the helper virus in cesium gradients forming the basis for a purification protocol. A fully deleted recombinant adenovirus that expresses human cystic fibrosis transmembrane conductance regulator was produced and used to transduce human airway epithelial cells derived from a cystic fibrosis patient. Packaging and propagation of a fully deleted adenovirus is an important step toward the development of a safer vector. Improved production and purification strategies need to be developed before this new vector system can be evaluated in vivo. PMID:8599194

  9. Autoradiography imaging in targeted alpha therapy with Timepix detector.

    PubMed

    A L Darwish, Ruqaya; Staudacher, Alexander Hugo; Bezak, Eva; Brown, Michael Paul

    2015-01-01

    There is a lack of data related to activity uptake and particle track distribution in targeted alpha therapy. These data are required to estimate the absorbed dose on a cellular level as alpha particles have a limited range and traverse only a few cells. Tracking of individual alpha particles is possible using the Timepix semiconductor radiation detector. We investigated the feasibility of imaging alpha particle emissions in tumour sections from mice treated with Thorium-227 (using APOMAB), with and without prior chemotherapy and Timepix detector. Additionally, the sensitivity of the Timepix detector to monitor variations in tumour uptake based on the necrotic tissue volume was also studied. Compartmental analysis model was used, based on the obtained imaging data, to assess the Th-227 uptake. Results show that alpha particle, photon, electron, and muon tracks were detected and resolved by Timepix detector. The current study demonstrated that individual alpha particle emissions, resulting from targeted alpha therapy, can be visualised and quantified using Timepix detector. Furthermore, the variations in the uptake based on the tumour necrotic volume have been observed with four times higher uptake for tumours pretreated with chemotherapy than for those without chemotherapy. PMID:25688285

  10. Noise evaluation of Compton camera imaging for proton therapy.

    PubMed

    Ortega, P G; Torres-Espallardo, I; Cerutti, F; Ferrari, A; Gillam, J E; Lacasta, C; Llosá, G; Oliver, J F; Sala, P R; Solevi, P; Rafecas, M

    2015-03-01

    Compton Cameras emerged as an alternative for real-time dose monitoring techniques for Particle Therapy (PT), based on the detection of prompt-gammas. As a consequence of the Compton scattering process, the gamma origin point can be restricted onto the surface of a cone (Compton cone). Through image reconstruction techniques, the distribution of the gamma emitters can be estimated, using cone-surfaces backprojections of the Compton cones through the image space, along with more sophisticated statistical methods to improve the image quality. To calculate the Compton cone required for image reconstruction, either two interactions, the last being photoelectric absorption, or three scatter interactions are needed. Because of the high energy of the photons in PT the first option might not be adequate, as the photon is not absorbed in general. However, the second option is less efficient. That is the reason to resort to spectral reconstructions, where the incoming ? energy is considered as a variable in the reconstruction inverse problem. Jointly with prompt gamma, secondary neutrons and scattered photons, not strongly correlated with the dose map, can also reach the imaging detector and produce false events. These events deteriorate the image quality. Also, high intensity beams can produce particle accumulation in the camera, which lead to an increase of random coincidences, meaning events which gather measurements from different incoming particles. The noise scenario is expected to be different if double or triple events are used, and consequently, the reconstructed images can be affected differently by spurious data. The aim of the present work is to study the effect of false events in the reconstructed image, evaluating their impact in the determination of the beam particle ranges. A simulation study that includes misidentified events (neutrons and random coincidences) in the final image of a Compton Telescope for PT monitoring is presented. The complete chain of detection, from the beam particle entering a phantom to the event classification, is simulated using FLUKA. The range determination is later estimated from the reconstructed image obtained from a two and three-event algorithm based on Maximum Likelihood Expectation Maximization. The neutron background and random coincidences due to a therapeutic-like time structure are analyzed for mono-energetic proton beams. The time structure of the beam is included in the simulations, which will affect the rate of particles entering the detector. PMID:25658644

  11. 705. A New Strategy for Cancer Therapy: Application of Adenovirus-Mediated Complete-Length Antibody Gene

    Microsoft Academic Search

    Chen Jie; Jiang Minghong; Guo Minggao; Su Changqing; Wang Xinghua; Cui Zhenfu; Liu Xinyuan; Wu Mengchao; Qian Qijun

    2005-01-01

    Antibody-based therapy has been proved to be efficient for cancer treatment. Due to high price, the application of antibody therapy has been limited, thereby the antibody gene therapy has been extensively explored. The instability and lacking of ADCC effects of small molecule antibodies made them difficult to be wildly used. No complete-length antibody gene system is currently available. Herceptin and

  12. Adaptive HIFU noise cancellation for simultaneous therapy and imaging using an integrated HIFU/imaging transducer

    PubMed Central

    Jeong, Jong Seob; Cannata, Jonathan Matthew; Shung, K Kirk

    2010-01-01

    It was previously demonstrated that it is feasible to simultaneously perform ultrasound therapy and imaging of a coagulated lesion during treatment with an integrated transducer that is capable of high intensity focused ultrasound (HIFU) and B-mode ultrasound imaging. It was found that coded excitation and fixed notch filtering upon reception could significantly reduce interference caused by the therapeutic transducer. During HIFU sonication, the imaging signal generated with coded excitation and fixed notch filtering had a range side-lobe level of less than ?40 dB, while traditional short-pulse excitation and fixed notch filtering produced a range side-lobe level of ?20 dB. The shortcoming is, however, that relatively complicated electronics may be needed to utilize coded excitation in an array imaging system. It is for this reason that in this paper an adaptive noise canceling technique is proposed to improve image quality by minimizing not only the therapeutic interference, but also the remnant side-lobe ‘ripples’ when using the traditional short-pulse excitation. The performance of this technique was verified through simulation and experiments using a prototype integrated HIFU/imaging transducer. Although it is known that the remnant ripples are related to the notch attenuation value of the fixed notch filter, in reality, it is difficult to find the optimal notch attenuation value due to the change in targets or the media resulted from motion or different acoustic properties even during one sonication pulse. In contrast, the proposed adaptive noise canceling technique is capable of optimally minimizing both the therapeutic interference and residual ripples without such constraints. The prototype integrated HIFU/imaging transducer is composed of three rectangular elements. The 6 MHz center element is used for imaging and the outer two identical 4 MHz elements work together to transmit the HIFU beam. Two HIFU elements of 14.4 mm × 20.0 mm dimensions could increase the temperature of the soft biological tissue from 55 °C to 71 °C within 60 s. Two types of experiments for simultaneous therapy and imaging were conducted to acquire a single scan-line and B-mode image with an aluminum plate and a slice of porcine muscle, respectively. The B-mode image was obtained using the single element imaging system during HIFU beam transmission. The experimental results proved that the combination of the traditional short-pulse excitation and the adaptive noise canceling method could significantly reduce therapeutic interference and remnant ripples and thus may be a better way to implement real-time simultaneous therapy and imaging. PMID:20224162

  13. Imaging of gene expression in vivo with photoacoustic tomography

    NASA Astrophysics Data System (ADS)

    Li, Li; Zemp, Roger J.; Lungu, Gina; Stoica, George; Wang, Lihong V.

    2006-02-01

    In the post-genomic era, there is an increasing interest in visualizing the expression of functional genes in vivo. With the assistance of the reporter gene technique, various imaging modalities have been adopted for this purpose. In vivo gene expression imaging promises to provide biologists with a powerful tool for deepening our understanding of developmental biology, expanding our knowledge of the genetic basis of disease, and advancing the development of medicine. In this paper, we demonstrate the feasibility of imaging gene expression with photoacoustic imaging, which offers unique absorption contrast with ultrasonic resolution in vivo. We mark tumors in rats with the lacZ reporter gene. The lacZ gene encodes an enzyme ?-galactosidase, which yields a dark blue product when acting on a colorimetric assay called X-gal. Photoacoustic tomography at 650nm clearly visualizes the presence of this blue product. The spectroscopic method can also potentially improve specificity. Considering how many staining methods are used in traditional biology, we believe that photoacoustic techniques will revolutionize the field of molecular imaging. The further development of reporter gene systems with high absorbing products in the NIR region is needed.

  14. Gene therapy strategies in glaucoma and application for steroid-induced hypertension

    PubMed Central

    Borrás, Teresa

    2011-01-01

    Gene therapy of the eye has a high potential of becoming the preferred treatment of a number of eye diseases. Because of its easy accessibility, all the tissues of the eye can be reached and genetically manipulated with nowadays standard gene delivery technologies. Gene therapy offers the possibility to do both, correct a genetic defect by replacing the mutated or missing gene and that of using genes as drugs. Gene drugs would be more specific and would have a longer duration of action and less toxicity than conventional drugs. Examples of both applications are beginning to emerge. Using gene replacement, vision has been restored in several patients of Leber congenital amaurosis (Maguire et al., 2009). Some gene drugs, such as siRNA, are currently in clinical trials to silence angiogenic factors in macular degeneration (Campa and Harding, 2011). In this manuscript we first give a short overview of the basics of gene therapy in the eye and then review the ongoing preclinical studies in our laboratory for the gene-drug treatment of steroid-induced ocular hypertension. PMID:23960949

  15. Inducible promoters for gene therapy of head and neck cancer: an in vitro study.

    PubMed

    Schmidt, Marianne; Heimberger, Tonja; Gruensfelder, Petra; Schler, Gabriele; Hoppe, Florian

    2004-04-01

    The aim of gene therapy includes the tight spatial and temporal control of transgenic expression. There are several approaches concerning externally inducible gene promoters used for the control of suicide genes. Two of the promoters that might play a role in head and neck cancer gene therapy are the hyperthermia-inducible human heat shock protein-70 (hsp70) promotor, as well as the radiation-inducible promoter of the early growth response-1 gene (egr-1). We tested the hsp-70 promoter as well as a promoter construct, containing synthetic radio-responsive elements of the egr-1 enhancer for the effect on reporter gene expression in two stably transfected head and neck carcinoma cell lines in vitro and measured the success of gene activation by FACS analysis, western blot analysis and fluorescence microscopy. With the hsp70 promoter we reached a 5.83-fold increase of reporter gene expression after hyperthermic treatment in one of the two cell lines tested. The radiation-inducible construct revealed only weak gene induction and was marked by high background expression. Both systems worked in a highly cell-type dependent manner. The possible clinical use of externally inducible transgene expression in head and neck carcinoma gene therapy is critically discussed. PMID:12915945

  16. on and Gene Therapy Volume 7, Number 1, 2001THE NEUROSCIENTIST

    E-print Network

    Fischer, Itzhak

    are lost after spinal cord injury because neurons die or atrophy and axons fail to regenerate. Until fairly recently, it was believed that damaged neurons could not be replaced and injured axons could not regenerate genes to protect neurons and to stimulate regeneration. The ability to engineer cells by gene therapy

  17. Adenovirus-mediated p53 tumor suppressor gene therapy of osteosarcoma

    Microsoft Academic Search

    Vladimir V Ternovoi; David T Curiel; Bruce F Smith; Gene P Siegal

    2006-01-01

    The clinical outcome for osteosarcoma (OS) remains discouraging despite efforts to optimize treatment using conventional modalities including surgery, radiotherapy and chemotherapy. Novel therapeutic approaches based on our expanding understanding of the mechanisms of tumor cell killing have the potential to alter this situation. Tumor suppressor gene therapy aims to restore the function of a tumor suppressor gene lost or functionally

  18. Toward Brain Tumor Gene Therapy Using Multipotent Mesenchymal Stromal Cell Vectors

    Microsoft Academic Search

    Daniel Bexell; Stefan Scheding; Johan Bengzon

    2010-01-01

    Gene therapy of solid cancers has been severely restricted by the limited distribution of vectors within tumors. However, cellular vectors have emerged as an effective migratory system for gene delivery to invasive cancers. Implanted and injected multipotent mesenchymal stromal cells (MSCs) have shown tropism for several types of primary tumors and metastases. This capacity of MSCs forms the basis for

  19. Down's syndrome-associated Single Minded 2 gene as a pancreatic cancer drug therapy target

    Microsoft Academic Search

    Maurice Phil DeYoung; Matthew Tress; Ramaswamy Narayanan

    2003-01-01

    We report here a pancreatic cancer drug therapy utility of a gene involved in Down's syndrome. Single Minded 2 gene (SIM2) from Down's Syndrome Critical Region was expressed in pancreatic cancer-derived cell lines as well as in tumor tissues, but not in the normal pancreas. A related member of the SIM family, SIM1, did not show similar specificity. Inhibition by

  20. Diagnostic test for prenatal identification of Down's syndrome and mental retardation and gene therapy therefor

    Microsoft Academic Search

    Desmond J. Smith; Edward M. Rubin

    2000-01-01

    A a diagnostic test useful for prenatal identification of Down syndrome and mental retardation. A method for gene therapy for correction and treatment of Down syndrome. DYRK gene involved in the ability to learn. A method for diagnosing Down's syndrome and mental retardation and an assay therefor. A pharmaceutical composition for treatment of Down's syndrome mental retardation.

  1. Challenges in Image-Guided Therapy System Design

    PubMed Central

    DiMaio, Simon; Kapur, Tina; Cleary, Kevin; Aylward, Stephen; Kazanzides, Peter; Vosburgh, Kirby; Ellis, Randy; Duncan, Jim; Farahani, Keyvan; Lemke, Heinz; Peters, Terry; Lorensen, Bill; Gobbi, David; Haller, John; Clarke, Larry; Pizer, Steve; Galloway, Bob; Fichtinger, Gabor; Hata, Noby; Lawson, Kim; Tempany, Clare; Kikinis, Ron; Jolesz, Ferenc

    2013-01-01

    System development for Image-Guided Therapy (IGT), or Image-Guided Interventions (IGI), continues to be an area of active interest across academic and industry groups. This is an emerging field that is growing rapidly: major academic institutions and medical device manufacturers have produced IGT technologies that are in routine clinical use, dozens of high-impact publications are published in well regarded journals each year, and several small companies have successfully commercialized sophisticated IGT systems. In meetings between IGT investigators over the last two years, a consensus has emerged that several key areas must be addressed collaboratively by the community to reach the next level of impact and efficiency in IGT research and development to improve patient care. These meetings culminated in a two-day workshop that brought together several academic and industrial leaders in the field today. The goals of the Workshop were to identify gaps in the engineering infrastructure available to IGT researchers, develop the role of research funding agencies and the recently established National Center for Image Guided Therapy (NCIGT), and ultimately to facilitate the transfer of technology among NIH-sponsored research centers. Workshop discussions spanned many of the current challenges in the development and deployment of new IGT systems. Key challenges were identified in a number of areas, including: validation standards; workflows, use-cases and application requirements; component reusability; and device interface standards. This report elaborates on these key points and proposes research challenges that are to be addressed by a joint effort between academic, industry, and NIH participants. PMID:17644360

  2. Current status of gene therapy for breast cancer: progress and challenges

    PubMed Central

    McCrudden, Cian M; McCarthy, Helen O

    2014-01-01

    Breast cancer is characterized by a series of genetic mutations and is therefore ideally placed for gene therapy intervention. The aim of gene therapy is to deliver a nucleic acid-based drug to either correct or destroy the cells harboring the genetic aberration. More recently, cancer gene therapy has evolved to also encompass delivery of RNA interference technologies, as well as cancer DNA vaccines. However, the bottleneck in creating such nucleic acid pharmaceuticals lies in the delivery. Deliverability of DNA is limited as it is prone to circulating nucleases; therefore, numerous strategies have been employed to aid with biological transport. This review will discuss some of the viral and nonviral approaches to breast cancer gene therapy, and present the findings of clinical trials of these therapies in breast cancer patients. Also detailed are some of the most recent developments in nonviral approaches to targeting in breast cancer gene therapy, including transcriptional control, and the development of recombinant, multifunctional bio-inspired systems. Lastly, DNA vaccines for breast cancer are documented, with comment on requirements for successful pharmaceutical product development. PMID:25419154

  3. Gene therapy in an era of emerging treatment options for hemophilia B.

    PubMed

    Monahan, P E

    2015-06-01

    Factor IX deficiency (hemophilia B) is less common than factor VIII deficiency (hemophilia A), and innovations in therapy for hemophilia B have generally lagged behind those for hemophilia A. Recently, the first sustained correction of the hemophilia bleeding phenotype by clotting factor gene therapy has been described using recombinant adeno-associated virus (AAV) to deliver factor IX. Despite this success, many individuals with hemophilia B, including children, men with active hepatitis, and individuals who have pre-existing natural immunity to AAV, are not eligible for the current iteration of hemophilia B gene therapy. In addition, recent advances in recombinant factor IX protein engineering have led some hemophilia treaters to reconsider the urgency of genetic cure. Current clinical and preclinical approaches to advancing AAV-based and alternative approaches to factor IX gene therapy are considered in the context of current demographics and treatment of the hemophilia B population. PMID:26149016

  4. Sleeping Beauty transposon system for genetic etiological research and gene therapy of cancers.

    PubMed

    Hou, Xiaomei; Du, Yan; Deng, Yang; Wu, Jianfeng; Cao, Guangwen

    2015-01-01

    Carcinogenesis is etiologically associated with somatic mutations of critical genes. Recently, a number of somatic mutations and key molecules have been found to be involved in functional networks affecting cancer progression. Suitable animal models are required to validate cancer-promoting or -inhibiting capacities of these mutants and molecules. Sleeping Beauty transposon system consists of a transposon that carries gene(s) of interest and a transposase that recognizes, excises, and reinserts genes in given location of the genome. It can create both gain-of-function and loss-of-function mutations, thus being frequently chosen to investigate the etiological mechanisms and gene therapy for cancers in animal models. In this review, we summarized current advances of Sleeping Beauty transposon system in revealing molecular mechanism of cancers and improving gene therapy. Understanding molecular mechanisms by which driver mutations contribute to carcinogenesis and metastasis may pave the way for the development of innovative prophylactic and therapeutic strategies against malignant diseases. PMID:25455252

  5. Neuroprotection for Amyotrophic Lateral Sclerosis: Role of Stem Cells, Growth Factors, and Gene Therapy

    PubMed Central

    Pandya, Rachna S.; Mao, Lilly L. J.; Zhou, Edward W.; Bowser, Robert; Zhu, Zhenglun; Zhu, Yongjin; Wang, Xin

    2014-01-01

    Various molecular mechanisms including apoptosis, inflammation, oxidative stress, and excitotoxicity have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), though the exact mechanisms have yet to be specified. Furthermore, the underlying restorative molecular mechanisms resulting in neuronal and/or non-neuronal regeneration have to be yet elucidated. Therapeutic agents targeting one or more of these mechanisms to combat either initiation or progression of the disease are under research. Novel treatments including stem cell therapy, growth factors, and gene therapy might prolong survival and delay progression of symptoms. Harnessing the regenerative potential of the central nervous system would be a novel approach for the treatment of motor neuron death resulting from ALS. Endogenous neural replacement, if augmented with administration of exogenous growth factors or with pharmaceuticals that increase the rate of neural progenitor formation, neural migration, and neural maturation could slow the rate of cell loss enough to result in clinical improvement. In this review, we discuss the impact of therapeutic treatment involving stem cell therapy, trophic factors, gene therapy, and combination therapy on disease onset and progression of ALS. In addition, we summarize human clinical trials of stem cell therapy, growth factor therapy, and gene therapy in individuals with ALS. PMID:22283698

  6. 286. Therapeutic Approach Using External Radiation and Suicide Gene Therapy Transduced by Chimeric Adenovirus Vector for Bladder Cancer

    Microsoft Academic Search

    Kazumasa Matsumoto; Norihiko Okuno; Bin S. Teh; Christian T. F. Freund; Julie X. Zhu; Maria T. Vlachaki; Alan R. Davis; Brian E. Butler; Seth P. Lerner

    2005-01-01

    Background: Radiation therapy is an established therapy for advanced bladder cancer. Interestingly, radiation therapy has been shown to improve both transduction efficiency and transgene expression. However, alteration of the coxsackie and adenovirus receptor (CAR) poses a barrier to adenovirus-mediated gene therapy, particularly in higher grade and stage bladder cancers with potential for metastasis. We have previously shown the efficacy of

  7. Improvement and Decline in Vision with Gene Therapy in Childhood Blindness

    PubMed Central

    Jacobson, Samuel G.; Cideciyan, Artur V.; Roman, Alejandro J.; Sumaroka, Alexander; Schwartz, Sharon B.; Heon, Elise; Hauswirth, William W.

    2015-01-01

    Summary Retinal gene therapy for Leber’s congenital amaurosis, an autosomal recessive childhood blindness, has been widely considered to be safe and efficacious. Three years after therapy, improvement in vision was maintained, but the rate of loss of photoreceptors in the treated retina was the same as that in the untreated retina. Here we describe long-term follow-up data from three treated patients. Topographic maps of visual sensitivity in treated regions, nearly 6 years after therapy for two of the patients and 4.5 years after therapy for the third patient, indicate progressive diminution of the areas of improved vision. PMID:25936984

  8. Chemical modifications and bioconjugate reactions of nanomaterials for sensing, imaging, drug delivery and therapy.

    PubMed

    Biju, Vasudevanpillai

    2014-02-01

    As prepared nanomaterials of metals, semiconductors, polymers and carbon often need surface modifications such as ligand exchange, and chemical and bioconjugate reactions for various biosensor, bioanalytical, bioimaging, drug delivery and therapeutic applications. Such surface modifications help us to control the physico-chemical, toxicological and pharmacological properties of nanomaterials. Furthermore, introduction of various reactive functional groups on the surface of nanomaterials allows us to conjugate a spectrum of contrast agents, antibodies, peptides, ligands, drugs and genes, and construct multifunctional and hybrid nanomaterials for the targeted imaging and treatment of cancers. This tutorial review is intended to provide an introduction to newcomers about how chemical and bioconjugate reactions transform the surface of nanomaterials such as silica nanoparticles, gold nanoparticles, gold quantum clusters, semiconductor quantum dots, carbon nanotubes, fullerene and graphene, and accordingly formulate them for applications such as biosensing, bioimaging, drug and gene delivery, chemotherapy, photodynamic therapy and photothermal therapy. Nonetheless, controversial reports and our growing concerns about toxicity and pharmacokinetics of nanomaterials suggest the need for not only rigorous in vivo experiments in animal models but also novel nanomaterials for practical applications in the clinical settings. Further reading of original and review articles cited herein is necessary to buildup in-depth knowledge about the chemistry, bioconjugate chemistry and biological applications of individual nanomaterials. PMID:24220322

  9. Nucleic Acids Electrotransfer-Based Gene Therapy (Electrogenetherapy): Past, Current, and Future

    Microsoft Academic Search

    L. M. Mir

    2009-01-01

    About 25 years after the publication of the first report on gene transfer in vitro in cultured cells by the means of electric\\u000a pulses delivery, reversible cell electroporation for gene transfer and gene therapy (DNA electrotransfer) is at a cross in\\u000a its development. Present knowledge on the effects of cell exposure to appropriate electric field pulses, particularly at the\\u000a level of

  10. MECP2 Isoform-Specific Vectors with Regulated Expression for Rett Syndrome Gene Therapy

    Microsoft Academic Search

    Mojgan Rastegar; Akitsu Hotta; Peter Pasceri; Maisam Makarem; Aaron Y. L. Cheung; Shauna Elliott; Katya J. Park; Megumi Adachi; Frederick S. Jones; Ian D. Clarke; Peter Dirks; James Ellis

    2009-01-01

    Background: Rett Syndrome (RTT) is an Autism Spectrum Disorder and the leading cause of mental retardation in females. RTT is caused by mutations in the Methyl CpG-Binding Protein-2 (MECP2) gene and has no treatment. Our objective is to develop viral vectors for MECP2 gene transfer into Neural Stem Cells (NSC) and neurons suitable for gene therapy of Rett Syndrome. Methodology\\/Principal

  11. MECP2 Isoform-Specific Vectors with Regulated Expression for Rett Syndrome Gene Therapy

    Microsoft Academic Search

    Mojgan Rastegar; Akitsu Hotta; Peter Pasceri; Maisam Makarem; Aaron Y. L. Cheung; Shauna Elliott; Katya J. Park; Megumi Adachi; Frederick S. Jones; Ian D. Clarke; Peter Dirks; James Ellis; Rafael Linden

    2009-01-01

    BackgroundRett Syndrome (RTT) is an Autism Spectrum Disorder and the leading cause of mental retardation in females. RTT is caused by mutations in the Methyl CpG-Binding Protein-2 (MECP2) gene and has no treatment. Our objective is to develop viral vectors for MECP2 gene transfer into Neural Stem Cells (NSC) and neurons suitable for gene therapy of Rett Syndrome.Methodology\\/Principal FindingsWe generated

  12. Midkine promoter-based adenoviral suicide gene therapy to midkine-positive pediatric tumor

    Microsoft Academic Search

    Yasuo Adachi; Shyuichiro Matsubara; Takashi Muramatsu; David T. Curiel; Paul N. Reynolds

    2002-01-01

    Background\\/Purpose: Suicide gene therapy based on the delivery of the herpes simplex virus thymidine kinase gene combined with ganciclovir (HSV-tk\\/GCV) is a promising approach for cancer treatment. Adenoviral (Ad) vectors are useful gene delivery vehicles for this approach; however, because these agents possess a high natural tropism for the liver, systems must be designed to avoid potential hepatotoxicity induced by

  13. Gene Therapy with Endogenous Inhibitors of Angiogenesis for Neovascular Age-Related Macular Degeneration: Beyond Anti-VEGF Therapy.

    PubMed

    Prea, Selwyn M; Chan, Elsa C; Dusting, Gregory J; Vingrys, Algis J; Bui, Bang V; Liu, Guei-Sheung

    2015-01-01

    Age-related macular degeneration (AMD) is the leading cause of substantial and irreversible vision loss amongst elderly populations in industrialized countries. The advanced neovascular (or "wet") form of the disease is responsible for severe and aggressive loss of central vision. Current treatments aim to seal off leaky blood vessels via laser therapy or to suppress vessel leakage and neovascular growth through intraocular injections of antibodies that target vascular endothelial growth factor (VEGF). However, the long-term success of anti-VEGF therapy can be hampered by limitations such as low or variable efficacy, high frequency of administration (usually monthly), potentially serious side effects, and, most importantly, loss of efficacy with prolonged treatment. Gene transfer of endogenous antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization and/or excessive vascular leakage in the eye. Preclinical studies of gene transfer in a large animal model have provided impressive preliminary results with a number of transgenes. In addition, a clinical trial in patients suffering from advanced neovascular AMD has provided proof-of-concept for successful gene transfer. In this mini review, we summarize current theories pertaining to the application of gene therapy for neovascular AMD and the potential benefits when used in conjunction with endogenous antiangiogenic proteins. PMID:25821585

  14. Gene Therapy with Endogenous Inhibitors of Angiogenesis for Neovascular Age-Related Macular Degeneration: Beyond Anti-VEGF Therapy

    PubMed Central

    Prea, Selwyn M.; Chan, Elsa C.; Dusting, Gregory J.; Vingrys, Algis J.; Bui, Bang V.

    2015-01-01

    Age-related macular degeneration (AMD) is the leading cause of substantial and irreversible vision loss amongst elderly populations in industrialized countries. The advanced neovascular (or “wet”) form of the disease is responsible for severe and aggressive loss of central vision. Current treatments aim to seal off leaky blood vessels via laser therapy or to suppress vessel leakage and neovascular growth through intraocular injections of antibodies that target vascular endothelial growth factor (VEGF). However, the long-term success of anti-VEGF therapy can be hampered by limitations such as low or variable efficacy, high frequency of administration (usually monthly), potentially serious side effects, and, most importantly, loss of efficacy with prolonged treatment. Gene transfer of endogenous antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization and/or excessive vascular leakage in the eye. Preclinical studies of gene transfer in a large animal model have provided impressive preliminary results with a number of transgenes. In addition, a clinical trial in patients suffering from advanced neovascular AMD has provided proof-of-concept for successful gene transfer. In this mini review, we summarize current theories pertaining to the application of gene therapy for neovascular AMD and the potential benefits when used in conjunction with endogenous antiangiogenic proteins. PMID:25821585

  15. Gold-silica quantum rattles for multimodal imaging and therapy.

    PubMed

    Hembury, Mathew; Chiappini, Ciro; Bertazzo, Sergio; Kalber, Tammy L; Drisko, Glenna L; Ogunlade, Olumide; Walker-Samuel, Simon; Krishna, Katla Sai; Jumeaux, Coline; Beard, Paul; Kumar, Challa S S R; Porter, Alexandra E; Lythgoe, Mark F; Boissière, Cédric; Sanchez, Clément; Stevens, Molly M

    2015-02-17

    Gold quantum dots exhibit distinctive optical and magnetic behaviors compared with larger gold nanoparticles. However, their unfavorable interaction with living systems and lack of stability in aqueous solvents has so far prevented their adoption in biology and medicine. Here, a simple synthetic pathway integrates gold quantum dots within a mesoporous silica shell, alongside larger gold nanoparticles within the shell's central cavity. This "quantum rattle" structure is stable in aqueous solutions, does not elicit cell toxicity, preserves the attractive near-infrared photonics and paramagnetism of gold quantum dots, and enhances the drug-carrier performance of the silica shell. In vivo, the quantum rattles reduced tumor burden in a single course of photothermal therapy while coupling three complementary imaging modalities: near-infrared fluorescence, photoacoustic, and magnetic resonance imaging. The incorporation of gold within the quantum rattles significantly enhanced the drug-carrier performance of the silica shell. This innovative material design based on the mutually beneficial interaction of gold and silica introduces the use of gold quantum dots for imaging and therapeutic applications. PMID:25653336

  16. Automatic Segmentation of Intra-Treatment CT Images for Adaptive Radiation Therapy of the

    E-print Network

    for prostate cancer is external beam radiation therapy, which uses high energy x-rays that are deliveredAutomatic Segmentation of Intra-Treatment CT Images for Adaptive Radiation Therapy of the Prostate for automatically quan- tifying organ motion for adaptive radiation therapy of the prostate. Our approach is based

  17. Gene replacement therapies for Duchenne muscular dystrophy using adeno-associated viral vectors

    PubMed Central

    Seto, Jane T.; Ramos, Julian N.; Muir, Lindsey; Chamberlain, Jeffrey S.

    2014-01-01

    The muscular dystrophies collectively represent a major health challenge, as few significant treatment options currently exist for any of these disorders. Recent years have witnessed a proliferation of novel approaches to therapy, spanning increased testing of existing and new pharmaceuticals, DNA delivery (both anti-sense oligonucleotides and plasmid DNA), gene therapies and stem cell technologies. While none of these has reached the point of being used in clinical practice, all show promise for being able to impact different types of muscular dystrophies. Our group has focused on developing direct gene replacement strategies to treat recessively inherited forms of muscular dystrophy, particularly Duchenne and Becker muscular dystrophy (DMD/BMD). Both forms of dystrophy are caused by mutations in the dystrophin gene and all cases can in theory be treated by gene replacement using synthetic forms of the dystrophin gene. The major challenges for success of this approach are the development of a suitable gene delivery shuttle, generating a suitable gene expression cassette able to be carries by such a shuttle, and achieving safe and effective delivery. This review summarizes the current state of the art in terms of using adeno-associated viral vectors to deliver synthetic dystrophin genes for the purpose of developing gene therapy for DMD. PMID:22533379

  18. Prospects for the Use of Artificial Chromosomes and Minichromosome-Like Episomes in Gene Therapy

    PubMed Central

    Pérez-Luz, Sara; Díaz-Nido, Javier

    2010-01-01

    Artificial chromosomes and minichromosome-like episomes are large DNA molecules capable of containing whole genomic loci, and be maintained as nonintegrating, replicating molecules in proliferating human somatic cells. Authentic human artificial chromosomes are very difficult to engineer because of the difficulties associated with centromere structure, so they are not widely used for gene-therapy applications. However, OriP/EBNA1-based episomes, which they lack true centromeres, can be maintained stably in dividing cells as they bind to mitotic chromosomes and segregate into daughter cells. These episomes are more easily engineered than true human artificial chromosomes and can carry entire genes along with all their regulatory sequences. Thus, these constructs may facilitate the long-term persistence and physiological regulation of the expression of therapeutic genes, which is crucial for some gene therapy applications. In particular, they are promising vectors for gene therapy in inherited diseases that are caused by recessive mutations, for example haemophilia A and Friedreich's ataxia. Interestingly, the episome carrying the frataxin gene (deficient in Friedreich's ataxia) has been demonstrated to rescue the susceptibility to oxidative stress which is typical of fibroblasts from Friedreich's ataxia patients. This provides evidence of their potential to treat genetic diseases linked to recessive mutations through gene therapy. PMID:20862363

  19. Molecular imaging of rheumatoid arthritis by radiolabelled monoclonal antibodies: new imaging strategies to guide molecular therapies

    Microsoft Academic Search

    G. Malviya; F. Conti; M. Chianelli; F. Scopinaro; R. A. Dierckx; A. Signore

    2010-01-01

    The closing of the last century opened a wide variety of approaches for inflammation imaging and treatment of patients with\\u000a rheumatoid arthritis (RA). The introduction of biological therapies for the management of RA started a revolution in the therapeutic\\u000a armamentarium with the development of several novel monoclonal antibodies (mAbs), which can be murine, chimeric, humanised\\u000a and fully human antibodies. Monoclonal

  20. Galactose as Broad Ligand for Multiple Tumor Imaging and Therapy

    PubMed Central

    Ma, Yuxiang; Chen, Haiyan; Su, Shanyuhan; Wang, Tong; Zhang, Congying; Fida, Guissi; Cui, Sisi; Zhao, Juan; Gu, Yueqing

    2015-01-01

    Galactose residues could be specifically recognized by the asialoglycoprotein receptor (ASGPR) which is highly exhibited on liver tissues. However, ASGPR has not been widely investigated on different tumor cell lines except for hepatoma carcinoma cells, which motivates us to investigate the possibility of galactose serving as a board tumor ligand. In this study, a galactose (Gal)-based probe conjugated with fluorescence dye MPA (Gal-MPA) was constructed for the evaluation of tumor affinities/targeted ability on different tumor cell lines. In the vitro cell study, it was indicated that the fluorescence probe Gal-MPA displayed higher cell affinity to tumor cells (HepG2, MCF-7 and A549) than that of the normal liver cells l02. In the vivo dynamic study of Gal-MPA in tumor-bearing mice (HepG2, MCF-7, A549, HCT116, U87, MDA-MB-231 and S180), it was shown that its high tumor targeted ability with the maximal tumor/normal tissue ratio reached up to 6.8. Meanwhile, the fast tumor-targeted ability within 2 hours and long retention on tumor site up to 120 hours were observed. Our results demonstrated that galactose should be a promising broad ligand for multiple tumor imaging and targeted therapy. Subsequently, Gal was covalently conjugated to doxorubicin (DOX) to form prodrug Gal-DOX for tumor targeted therapy. The therapeutic results of Gal-DOX than DOX being better suggested that galactosylated prodrugs might have the prospective potential in tumor targeted therapy. PMID:26078797

  1. Involvement of regucalcin as a suppressor protein in human carcinogenesis: insight into the gene therapy.

    PubMed

    Yamaguchi, Masayoshi

    2015-08-01

    Regucalcin, which its gene is located on the X chromosome, plays a multifunctional role as a suppressor protein in cell signal transduction in various types of cells and tissues. The suppression of regucalcin gene expression has been shown to involve in carcinogenesis. Regucalcin gene expression was uniquely downregulated in carcinogenesis of rat liver in vivo, although the expression of other many genes was upregulated, indicating that endogenous regucalcin plays a suppressive role in the development of hepatocarcinogenesis. Overexpression of endogenous regucalcin was found to suppress proliferation of rat cloned hepatoma cells in vitro. Moreover, the regucalcin gene and its protein levels were demonstrated specifically to downregulate in human hepatocellular carcinoma by analysis with multiple gene expression profiles and proteomics. Regucalcin gene expression was also found to suppress in human tumor tissues including kidney, lung, brain, breast and prostate, suggesting that repressed regucalcin gene expression leads to the development of carcinogenesis in various tissues. Regucalcin may play a role as a suppressor protein in carcinogenesis. Overexpression of endogenous regucalcin is suggested to reveal preventive and therapeutic effects on carcinogenesis. Delivery of the regucalcin gene may be a novel useful tool in the gene therapy of carcinogenesis. This review will discuss regarding to an involvement of regucalcin as a suppressor protein in human carcinogenesis in insight into the gene therapy. PMID:25230901

  2. Theranostic Studies of Human Sodium Iodide Symporter Imaging and Therapy Using 188Re: A Human Glioma Study in Mice

    PubMed Central

    Guo, Rui; Zhang, M.; Xi, Yun; Ma, Yufei; Liang, Sheng; Shi, Shuo; Miao, Ying; Li, Biao

    2014-01-01

    Objective To investigate the role of 188Re in human sodium iodide symporter (hNIS) theranostic gene-mediated human glioma imaging and therapy in model mice. Methods The human glioma cell line U87 was transfected with recombinant lentivirus encoding the hNIS gene under the control of cytomegalovirus promoter (U87-hNIS). The uptake and efflux of 188Re were determined after incubating the cells with 188Re. 188Re uptake experiments in the presence of various concentrations of sodium perchlorate were carried out. In vitro cell killing tests with 188Re were performed. U87-hNIS mediated 188Re distribution, imaging and therapy in nude mice were also tested. Results U87-hNIS cell line was successfully established. The uptake of 188Re in U87-hNIS cells increased up to 26-fold compared to control cells, but was released rapidly with a half-life of approximately 4 minutes. Sodium perchlorate reduced hNIS-mediated 188Re uptake to levels of control cell lines. U87-hNIS cells were selectively killed following exposure to 188Re, with a survival of 21.4%, while control cells had a survival of 92.1%. Unlike in vitro studies, U87-hNIS tumor showed a markedly increased 188Re retention even 48 hours after 188Re injection. In the therapy study, there was a significant difference in tumor size between U87-hNIS mice (317±67 mm3) and control mice (861±153 mm3) treated with 188Re for 4 weeks (P<0.01). Conclusion The results indicate that inserting the hNIS gene into U87 cells is sufficient to induce specific 188Re uptake, which has a cell killing effect both in vitro and in vivo. Moreover, our study, based on the function of hNIS as a theranostic gene allowing noninvasive imaging of hNIS expression by 188Re scintigraphy, provides detailed characterization of in vivo vector biodistribution and level, localization, essential prerequisites for precise planning and monitoring of clinical gene therapy that aims to individualize gene therapy concept. PMID:25000403

  3. Engineering optically triggered droplets for photoacoustic imaging and therapy.

    PubMed

    Dove, Jacob D; Mountford, Paul A; Murray, Todd W; Borden, Mark A

    2014-12-01

    Liquid perfluorocarbon (PFC) droplets incorporating optical absorbers can be vaporized through photothermal heating using a pulsed laser source. Here, we report on the effect of droplet core material on the optical fluence required to produce droplet vaporization. We fabricate gold nanoparticle templated microbubbles filled with various PFC gases (C3F8, C4F10, and C5F12) and apply pressure to condense them into droplets. The core material is found to have a strong effect on the threshold optical fluence, with lower boiling point droplets allowing for vaporization at lower laser fluence. The impact of droplet size on vaporization threshold is discussed, as well as a proposed mechanism for the relatively broad distribution of vaporization thresholds observed within a droplet population with the same core material. We propose that the control of optical vaporization threshold enabled by engineering the droplet core may find application in contrast enhanced photoacoustic imaging and therapy. PMID:25574448

  4. Image-guided ablation therapy of bone tumors.

    PubMed

    Sabharwal, Tarun; Katsanos, Konstantinos; Buy, Xavier; Gangi, Afshin

    2009-04-01

    A wide range of thermal and cryoablation methods is currently available for the curative eradication or palliative treatment of a variety of bone and soft-tissue tumors. Radiofrequency ablation has been developed as a multipurpose tool for the skeletal system. Cryoablation has the added advantages of direct computed tomography or magnetic resonance visualization and monitoring of treatment outcome with less peri- and postoperative pain. Use of appropriate thermo-sensors and insulation techniques, like carbon dioxide insufflation, results in enhanced safety and efficacy. Ablation of weight-bearing bones has to be supplemented with cement consolidation. The authors present an overview of the current status of percutaneous image-guided ablation therapy of bone and soft-tissue tumors, analyze the merits and limitations of the various systems available, and discuss possible new applications for the future. PMID:19358439

  5. Ferritin reporter used for gene expression imaging by magnetic resonance

    SciTech Connect

    Ono, Kenji; Fuma, Kazuya; Tabata, Kaori [Department of Brain Functions, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 464-8601 (Japan)] [Department of Brain Functions, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 464-8601 (Japan); Sawada, Makoto, E-mail: msawada@riem.nagoya-u.ac.jp [Department of Brain Functions, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 464-8601 (Japan)] [Department of Brain Functions, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi 464-8601 (Japan)

    2009-10-23

    Magnetic resonance imaging (MRI) is a minimally invasive way to provide high spatial resolution tomograms. However, MRI has been considered to be useless for gene expression imaging compared to optical imaging. In this study, we used a ferritin reporter, binding with biogenic iron, to make it a powerful tool for gene expression imaging in MRI studies. GL261 mouse glioma cells were over-expressed with dual-reporter ferritin-DsRed under {beta}-actin promoter, then gene expression was observed by optical imaging and MRI in a brain tumor model. GL261 cells expressing ferritin-DsRed fusion protein showed enhanced visualizing effect by reducing T2-weighted signal intensity for in vitro and in vivo MRI studies, as well as DsRed fluorescence for optical imaging. Furthermore, a higher contrast was achieved on T2-weighted images when permeating the plasma membrane of ferritin-DsRed-expressing GL261. Thus, a ferritin expression vector can be used as an MRI reporter to monitor in vivo gene expression.

  6. Renal therapy using tissue-engineered constructs and gene delivery

    Microsoft Academic Search

    Gilad E. Amiel; James J. Yoo; Anthony Atala

    2000-01-01

    Currently available renal replacement therapies are not optimal for most patients. In addition to the inherent shortage of\\u000a transplant organs, significant complications are associated with renal transplantation and immunosuppressive therapy. Dialysis\\u000a neglects the resorptive, homeostatic, metabolic, and endocrinologic functions of the kidney and only partially replaces its\\u000a filtration properties, resulting in morbidity and mortality. Application of tissue-engineering techniques may improve

  7. 17th Annual Meeting of the German Society for Gene Therapy.

    PubMed

    Büning, Hildegard; Baum, Christopher; Ehrhardt, Anja; Nettelbeck, Dirk M; Ogris, Manfred

    2011-01-01

    The 17th Annual Meeting of the German Society for Gene Therapy was held at the Chemistry and Pharmacy Campus of the University of Munich in conjunction with and supported by the British Society for Gene Therapy, the Viral Vectors Study Group of the German Society for Virology, the Research Priority Program SPP1230, the Nanosystems Initiative Munich and the Helmholtz Center Munich. The German Research Foundation provided financial support for the invited international speakers. In addition to 25 invited lectures, 21 oral presentations were selected out of more than 100 submitted abstracts. State-of-the-art advances in the field of gene therapy were presented, a field that has considerably evolved within recent years. More than 200 researchers from Germany and other European countries, as well as the USA, Canada and Japan attended the meeting. Prior to the official meeting, a public day was organized, in which the interested public could participate in talks and discussions concerning gene therapy issues. Furthermore, at the 'kids workshop' young scientists aged 8-10 years were discovering cellular and genetic mechanisms and the principles of gene therapy. PMID:22833922

  8. Segmentation of left atrial intracardiac ultrasound images for image guided cardiac ablation therapy

    NASA Astrophysics Data System (ADS)

    Rettmann, M. E.; Stephens, T.; Holmes, D. R.; Linte, C.; Packer, D. L.; Robb, R. A.

    2013-03-01

    Intracardiac echocardiography (ICE), a technique in which structures of the heart are imaged using a catheter navigated inside the cardiac chambers, is an important imaging technique for guidance in cardiac ablation therapy. Automatic segmentation of these images is valuable for guidance and targeting of treatment sites. In this paper, we describe an approach to segment ICE images by generating an empirical model of blood pool and tissue intensities. Normal, Weibull, Gamma, and Generalized Extreme Value (GEV) distributions are fit to histograms of tissue and blood pool pixels from a series of ICE scans. A total of 40 images from 4 separate studies were evaluated. The model was trained and tested using two approaches. In the first approach, the model was trained on all images from 3 studies and subsequently tested on the 40 images from the 4th study. This procedure was repeated 4 times using a leave-one-out strategy. This is termed the between-subjects approach. In the second approach, the model was trained on 10 randomly selected images from a single study and tested on the remaining 30 images in that study. This is termed the within-subjects approach. For both approaches, the model was used to automatically segment ICE images into blood and tissue regions. Each pixel is classified using the Generalized Liklihood Ratio Test across neighborhood sizes ranging from 1 to 49. Automatic segmentation results were compared against manual segmentations for all images. In the between-subjects approach, the GEV distribution using a neighborhood size of 17 was found to be the most accurate with a misclassification rate of approximately 17%. In the within-subjects approach, the GEV distribution using a neighborhood size of 19 was found to be the most accurate with a misclassification rate of approximately 15%. As expected, the majority of misclassified pixels were located near the boundaries between tissue and blood pool regions for both methods.

  9. ADA (adenosine deaminase) gene therapy enters the competition

    SciTech Connect

    Culliton, B.J.

    1990-08-31

    Around the world, some 70 children are members of a select and deadly club. Born with an immune deficiency so severe that they will die of infection unless their immune systems can be repaired, they have captured the attention of would-be gene therapists who believe that a handful of these kids--the 15 or 20 who lack functioning levels of the enzyme adenosine deaminase (ADA)--could be saved by a healthy ADA gene. A team of gene therapists is ready to put the theory to the test. In April 1987, a team of NIH researchers headed by R. Michael Blaese and W. French Anderson came up with the first formal protocol to introduce a healthy ADA gene into an unhealthy human. After 3 years of line-by-line scrutiny by five review committees, they have permission to go ahead. Two or three children will be treated in the next year, and will be infused with T lymphocytes carrying the gene for ADA. If the experiment works, the ADA gene will begin producing normal amounts of ADA. An interesting feature of ADA deficiency, that makes it ideal for initial gene studies, is that the amount of ADA one needs for a healthy immune system is quite variable. Hence, once inside a patient's T cells, the new ADA gene needs only to express the enzyme in moderate amounts. No precise gene regulation is necessary.

  10. Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy.

    PubMed

    Chandler, Randy J; LaFave, Matthew C; Varshney, Gaurav K; Trivedi, Niraj S; Carrillo-Carrasco, Nuria; Senac, Julien S; Wu, Weiwei; Hoffmann, Victoria; Elkahloun, Abdel G; Burgess, Shawn M; Venditti, Charles P

    2015-02-01

    The use of adeno-associated virus (AAV) as a gene therapy vector has been approved recently for clinical use and has demonstrated efficacy in a growing number of clinical trials. However, the safety of AAV as a vector has been challenged by a single study that documented hepatocellular carcinoma (HCC) after AAV gene delivery in mice. Most studies have not noted genotoxicity following AAV-mediated gene delivery; therefore, the possibility that there is an association between AAV and HCC is controversial. Here, we performed a comprehensive study of HCC in a large number of mice following therapeutic AAV gene delivery. Using a sensitive high-throughput integration site-capture technique and global expressional analysis, we found that AAV integration into the RNA imprinted and accumulated in nucleus (Rian) locus, and the resulting overexpression of proximal microRNAs and retrotransposon-like 1 (Rtl1) were associated with HCC. In addition, we demonstrated that the AAV vector dose, enhancer/promoter selection, and the timing of gene delivery are all critical factors for determining HCC incidence after AAV gene delivery. Together, our results define aspects of AAV-mediated gene therapy that influence genotoxicity and suggest that these features should be considered for design of both safer AAV vectors and gene therapy studies. PMID:25607839

  11. Deformable registration of the planning image (kVCT) and the daily images (MVCT) for adaptive radiation therapy

    Microsoft Academic Search

    Weiguo Lu; Gustavo H. Olivera; Quan Chen; Kenneth J. Ruchala; Jason Haimerl; Sanford L. Meeks; Katja M. Langen; Patrick A. Kupelian

    2006-01-01

    The incorporation of daily images into the radiotherapy process leads to adaptive radiation therapy (ART), in which the treatment is evaluated periodically and the plan is adaptively modified for the remaining course of radiotherapy. Deformable registration between the planning image and the daily images is a key component of ART. In this paper, we report our researches on deformable registration

  12. PTTG: an important target gene for ovarian cancer therapy

    Microsoft Academic Search

    Siva Kumar Panguluri; Casey Yeakel; Sham S Kakar

    2008-01-01

    Pituitary tumor transforming gene (PTTG), also known as securin is an important gene involved in many biological functions including inhibition of sister chromatid separation, DNA repair, organ development, and expression and secretion of angiogenic and metastatic factors. Proliferating cancer cells and most tumors express high levels of PTTG. Overexpression of PTTG in vitro induces cellular transformation and development of tumors

  13. Kalman Filtered MR Temperature Imaging for Laser Induced Thermal Therapies

    PubMed Central

    Fuentes, D.; Yung, J.; Hazle, J. D.; Weinberg, J. S.; Stafford, R. J.

    2013-01-01

    The feasibility of using a stochastic form of Pennes bioheat model within a 3D finite element based Kalman filter (KF) algorithm is critically evaluated for the ability to provide temperature field estimates in the event of magnetic resonance temperature imaging (MRTI) data loss during laser induced thermal therapy (LITT). The ability to recover missing MRTI data was analyzed by systematically removing spatiotemporal information from a clinical MR-guided LITT procedure in human brain and comparing predictions in these regions to the original measurements. Performance was quantitatively evaluated in terms of a dimensionless L2 (RMS) norm of the temperature error weighted by acquisition uncertainty. During periods of no data corruption, observed error histories demonstrate that the Kalman algorithm does not alter the high quality temperature measurement provided by MR thermal imaging. The KF-MRTI implementation considered is seen to predict the bioheat transfer with RMS error < 4 for a short period of time, ?t < 10sec, until the data corruption subsides. In its present form, the KF-MRTI method currently fails to compensate for consecutive for consecutive time periods of data loss ?t > 10sec. PMID:22203706

  14. Gene therapy for inherited muscle diseases: where genetics meets rehabilitation medicine.

    PubMed

    Braun, Robynne; Wang, Zejing; Mack, David L; Childers, Martin K

    2014-11-01

    The development of clinical vectors to correct genetic mutations that cause inherited myopathies and related disorders of skeletal muscle is advancing at an impressive rate. Adeno-associated virus vectors are attractive for clinical use because (1) adeno-associated viruses do not cause human disease and (2) these vectors are able to persist for years. New vectors are now becoming available as gene therapy delivery tools, and recent preclinical experiments have demonstrated the feasibility, safety, and efficacy of gene therapy with adeno-associated virus for long-term correction of muscle pathology and weakness in myotubularin-deficient canine and murine disease models. In this review, recent advances in the application of gene therapies to treat inherited muscle disorders are presented, including Duchenne muscular dystrophy and x-linked myotubular myopathy. Potential areas for therapeutic synergies between rehabilitation medicine and genetics are also discussed. PMID:25313664

  15. High quantum efficiency megavoltage imaging with thick scintillator detectors for image guided radiation therapy

    NASA Astrophysics Data System (ADS)

    Gopal, Arun

    In image guided radiation therapy (IGRT), imaging devices serve as guidance systems to aid patient set-up and tumor volume localization. Traditionally, 2-D megavoltage x-ray imagers, referred to as electronic portal imaging devices (EPIDs), have been used for planar target localization, and have recently been extended to perform 3-D volumetric reconstruction via cone-beam computed tomography (CBCT). However, current EPIDs utilize thin and inefficient phosphor screen detectors and are subsequently limited by poor soft tissue visualization, which limits their use for CBCT. Therefore, the use of thick scintillation media as megavoltage x-ray detectors for greater x-ray sensitivity and enhanced image quality has recently been of significant interest. In this research, two candidates for thick scintillators: CsI(Tl) and terbium doped scintillation glass were investigated in separate imaging configurations. In the first configuration, a thick scintillation crystal (TSC) consisting of a thick, monolithic slab of CsI(Tl) was coupled to a mirror-lens-camera system. The second configuration is based on a fiber-optic scintillation glass array (FOSGA), wherein the scintillation glass is drawn into long fiber-optic conduits, inserted into a grid-type housing constructed out of polymer-tungsten alloy, and coupled to an array of photodiodes for digital read-out. The imaging prototypes were characterized using theoretical studies and imaging measurements to obtain fundamental metrics of imaging performance. Spatial resolution was measured based on a modulation transfer function (MTF), noise was evaluated in terms of a noise power spectrum (NPS), and overall contrast was characterized in the form of detective quantum efficiency (DQE). The imaging studies were used to optimize the TSC and FOSGA imagers and propose prototype configurations for order-of-magnitude improvements in overall image quality. In addition, a fast and simple technique was developed to measure the MTF, NPS, and DQE metrics for clinical EPID and CBCT systems based on a novel adaptation of a traditional line-pair resolution bar-pattern. This research provides two significant benefits to radiotherapy: the characterization of a new generation of thick scintillator based megavoltage x-ray imagers for CBCT based IGRT, and the novel adaptation of fundamental imaging metrics from imaging research to routine clinical performance monitoring.

  16. Nanoparticles for biomedical imaging, therapy, and quantitative diagnostics

    NASA Astrophysics Data System (ADS)

    Yust, Brian G.

    Nanoparticles and nanomaterials are known to exhibit extraordinary characteristics and have a wide range of application which utilizes their unique properties. In particular, nanoparticles have shown great promise towards advancing the state of biological and biomedical techniques such as in vivo and in vitro imaging modalities, biosensing, and disease detection and therapy. Nanocrystalline hosts: NaYF4, KYF4, KGdF4, NaMF3, and KMF3 (M=Mg, Ba, Mn, Fe, Co, Ni, Cr) doped with rare earth ions have been synthesized by thermolysis, solvothermal, and hydrothermal methods. The morphology and spectroscopic properties have been thoroughly characterized. These nanoparticles (NP) are particularly useful for biomedical purposes since both the exciting and emitting wavelengths are in the near-infrared, where most tissues do not strongly absorb or scatter light. In vivo and in vitro imaging was performed with a 980 nm excitation source. Finally, NPs were conjugated with zinc phthalocyanine, a photosensitizer with a large absorption coefficient in the red and NIR regions, to illustrate the efficacy of these NPs as a platform for dual-mode infrared-activated imaging and photodynamic platforms. In addition, nonlinear optical nanomaterials, such as BaTiO3 and Ag@BaTiO3, were also synthesized and characterized. The nonlinear optical properties were investigated, and it is demonstrated that these nanoparticles can produce phase conjugate waves when used in a counterpropagating four wave mixing setup. The third order susceptibility is quantified using the z-scan technique, and the toxicity of these nanoparticles is also explored.

  17. Targeting cancer by transcriptional control in cancer gene therapy and viral oncolysis

    Microsoft Academic Search

    Dominik E. Dorer; Dirk M. Nettelbeck

    2009-01-01

    Cancer-specificity is the key requirement for a drug or treatment regimen to be effective against malignant disease—and has rarely been achieved adequately to date. Therefore, targeting strategies need to be implemented for future therapies to ensure efficient activity at the site of patients' tumors or metastases without causing intolerable side-effects. Gene therapy and viral oncolysis represent treatment modalities that offer

  18. Experimental studies on PNP suicide gene therapy of hepatoma

    Microsoft Academic Search

    Cai Xiaokun; Zhou Junli; Lin Jusheng; Sun Xuemei; Xue Xiulan; Li Chao

    2005-01-01

    Summary  To investigate the killing effect ofPNP\\/MeP-dR suicide gene system on hepatoma cells, pcDNA3. 0\\/PNP, an eukaryotic expression vector harboringE. coli PNP gene, was transfected into human hepatoma HepG2 cells by liposome-mediated method. A HepG2 cell line with stablePNP gene expression, HepG2\\/PNP, was established with presence of G418 selection. The cell growth curves were determined with trypan blue staining. The sensitivity

  19. Understanding the Tumor Microenvironment and Radioresistance by Combining Functional Imaging With Global Gene Expression

    PubMed Central

    Dewhirst, Mark W.; Chi, Jen-Tsan

    2013-01-01

    The objective of this review is to present an argument for performing joint analyses between functional imaging with global gene expression studies. The reason for making this link is that tumor microenvironmental influences on functional imaging can be uncovered. Such knowledge can lead to (1) more informed decisions regarding how to use functional imaging to guide therapy and (2) discovery of new therapeutic targets. As such, this approach could lead to identification of patients who need aggressive treatment tailored toward the phenotype of their tumor vs those who could be spared treatment that carries risk for more normal tissue complications. Only a handful of papers have been published on this topic thus far, but all show substantial promise. PMID:24012344

  20. Developing the concept of adoptive cellular gene therapy of rheumatoid arthritis.

    PubMed

    Tarner, Ingo H; Neumann, Elena; Gay, Steffen; Fathman, C Garrison; Müller-Ladner, Ulf

    2006-02-01

    Progressive destruction of articular cartilage and bone is the pivotal problem of rheumatoid arthritis (RA). Joint destruction is the cause of severe disability and determines the long-term outcome of disease. Conventional therapy does not control this destructive process sufficiently and the anti-rheumatic drugs available today can cause severe systemic adverse effects. Local application of chondroprotective and osteoprotective agents by means of gene therapy would be an attractive alternative to conventional therapy of RA and could provide long-term expression of the therapeutic agents and minimize systemic adverse effects. For this purpose, we have developed the concept of adoptive cellular gene therapy. This treatment strategy is based on using genetically engineered cells that home specifically to sites of autoimmune inflammation and thus allow local delivery of therapeutic gene products. Ex vivo transduction of these cells avoids systemic exposure of the host to the transgene-encoding vector and thus adds to the safety of this approach. In this article of the CIS Spring School in Autoimmune Diseases 2005 proceedings, we review our work on developing the strategy of adoptive cellular gene therapy and summarize recent advances in the evaluation of therapeutic effects and the identification of novel therapeutic targets. PMID:16431349

  1. Cell-based reporter gene assay for therapy-induced neutralizing antibodies to interferon-beta in multiple sclerosis.

    PubMed

    Martins, Thomas B; Rose, John W; Gardiner, Gareth L; Kusukawa, Noriko; Husebye, Dee; Hill, Harry R

    2013-02-01

    Patients with therapy-induced neutralizing antibodies (NAbs) to interferon-beta (IFN-?) have reduced responses to IFN-? treatment, resulting in higher relapse rates, increased magnetic resonance imaging activity, and a higher risk of disease progression. A functional assay was employed for both screening and titering of IFN-? NAbs utilizing a human cell line transfected with a luciferase reporter gene responsive to IFN-?. This assay demonstrated 100% sensitivity and specificity compared with the traditional cytopathic effect (CPE) assay and normal donor specimens. Additionally, 183 patients with multiple sclerosis (MS) undergoing therapy with IFN-? were tested in the reporter gene assay. Percent positivity for NAbs to the IFN-? was as follows: Avonex (1?) 26.5%, Rebif (1?) 34.1%, and Betaseron (1?) 31.8%. The IFN-? reporter gene assay showed excellent correlation with the well-established CPE assay offering clear advantages. The 50% false-positivity rate typically seen in enzyme-linked immunosorbent assays could be eliminated by using a functional assay for both screening and titering. Results can be reported within 20 h, and the cell line is cryopreserved, eliminating the need to maintain live viral and cell cultures. The use of this functional assay should be a valuable tool for detecting and monitoring the presence of NAbs in IFN-?-treated patients with MS. PMID:23153300

  2. Monitoring proton radiation therapy with in-room PET imaging

    PubMed Central

    Zhu, Xuping; España, Samuel; Daartz, Juliane; Liebsch, Norbert; Ouyang, Jinsong; Paganetti, Harald; Bortfeld, Thomas R; El Fakhri, Georges

    2011-01-01

    Purpose We used a mobile PET scanner positioned within the proton therapy treatment room to study the feasibility of proton range verification with an in-room, stand-alone PET system, and compared with off-line equivalent studies. Methods and materials Two subjects with adenoid cystic carcinoma were enrolled into a pilot study in which in-room PET scans were acquired in list-mode after a routine fractionated treatment session. The list-mode PET data were reconstructed with different time schemes to generate in-room short, in-room long and off-line equivalent (by skipping coincidences from the first 15 minutes during the list-mode reconstruction) PET images for comparison in activity distribution patterns. A phantom study was followed to evaluate the accuracy of range verification for different reconstruction time schemes quantitatively. Results The in-room PET has a higher sensitivity compared to the off-line modality so that the PET acquisition time can be greatly reduced from 30 min to <5 min. Features in deep-site, soft-tissue regions were better retained with in-room short PET acquisitions because of the collection of 15O component and lower biological washout. For soft tissue-equivalent material, the distal fall-off edge of an in-room short acquisition is deeper compared to an off-line equivalent scan, indicating a better coverage of the high-dose end of the beam. Conclusions In-room PET is a promising low cost, high sensitivity modality for the in vivo verification of proton therapy. Better accuracy in Monte Carlo predictions, especially for biological decay modeling, is necessary. PMID:21677366

  3. Delivery of gene silencing agents for breast cancer therapy

    PubMed Central

    2013-01-01

    The discovery of RNA interference has opened the door for the development of a new class of cancer therapeutics. Small inhibitory RNA oligos are being designed to specifically suppress expression of proteins that are traditionally considered nondruggable, and microRNAs are being evaluated to exert broad control of gene expression for inhibition of tumor growth. Since most naked molecules are not optimized for in vivo applications, the gene silencing agents need to be packaged into delivery vehicles in order to reach the target tissues as their destinations. Thus, the selection of the right delivery vehicles serves as a crucial step in the development of cancer therapeutics. The current review summarizes the status of gene silencing agents in breast cancer and recent development of candidate cancer drugs in clinical trials. Nanotechnology-based delivery vectors for the formulation and packaging of gene silencing agents are also described. PMID:23659575

  4. Viral genes as oncolytic agents for cancer therapy.

    PubMed

    Gupta, Shishir Kumar; Gandham, Ravi Kumar; Sahoo, A P; Tiwari, A K

    2015-03-01

    Many viruses have the ability to modulate the apoptosis, and to accomplish it; viruses encode proteins which specifically interact with the cellular signaling pathways. While some viruses encode proteins, which inhibit the apoptosis or death of the infected cells, there are viruses whose encoded proteins can kill the infected cells by multiple mechanisms, including apoptosis. A particular class of these viruses has specific gene(s) in their genomes which, upon ectopic expression, can kill the tumor cells selectively without affecting the normal cells. These genes and their encoded products have demonstrated great potential to be developed as novel anticancer therapeutic agents which can specifically target and kill the cancer cells leaving the normal cells unharmed. In this review, we will discuss about the viral genes having specific cancer cell killing properties, what is known about their functioning, signaling pathways and their therapeutic applications as anticancer agents. PMID:25408521

  5. Nutrition Therapy for Mitochondrial Neurogastrointestinal Encephalopathy with Homozygous Mutation of the TYMP Gene

    PubMed Central

    Wang, Jing; Wang, Fang; Wu, Dong; Qian, Jiaming; Kang, Junren; Li, Hailong; Ma, Enling

    2015-01-01

    Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is characterized by significant gastrointestinal dysmotility. Early and long-term nutritional therapy is highly recommended. We report a case of MNGIE in a patient who was undergoing long-term nutrition therapy. The patient was diagnosed with a serious symptom of fatty liver and hyperlipidemia complications, along with homozygous mutation of the thymidine phosphorylase (TYMP) gene (c.217G > A). To our knowledge, this is the first report of such a case. Herein, we describe preventive measures for the aforementioned complications and mitochondrial disease-specific nutritional therapy. PMID:25954734

  6. Development of an interleukin 2 receptor targeted gene therapy vehicle

    E-print Network

    Wattanakaroon, Wanida

    2006-08-16

    for the malignant phenotype in human cancer. Gene alterations include serial oncogene activation and tumor suppressor gene inactivation (Tripathy, 2000). The leukemias and lymphomas are malignant tumors or cancers of hematopoietic cells of the bone marrow. T... Publishing Group). Allograft rejection Bone marrow Cardiac Liver Renal Autoimmune disease Aplastic anaemia Behcet?s syndrome Crohn?s disease Giant cell arteritis Juvenile rheumatoid arthritis Kawasaki disease Multiple sclerosis Polymalgia...

  7. Allium sativum potentiates suicide gene therapy for murine transitional cell carcinoma.

    PubMed

    Moon, D G; Cheon, J; Yoon, D H; Park, H S; Kim, H K; Kim, J J; Koh, S K

    2000-01-01

    This study evaluated the synergistic effect of Allium sativum (AS) with suicide gene therapy for transitional cell carcinoma (TCC) of the bladder. Subcutaneous TCCs were established in syngeneic C3H/He mice with 1 x 10(5) MBT-2 cells. AS liquid extract was injected at the site of tumor transplantation on Day 1 for three weeks (Experiment I) and into the established tumors weekly for five weeks (Experiment II) in combination with or without gene therapy using a replication-defective adenoviral vector containing a herpes simplex virus thymidine kinase (HSV-TK) gene under the transcriptional control of Rous sarcoma virus (RSV) promoter (Ad-RSV-TK, 5 x 10(8) plaque-forming units) plus ganciclovir (20 mg/kg/day i.p.). AS demonstrated a statistically significant reduction in incidence of TCC (cumulative dose 25 mg of AS). Combination AS-suicide gene therapy significantly inhibited the tumor growth compared with the controls, which was evidenced by apoptosis on histomorphological and immunohistochemical studies. These results suggest that AS had a definite antitumor effect in inhibiting tumorigenesis and growth of TCC in a murine model. AS treatment combined with suicide gene therapy had significant additive antitumor effects on TCC and may provide a novel and effective treatment modality for TCC of the bladder. PMID:11341051

  8. Gene therapy to restore prostacyclin presence to injured endothelium.

    PubMed Central

    Willerson, J. T.; Zoldhelyi, P.; Meidell, R.; McNatt, J.; Xu, X. M.; Wu, K. K.

    1995-01-01

    These preliminary studies demonstrate the feasibility of restoration of prostacyclin synthesis in mechanically-injured porcine carotid arteries following angioplasty. Our initial data suggest the possibility of inhibiting thrombus development by adenovirus-CMV-PGHS-1 therapy in the initial 10 days following angioplasty. PMID:7483165

  9. In Vivo Gene Therapy of Hemophilia B: Sustained Partial Correction in Factor IX-Deficient Dogs

    NASA Astrophysics Data System (ADS)

    Kay, Mark A.; Rothenberg, Steven; Landen, Charles N.; Bellinger, Dwight A.; Leland, Frances; Toman, Carol; Finegold, Milton; Thompson, Arthur R.; Read, M. S.; Brinkhous, Kenneth M.; Woo, Savio L. C.

    1993-10-01

    The liver represents a model organ for gene therapy. A method has been developed for hepatic gene transfer in vivo by the direct infusion of recombinant retroviral vectors into the portal vasculature, which results in the persistent expression of exogenous genes. To determine if these technologies are applicable for the treatment of hemophilia B patients, preclinical efficacy studies were done in a hemophilia B dog model. When the canine factor IX complementary DNA was transduced directly into the hepatocytes of affected dogs in vivo, the animals constitutively expressed low levels of canine factor IX for more than 5 months. Persistent expression of the clotting. factor resulted in reductions of whole blood clotting and partial thromboplastin times of the treated animals. Thus, long-term treatment of hemophilia B patients may be feasible by direct hepatic gene therapy in vivo.

  10. Transcriptional targeting of dendritic cells for gene therapy using the promoter of the cytoskeletal protein fascin

    Microsoft Academic Search

    R Ross; S Sudowe; J Beisner; X-L Ross; I Ludwig-Portugall; J Steitz; T Tüting; J Knop; A B Reske-Kunz

    2003-01-01

    Strong cell-type-specific promoters are basic tools in gene therapy allowing for novel applications and focused strategies by transcriptionally targeting gene expression to selected cells. In immunotherapy, dendritic cells (DC) are of central importance, since they represent the principal inducers of immune responses. Here we describe isolation and use of the promoter of the murine actin-bundling protein fascin to target transcriptionally

  11. Glucose transport and apoptosis after gene therapy with HSV thymidine kinase

    Microsoft Academic Search

    Uwe Haberkorn; Annette Altmann; Huse Kamencic; Iris Morr; Ulrike Traut; Marcus Henze; Shiming Jiang; Jürgen Metz; Ralf Kinscherf

    2001-01-01

    The relation between tumour metabolism and induction of apoptosis by gene therapy was investigated in a rat Morris hepatoma (MH3924A) model expressing the HSV thymidine kinase (HSVtk) gene. In vivo the amount of glucose transporter (GLUT1 and GLUT3 isoforms) expressing cells was determined in tumours of untreated and treated animals using immunohistochemistry. In vitro uptake studies with 2-fluoro-2-deoxy-D-glucose (FDG), 3-O-methylglucose

  12. Evaluation of fibroblast-mediated gene therapy in a feline model of mucopolysaccharidosis type VI

    Microsoft Academic Search

    Gouri Yogalingam; Allison Crawley; John J Hopwood; Donald S Anson

    1999-01-01

    Fibroblast-mediated ex vivo gene therapy was evaluated in the N-acetylgalactosamine 4-sulfatase (4S) deficient mucopolysaccharidosis type VI (MPS VI) cat. Skin biopsies were obtained at birth from severely affected MPS VI kittens and used to initiate fibroblast outgrowths for retroviral transduction with the 4S cDNA. 4S gene expression in transduced cells was under the transcriptional control of the MoMLV long terminal

  13. Combined radiation and p53 gene therapy of malignant glioma cells

    Microsoft Academic Search

    Behnam Badie; Chern Sing Goh; Jessica Klaver; Hans Herweijer; David A Boothman

    1999-01-01

    More than half of malignant gliomas reportedly have alterations in the p53 tumor suppressor gene. Because p53 plays a key role in the cellular response to DNA-damaging agents, we investigated the role of p53 gene therapy before ionizing radiation in cultured human glioma cells containing normal or mutated p53. Three established human glioma cell lines expressing the wild-type (U87 MG,

  14. Gene therapy approaches to regenerating the musculoskeletal system.

    PubMed

    Evans, Christopher H; Huard, Johnny

    2015-04-01

    Injuries to the musculoskeletal system are common, debilitating and expensive. In many cases, healing is imperfect, which leads to chronic impairment. Gene transfer might improve repair and regeneration at sites of injury by enabling the local, sustained and potentially regulated expression of therapeutic gene products; such products include morphogens, growth factors and anti-inflammatory agents. Proteins produced endogenously as a result of gene transfer are nascent molecules that have undergone post-translational modification. In addition, gene transfer offers particular advantages for the delivery of products with an intracellular site of action, such as transcription factors and noncoding RNAs, and proteins that need to be inserted into a cell compartment, such as a membrane. Transgenes can be delivered by viral or nonviral vectors via in vivo or ex vivo protocols using progenitor or differentiated cells. The first gene transfer clinical trials for osteoarthritis and cartilage repair have already been completed. Various bone-healing protocols are at an advanced stage of development, including studies with large animals that could lead to human trials. Other applications in the repair and regeneration of skeletal muscle, intervertebral disc, meniscus, ligament and tendon are in preclinical development. In addition to scientific, medical and safety considerations, clinical translation is constrained by social, financial and logistical issues. PMID:25776949

  15. The American Society of Gene Therapy 244 www.moleculartherapy.org vol.16no.2,244251feb.2008

    E-print Network

    Cai, Long

    © The American Society of Gene Therapy 244 www.moleculartherapy.org vol.16no.2,244­251feb.2008 Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic Adenovirus gene therapy for intraperitoneal (IP) cancer is limited in clinical trials by inefficient tumor cell trans- duction and development

  16. Gene Therapy (1998) 5, 196208 1998 Stockton Press All rights reserved 0969-7128/98 $12.00

    E-print Network

    Engelhardt, John F.

    1998-01-01

    , hyperbaric oxygen and chemical toxins.20­28 Interventional approaches toward modulation of levelsGene Therapy (1998) 5, 196­208 © 1998 Stockton Press All rights reserved 0969-7128/98 $12.00 Prevention of late effects of irradiation lung damage by manganese superoxide dismutase gene therapy M

  17. Faster T-cell development following gene therapy compared with haploidentical HSCT in the treatment of SCID-X1.

    PubMed

    Touzot, Fabien; Moshous, Despina; Creidy, Rita; Neven, Bénédicte; Frange, Pierre; Cros, Guilhem; Caccavelli, Laure; Blondeau, Johanna; Magnani, Alessandra; Luby, Jean-Marc; Ternaux, Brigitte; Picard, Capucine; Blanche, Stéphane; Fischer, Alain; Hacein-Bey-Abina, Salima; Cavazzana, Marina

    2015-06-01

    During the last decade, gene therapy via ex vivo gene transfer into autologous hematopoietic stem cells has emerged as a convincing therapy for severe combined immunodeficiency caused by ILR2G mutation (SCID-X1) despite the occurrence of genotoxicity caused by the integration of first-generation retroviral vectors. However, the place of gene therapy among the therapeutic armamentarium remains to be defined. We retrospectively analyze and compare clinical outcomes and immune reconstitution in 13 consecutive SCID-X1 patients having undergone haploidentical hematopoietic stem cell transplantation (HSCT) and 14 SCID-X1 patients treated with gene therapy over the same period at a single center level: the Necker Children's Hospital (Paris, France). Our results show a clear advantage in terms of T-cell development of gene therapy over HSCT with a mismatched donor. Patients treated with gene therapy display a faster T-cell reconstitution and a better long-term thymic output. Interestingly, this advantage of gene therapy vs haploidentical HSCT seems to be independent of the existence of clinical graft-versus-host disease in the latter condition. If data of safety are confirmed over the long term, gene therapy for SCID-X1 appears to be an equal, if not superior, alternative to haploidentical HSCT. PMID:25869287

  18. Phthalocyanine-labeled LDL for tumor imaging and photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Li, Hui; Marotta, Diane; Kim, Soungkyoo; Chance, Britton; Glickson, Jerry D.; Busch, Theresa M.; Zheng, Gang

    2005-01-01

    Current limitation of both near-infrared (NIR) tumor imaging and photodynamic therapy (PDT) is their lack of sufficient tumor-to-tissue contrast due to the relatively non-specific nature of delivering dye to the tumor, which has led to false negatives for NIR imaging and inadequate therapeutic ratio for PDT. Hence, agents targeting "cancer signatures", i.e. molecules that accumulate selectively in cancer cells, are particular attractive. One of these signatures is low-density-lipoprotein receptor (LDLR), which is overexpressed in many tumors. We have developed pyropheophorbide cholesterol oleate reconstituted LDL as a LDLR-targeting photosensitizer (PS) and demonstrated its LDLR-mediated uptake in vitro and in vivo. To improve the labeling efficiency for achieving high probe/protein ratio, tetra-t-butyl silicon phthalocyanine bearing two oleate moieties at its axial positions, (tBu)4SiPcBOA, was designed and synthesized. This compound was designed to 1) prevent the PS aggregation; 2) improve the PS solubility in non-polar solvent; and 3) maximize the PS binding to LDL phospholipid monolayer. Using this novel strategy, (tBu)4SiPcBOA was reconstituted into LDL (r-SiPcBOA-LDL) with a very high payload (500:1 molar ratio). In addition, (tBu)4SiPcBOA reconstituted acetylated LDL (r-SiPcBOA)-AcLDL with similar payload was also prepared. Since Ac-LDL cannot bind to LDLR, (r-SiPcBOA)-AcLDL can serve as the negative control to evaluate LDLR targeting specificity. For biological evaluation of these new agents, confocal microscopy and in vitro PDT protocols were performed using LDLR-overexpressing human hepatoblastoma G2 (HepG2) tumor model. These studies suggest that LDL serves as a delivery vehicle to bring large amount of the NIR/PDT agents selectively to tumor cells overexpressing LDLR.

  19. Flat-panel cone-beam computed tomography for image-guided radiation therapy

    Microsoft Academic Search

    David A Jaffray; Jeffrey H Siewerdsen; John W Wong; Alvaro A Martinez

    2002-01-01

    Purpose: Geometric uncertainties in the process of radiation planning and delivery constrain dose escalation and induce normal tissue complications. An imaging system has been developed to generate high-resolution, soft-tissue images of the patient at the time of treatment for the purpose of guiding therapy and reducing such uncertainties. The performance of the imaging system is evaluated and the application to

  20. Automatic 3D Ultrasound Calibration for Image Guided Therapy Using Intramodality Image Registration

    PubMed Central

    Schlosser, Jeffrey; Kirmizibayrak, Can; Shamdasani, Vijay; Metz, Steve; Hristov, Dimitre

    2013-01-01

    Many real time ultrasound (US) guided therapies can benefit from management of motion-induced anatomical changes with respect to a previously acquired computerized anatomy model. Spatial calibration is a prerequisite to transforming US image information to the reference frame of the anatomy model. We present a new method for calibrating 3D US volumes using intramodality image registration, derived from the “hand eye” calibration technique. The method is fully automated by implementing data rejection based on sensor displacements, automatic registration over overlapping image regions, and a self-consistency error metric evaluated continuously during calibration. We also present a novel method for validating US calibrations based on measurement of physical phantom displacements within US images. Both calibration and validation can be performed on arbitrary phantoms. Results indicate that normalized mutual information and localized cross correlation produce the most accurate 3D US registrations for calibration. Volumetric image alignment is more accurate and reproducible than point selection for validating the calibrations, yielding <1.5 mm root mean square error, a significant improvement relative to previously reported hand eye US calibration results. Comparison of two different phantoms for calibration and for validation revealed significant differences for validation (p=0.003) but not for calibration (p=0.795). PMID:24099806

  1. Non Viral Vectors in Gene Therapy- An Overview

    PubMed Central

    Narvekar, Aparna

    2015-01-01

    Non-viral vectors are simple in theory but complex in practice. Apart from intra cellular and extracellular barriers, number of other challenges also needs to be overcome in order to increase the effectiveness of non-viral gene transfer. These barriers are categorized as production, formulation and storage. No one-size-fits-all solution to gene delivery, which is why in spite of various developments in liposome, polymer formulation and optimization, new compounds are constantly being proposed and investigated. In this review, we will see in detail about various types of non-viral vectors highlighting promising development and recent advances that had improved the non-viral gene transfer efficiency of translating from “Bench to bedside”. PMID:25738007

  2. Intelligent image analysis for image-guided hair removal and skin therapy

    NASA Astrophysics Data System (ADS)

    Walker, Brian; Lu, Thomas; Chao, Tien-Hsin

    2012-02-01

    We present the development of advanced automatic target recognition (ATR) algorithms for the hair follicles identification in digital skin images to accurately direct the laser beam to remove the hair. The ATR system first performs a wavelet filtering to enhance the contrast of the hair features in the image. The system then extracts the unique features of the targets and sends the features to an Adaboost based classifier for training and recognition operations. The ATR system automatically classifies the hair, moles, or other skin lesion and provides the accurate coordinates of the intended hair follicle locations. The coordinates can be used to guide a scanning laser to focus energy only on the hair follicles. The intended benefit would be to protect the skin from unwanted laser exposure and to provide more effective skin therapy.

  3. An integrated platform for image-guided cardiac resynchronization therapy

    NASA Astrophysics Data System (ADS)

    Ma, Ying Liang; Shetty, Anoop K.; Duckett, Simon; Etyngier, Patrick; Gijsbers, Geert; Bullens, Roland; Schaeffter, Tobias; Razavi, Reza; Rinaldi, Christopher A.; Rhode, Kawal S.

    2012-05-01

    Cardiac resynchronization therapy (CRT) is an effective procedure for patients with heart failure but 30% of patients do not respond. This may be due to sub-optimal placement of the left ventricular (LV) lead. It is hypothesized that the use of cardiac anatomy, myocardial scar distribution and dyssynchrony information, derived from cardiac magnetic resonance imaging (MRI), may improve outcome by guiding the physician for optimal LV lead positioning. Whole heart MR data can be processed to yield detailed anatomical models including the coronary veins. Cine MR data can be used to measure the motion of the LV to determine which regions are late-activating. Finally, delayed Gadolinium enhancement imaging can be used to detect regions of scarring. This paper presents a complete platform for the guidance of CRT using pre-procedural MR data combined with live x-ray fluoroscopy. The platform was used for 21 patients undergoing CRT in a standard catheterization laboratory. The patients underwent cardiac MRI prior to their procedure. For each patient, a MRI-derived cardiac model, showing the LV lead targets, was registered to x-ray fluoroscopy using multiple views of a catheter looped in the right atrium. Registration was maintained throughout the procedure by a combination of C-arm/x-ray table tracking and respiratory motion compensation. Validation of the registration between the three-dimensional (3D) roadmap and the 2D x-ray images was performed using balloon occlusion coronary venograms. A 2D registration error of 1.2 ± 0.7 mm was achieved. In addition, a novel navigation technique was developed, called Cardiac Unfold, where an entire cardiac chamber is unfolded from 3D to 2D along with all relevant anatomical and functional information and coupled to real-time device detection. This allowed more intuitive navigation as the entire 3D scene was displayed simultaneously on a 2D plot. The accuracy of the unfold navigation was assessed off-line using 13 patient data sets by computing the registration error of the LV pacing lead electrodes which was found to be 2.2 ± 0.9 mm. Furthermore, the use of Unfold Navigation was demonstrated in real-time for four clinical cases.

  4. original article The American Society of Gene & Cell Therapy Molecular Therapy vol. 17 no. 8, 13651372 aug. 2009 1365

    E-print Network

    Cai, Long

    warrants development of innovative therapies. Cancer therapy using oncolytic viruses represents a promising therapies for advanced disease, such as chemotherapy and radiation therapy, rarely result in long approaches to control advanced stage ovarian carcinoma. Cancer therapy using oncolytic viruses represents

  5. GENE THERAPY Preclinical in vivo evaluation of pseudotyped adeno-associated virus vectors

    E-print Network

    Kay, Mark A.

    and particle doses, hepatic vector administration yielded up to 84-fold more hFIX protein than tail vein the development of AAV pseudotype-based gene therapies for he- mophilia B and other liver-related dis- eases. (Blood. 2003;102:2412-2419) © 2003 by The American Society of Hematology Introduction Hemophilia B

  6. Role of gene therapy in tissue engineering procedures in rheumatology: the use of animal models

    Microsoft Academic Search

    Peter M. van der Kraan; Wim B. van den Berg

    2004-01-01

    Tissue engineering is not only the application of cells and scaffolds to generate a new tissue but should also bring into play biological principles to guide cellular behavior. A way to modify cellular behavior is genetic modification of the cells used for tissue engineering (gene therapy). In the field of rheumatic diseases, cellular modification by overexpressing anabolic factors, such as

  7. Comparison of ventricular and intravenous lentiviral-mediated gene therapy for murine MPS VII

    Microsoft Academic Search

    Julie Bielicki; Chantelle McIntyre; Donald S. Anson

    2010-01-01

    Mucopolysaccharidosis type VII (MPS VII) is caused by the deficiency of the lysosomal hydrolase ?-glucuronidase. Symptoms include intellectual impairment, growth retardation, visual and hearing deficits and organ malfunction. The MPS VII mouse displays most of the symptoms variously associated with the MPS disorders, and has been widely used as a developmental paradigm for gene therapy.In this study, a lentiviral vector

  8. HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Neonatal or hepatocyte growth factorpotentiated adult gene therapy with a

    E-print Network

    Ponder, Katherine P.

    gene therapy with a retroviral vector results in therapeutic levels of canine factor IX for hemophilia, Robin A. Raymer, Stephanie McCorquodale, and Katherine Parker Ponder Hemophilia B is a bleeding disorder in plasma (100% is 5 g/ mL), which was functional in vitro and in vivo. Three newborn hemophilia B dogs

  9. Effective healing of diabetic skin wounds by using nonviral gene therapy based on minicircle vascular

    E-print Network

    Park, Jong-Sang

    is urgently required for diabetic patients suffering a threat of limb amputations. Various growth factors haveEffective healing of diabetic skin wounds by using nonviral gene therapy based on minicircle subcutaneously into the skin wounds of diabetic mice. Results Actively proliferating cells in wound tissue were

  10. Gene therapy and radiation of malignant glioma by targeting glioma specific lactate transporter

    Microsoft Academic Search

    Chaim B Colen

    2005-01-01

    Glioblastoma multiforme are highly malignant tumors that produce large amounts of lactate as a by-product of glucose consumption. We investigated inhibition of lactate efflux as a novel method to destructively alter the metabolite profile in these tumors to induce tumor-specific apoptosis and radiosensitization, thus adding a wing to our current growing armament of gene therapies against cancer. Thus, our main

  11. Gene Therapy for the Treatment of Chronic Peripheral Nervous System Pain

    PubMed Central

    Goins, William F.; Cohen, Justus B.; Glorioso, Joseph C.

    2012-01-01

    Chronic pain is a major health concern affecting 80 million Americans at some time in their lives with significant associated morbidity and effects on individual quality of life. Chronic pain can result from a variety of inflammatory and nerve damaging events that include cancer, infectious diseases, autoimmune-related syndromes and surgery. Current pharmacotherapies have not provided an effective long-term solution as they are limited by drug tolerance and potential abuse. These concerns have led to the development and testing of gene therapy approaches to treat chronic pain. The potential efficacy of gene therapy for pain has been reported in numerous pre-clinical studies that demonstrate pain control at the level of the spinal cord. This promise has been recently supported by a Phase-I human trial in which a replication-defective herpes simplex virus (HSV) vector was used to deliver the human pre-proenkephalin (hPPE) gene, encoding the natural opioid peptides met- and leu-enkephalin (ENK), to cancer patients with intractable pain resulting from bone metastases (Fink et al., 2011). The study showed that the therapy was well tolerated and that patients receiving the higher doses of therapeutic vector experienced a substantial reduction in their overall pain scores for up to a month post vector injection. These exciting early clinical results await further patient testing to demonstrate treatment efficacy and will likely pave the way for other gene therapies to treat chronic pain. PMID:22668775

  12. REPORT AND RECOMMENDATIONS OF THE PANEL TO ASSESS THE NIH INVESTMENT IN RESEARCH ON GENE THERAPY

    Microsoft Academic Search

    Stuart H. Orkin; Arno G. Motulsky

    Dr. Harold Varmus, Director, National Institutes of Health (NIH), appointed an ad hoc committee to assess the current status and promise of gene therapy and provide recommendations regarding future NIH-sponsored research in this area. The Panel was asked specifically to comment on how funds and efforts should be distributed among various research areas and what funding mechanisms would be most

  13. Public Attitudes to Human Gene Therapy: A Pilot Study in Wales

    Microsoft Academic Search

    Rachel Iredale; Gina Dolan; Kevin McDonald; Maggie Kirk

    2003-01-01

    Objective: This study aimed to explore some factors influencing perceptions of human gene therapy. Method: A small qualitative study using two semi-structured interviews per participant (n = 22). The groups comprised (1) people with cystic fibrosis and members of their family (n = 9), and (2) students from a science evening class as well as lay members of the public

  14. Combinatorial Anti-HIV Gene Therapy: Using a Multi-Pronged Approach to Reach Beyond HAART

    PubMed Central

    Peterson, Christopher W; Younan, Patrick; Jerome, Keith R; Kiem, Hans-Peter

    2013-01-01

    The “Berlin Patient,” who maintains suppressed levels of HIV viremia in the absence of antiretroviral therapy, continues to be a standard bearer in HIV eradication research. However, the unique circumstances surrounding his functional cure are not applicable to most HIV+ patients. To achieve a functional or sterilizing cure in a greater number of infected individuals worldwide, combinatorial treatments, targeting multiple stages of the viral life cycle, will be essential. Several anti-HIV gene therapy approaches have recently been explored, including disruption of the CCR5 and CXCR4 coreceptor loci in CD4+ T-cells and CD34+ hematopoietic stem cells. However, less is known about the efficacy of these strategies in patients and more relevant HIV model systems such as nonhuman primates. Combinatorial approaches, including genetic disruption of integrated provirus, functional enhancement of endogenous restriction factors, and/or the use of pharmacological adjuvants, could amplify the anti-HIV effects of CCR5/CXCR4 gene disruption. Importantly, delivering gene disruption molecules to genetic sites of interest will likely require optimization on a cell type-by-cell type basis. In this review, we highlight the most promising gene therapy approaches to combat HIV infection, methods to deliver these therapies to hematopoietic cells, and emphasize the need to target viral replication pre- and post-entry in order to mount a suitably robust defense against spreading infection. PMID:23364313

  15. Genome medicine: gene therapy for the millennium, 30 September–3 October 2001, Rome, Italy

    Microsoft Academic Search

    D C Gruenert; G Novelli; B Dallapiccola; A Colosimo

    2002-01-01

    The recent surge of DNA sequence information resulting from the efforts of agencies interested in deciphering the human genetic code has facilitated technological developments that have been critical in the identification of genes associated with numerous disease pathologies. In addition, these efforts have opened the door to the opportunity to develop novel genetic therapies to treat a broad range of

  16. Identification and removal of colanic acid from plasmid DNA preparations: implications for gene therapy

    Microsoft Academic Search

    P Firozi; W Zhang; L Chen; F A Quiocho; K C Worley; N S Templeton

    2010-01-01

    Polysaccharide contaminants in plasmid DNA, including current good manufacturing practices (cGMP) clinical preparations, must be removed to provide the greatest safety and efficacy for use in gene therapy and other clinical applications. We developed assays and methods for the detection and removal of these polysaccharides, our Super Clean DNA (SC-DNA) process, and have shown that these contaminants in plasmid DNA

  17. Sleeping Beauty Transposon?Mediated Gene Therapy for Prolonged Expression

    Microsoft Academic Search

    Perry B. Hackett; Stephen C. Ekker; David A. Largaespada; R. Scott McIvor

    2005-01-01

    The Sleeping Beauty (SB) transposon system represents a new vector for non?viral gene transfer that melds advantages of viruses and other forms of naked DNA transfer. The transposon itself is comprised of two inverted terminal repeats of about 340 base pairs each. The SB system directs precise transfer of specific constructs from a donor plasmid into a mammalian chromosome. The

  18. Imaging, Diagnosis, Prognosis Gene Expression Analysis Identifies Potential Biomarkers of

    E-print Network

    Hammerton, James

    Imaging, Diagnosis, Prognosis Gene Expression Analysis Identifies Potential Biomarkers to verify NF1 diagnosis, monitor tumor burden, and/or detect transformation. Experimental Design: We used of transformation to MPNST. Clin Cancer Res; 16(20); 5048­57. ©2010 AACR. Neurofibromatosis type 1 (NF1

  19. Feasibility of an image planning system for kilovoltage image-guided radiation therapy

    SciTech Connect

    Thapa, Bishnu B.; Molloy, Janelle A. [Department of Radiation Medicine, University of Kentucky, Lexington, Kentucky 40536-0293 (United States)

    2013-06-15

    Purpose: Image guidance has become a standard of care for many treatment scenarios in radiation therapy. This is most typically accomplished by use of kV x-ray devices mounted onto the linear accelerator (Linac) gantry that yield planar, fluoroscopic, and cone-beam computed tomography (CBCT) images. Image acquisition parameters are chosen via preset techniques that rely on broad categorizations in patient anatomy and imaging goal. However, the optimal imaging technique results in detectability of the features of interest while exposing the patient to minimum dose. Herein, the authors present an investigation into the feasibility of developing an image planning system (IPS) for radiotherapy.Methods: In this first phase, the authors focused on developing an algorithm to predict tissue contrast produced by a common radiotherapy planar imaging chain. Input parameters include a CT dataset and simulated planar imaging technique settings that include kV and mAs. Energy-specific attenuation through each voxel of the CT dataset was calculated in the algorithm to derive a net transmitted intensity. The response of the flat panel detector was integrated into the image simulation algorithm. Verification was conducted by comparing simulated and measured images using four phantoms. Comparisons were made in both high and low contrast settings, as well as changes in the geometric appearance due to image saturation. Results: The authors studied a lung nodule test object to assess the planning system's ability to predict object contrast and detectability. Verification demonstrated that the slope of the pixel intensities is similar, the presence of the nodule is evident, and image saturation at high mAs values is evident in both images. The appearance of the lung nodule is a function of the image detector saturation. The authors assessed the dimensions of the lung nodule in measured and simulated images. Good quantitative agreement affirmed the algorithm's predictive capabilities. The invariance of contrast with kVp and mAs prior to saturation was predicted, as well as the gradual loss of object detectability as saturation was approached. Small changes in soft tissue density were studied using a mammography step wedge phantom. Data were acquired at beam qualities of 80 and 120 kVp and over exposure values ranging from 0.04 to 500 mAs. The data showed good agreement in terms of the absolute value of pixel intensities predicted, as well as small variations across the step wedge pattern. The saturation pixel intensity was consistent between the two beam qualities studied. Boney tissue contrast was assessed using two abdominal phantoms. Measured and calculated values agree in terms of predicting the mAs value at which detector saturation, and subsequent loss of contrast occurs. The lack of variation in contrast over mAs values lower than 10 suggests that there is wide latitude for minimizing patient dose. Conclusions: The authors developed and tested an algorithm that can be used to assist in kV imaging technique selection during localization for radiotherapy. Phantom testing demonstrated the algorithm's predictive accuracy for both low and high contrast imaging scenarios. Detector saturation with subsequent loss of imaging detail, both in terms of object size and contrast were accurately predicted by the algorithm.

  20. Gene therapy for pancreatic cancer targeting the genomic alterations of tumor suppressor genes using replication-selective oncolytic adenovirus

    Microsoft Academic Search

    Makoto Sunamura; Masaru Oonuma; Fuyuhiko Motoi; Hisashi Abe; Yukoh Saitoh; Toru Hoshida; Shigeru Ottomo; Akira Horii; Seiki Matsuno

    2002-01-01

    In order to develop an effective therapeutic intervention for patients with pancreatic cancer, we examined the genetic alternations\\u000a of pancreatic cancer. Based on these results, we are developing a new gene therapy targeting the genetic character of pancreatic\\u000a cancer using mutant adenoviruses selectively replication-competent in tumor cells. Loss of heterozygosity (LOH) of 30% or\\u000a more were observed on chromosome arms

  1. Implementation of Remote 3-Dimensional Image Guided Radiation Therapy Quality Assurance for Radiation Therapy Oncology Group Clinical Trials

    SciTech Connect

    Cui Yunfeng [Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States)] [Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Galvin, James M. [Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States) [Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Radiation Therapy Oncology Group, American College of Radiology, Philadelphia, Pennsylvania (United States); Parker, William [Department of Medical Physics, McGill University Health Center, Montreal, QC (Canada)] [Department of Medical Physics, McGill University Health Center, Montreal, QC (Canada); Breen, Stephen [Department of Radiation Physics, Princess Margaret Hospital, Toronto, ON (Canada)] [Department of Radiation Physics, Princess Margaret Hospital, Toronto, ON (Canada); Yin Fangfang; Cai Jing [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States)] [Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina (United States); Papiez, Lech S. [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States)] [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Li, X. Allen [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States)] [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Bednarz, Greg [Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (United States)] [Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (United States); Chen Wenzhou [Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States)] [Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Xiao Ying, E-mail: ying.xiao@jefferson.edu [Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Radiation Therapy Oncology Group, American College of Radiology, Philadelphia, Pennsylvania (United States)

    2013-01-01

    Purpose: To report the process and initial experience of remote credentialing of three-dimensional (3D) image guided radiation therapy (IGRT) as part of the quality assurance (QA) of submitted data for Radiation Therapy Oncology Group (RTOG) clinical trials; and to identify major issues resulting from this process and analyze the review results on patient positioning shifts. Methods and Materials: Image guided radiation therapy datasets including in-room positioning CT scans and daily shifts applied were submitted through the Image Guided Therapy QA Center from institutions for the IGRT credentialing process, as required by various RTOG trials. A centralized virtual environment is established at the RTOG Core Laboratory, containing analysis tools and database infrastructure for remote review by the Physics Principal Investigators of each protocol. The appropriateness of IGRT technique and volumetric image registration accuracy were evaluated. Registration accuracy was verified by repeat registration with a third-party registration software system. With the accumulated review results, registration differences between those obtained by the Physics Principal Investigators and from the institutions were analyzed for different imaging sites, shift directions, and imaging modalities. Results: The remote review process was successfully carried out for 87 3D cases (out of 137 total cases, including 2-dimensional and 3D) during 2010. Frequent errors in submitted IGRT data and challenges in the review of image registration for some special cases were identified. Workarounds for these issues were developed. The average differences of registration results between reviewers and institutions ranged between 2 mm and 3 mm. Large discrepancies in the superior-inferior direction were found for megavoltage CT cases, owing to low spatial resolution in this direction for most megavoltage CT cases. Conclusion: This first experience indicated that remote review for 3D IGRT as part of QA for RTOG clinical trials is feasible and effective. The magnitude of registration discrepancy between institution and reviewer was presented, and the major issues were investigated to further improve this remote evaluation process.

  2. The use of retroviral vectors for gene therapy-what are the risks? A review of retroviral pathogenesis and its relevance to retroviral vector-mediated gene delivery

    Microsoft Academic Search

    Donald S Anson

    2004-01-01

    Retroviral vector-mediated gene transfer has been central to the development of gene therapy. Retroviruses have several distinct advantages over other vectors, especially when permanent gene transfer is the preferred outcome. The most important advantage that retroviral vectors offer is their ability to transform their single stranded RNA genome into a double stranded DNA molecule that stably integrates into the target

  3. Regulatory structures for gene therapy medicinal products in the European Union.

    PubMed

    Klug, Bettina; Celis, Patrick; Carr, Melanie; Reinhardt, Jens

    2012-01-01

    Taking into account the complexity and technical specificity of advanced therapy medicinal products: (gene and cell therapy medicinal products and tissue engineered products), a dedicated European regulatory framework was needed. Regulation (EC) No. 1394/2007, the "ATMP Regulation" provides tailored regulatory principles for the evaluation and authorization of these innovative medicines. The majority of gene or cell therapy product development is carried out by academia, hospitals, and small- and medium-sized enterprises (SMEs). Thus, acknowledging the particular needs of these types of sponsors, the legislation also provides incentives for product development tailored to them. The European Medicines Agency (EMA) and, in particular, its Committee for Advanced Therapies (CAT) provide a variety of opportunities for early interaction with developers of ATMPs to enable them to have early regulatory and scientific input. An important tool to promote innovation and the development of new medicinal products by micro-, small-, and medium-sized enterprises is the EMA's SME initiative launched in December 2005 to offer financial and administrative assistance to smaller companies. The European legislation also foresees the involvement of stakeholders, such as patient organizations, in the development of new medicines. Considering that gene therapy medicinal products are developed in many cases for treatment of rare diseases often of monogenic origin, the involvement of patient organizations, which focus on rare diseases and genetic and congenital disorders, is fruitful. Two such organizations are represented in the CAT. Research networks play another important role in the development of gene therapy medicinal products. The European Commission is funding such networks through the EU Sixth Framework Program. PMID:22365782

  4. Mesenchymal stem cells as cellular vehicles for prodrug gene therapy against tumors.

    PubMed

    Amara, Ikrame; Touati, Walid; Beaune, Philippe; de Waziers, Isabelle

    2014-10-01

    Gene-directed enzyme prodrug therapy (GDEPT) consists of targeted delivery to tumor cells of a suicide gene responsible for the in situ conversion of a prodrug into cytotoxic metabolites. One of the major impediments of GDEPT is to target specifically the tumor cells with the suicide gene. Among gene delivery methods, mesenchymal stem cells (MSCs) have emerged recently as potential cellular vehicles for gene delivery. MSCs are particularly suited for gene transduction. They exhibit remarkable migratory property towards tumors and their metastases and they are weakly immunogenic. This review will summarize the current knowledge about MSCs engineered to express different suicide genes (cytosine deaminase, thymidine kinase, carboxylesterase, cytochrome P450) to elicit a significant antitumor response against brain tumors, ovarian, hepatocellular, pancreatic, renal or medullary thyroid carcinomas, breast or prostate cancer and pulmonary metastases. The potential side effects of these MSC-based tumor therapies will also be considered to highlight certain aspects that need to be improved prior to clinical use. PMID:24977933

  5. Improving the safety of cell therapy products by suicide gene transfer

    PubMed Central

    Jones, Benjamin S.; Lamb, Lawrence S.; Goldman, Frederick; Di Stasi, Antonio

    2014-01-01

    Adoptive T-cell therapy can involve donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation, the administration of tumor infiltrating lymphocyte expanded ex-vivo, or more recently the use of T cell receptor or chimeric antigen receptor redirected T cells. However, cellular therapies can pose significant risks, including graft-vs.-host-disease and other on and off-target effects, and therefore strategies need to be implemented to permanently reverse any sign of toxicity. A suicide gene is a genetically encoded molecule that allows selective destruction of adoptively transferred cells. Suicide gene addition to cellular therapeutic products can lead to selective ablation of gene-modified cells, preventing collateral damage to contiguous cells and/or tissues. The “ideal” suicide gene would ensure the safety of gene modified cellular applications by granting irreversible elimination of “all” and “only” the cells responsible for the unwanted toxicity. This review presents the suicide gene safety systems reported to date, with a focus on the state-of-the-art and potential applications regarding two of the most extensively validated suicide genes, including the clinical setting: herpes-simplex-thymidine-kinase and inducible-caspase-9. PMID:25505885

  6. Gene therapy and stem cell therapy for cardiovascular diseases today: a model for translational research

    Microsoft Academic Search

    Javier Sanz; Valentin Fuster

    2007-01-01

    Clinical trials looking at ways to promote myocardial regeneration have reported that the administered therapies have either neutral effects or modest benefits of questionable impact. These somewhat disappointing results should emphasize the need for translational research, with bidirectional feedback between the basic research laboratory and the clinical arena. Such a translational pathway is illustrated by the quest to find an

  7. The human visual cortex responds to gene therapy–mediated recovery of retinal function

    PubMed Central

    Ashtari, Manzar; Cyckowski, Laura L.; Monroe, Justin F.; Marshall, Kathleen A.; Chung, Daniel C.; Auricchio, Alberto; Simonelli, Francesca; Leroy, Bart P.; Maguire, Albert M.; Shindler, Kenneth S.; Bennett, Jean

    2011-01-01

    Leber congenital amaurosis (LCA) is a rare degenerative eye disease, linked to mutations in at least 14 genes. A recent gene therapy trial in patients with LCA2, who have mutations in RPE65, demonstrated that subretinal injection of an adeno-associated virus (AAV) carrying the normal cDNA of that gene (AAV2-hRPE65v2) could markedly improve vision. However, it remains unclear how the visual cortex responds to recovery of retinal function after prolonged sensory deprivation. Here, 3 of the gene therapy trial subjects, treated at ages 8, 9, and 35 years, underwent functional MRI within 2 years of unilateral injection of AAV2-hRPE65v2. All subjects showed increased cortical activation in response to high- and medium-contrast stimuli after exposure to the treated compared with the untreated eye. Furthermore, we observed a correlation between the visual field maps and the distribution of cortical activations for the treated eyes. These data suggest that despite severe and long-term visual impairment, treated LCA2 patients have intact and responsive visual pathways. In addition, these data suggest that gene therapy resulted in not only sustained and improved visual ability, but also enhanced contrast sensitivity. PMID:21606598

  8. Oral cytokine gene therapy against murine tumor using attenuated Salmonella typhimurium.

    PubMed

    Yuhua, L; Kunyuan, G; Hui, C; Yongmei, X; Chaoyang, S; Xun, T; Daming, R

    2001-11-01

    An attenuated strain of Salmonella typhimurium was used as a vehicle for oral gene therapy against murine tumor. Eukaryotic expression vectors containing genes of human interleukin-12 (hIL-12), human granulocyte/macrophage colony-stimulating factor (hGM-CSF), mouse (m)IL-12, mGM-CSF and green fluorescent protein (GFP) were used to transform attenuated Salmonella (SL3261), and such transformants were administered orally to BALB/c and C57BL/6 mice. As a reporter gene, GFP expression in murine liver, spleen, tumor, intestine and kidney was confirmed by confocal and flow cytometry. Soluble cytokines were detected in murine sera, and the concentrations were much higher than those of the control, which contributed to the increased number of cytotoxic T cells and prolongation of survival. Oral cytokine gene therapy using live attenuated Salmonella demonstrated a significant protection against the development of two unrelated murine tumors. These results suggest that such gene therapy has the potential to be simple, effective and (above all) safe against tumor. PMID:11745427

  9. Lentivirus-based Gene Therapy of Hematopoietic Stem Cells in Wiskott-Aldrich Syndrome

    PubMed Central

    Aiuti, Alessandro; Biasco, Luca; Scaramuzza, Samantha; Ferrua, Francesca; Cicalese, Maria Pia; Baricordi, Cristina; Dionisio, Francesca; Calabria, Andrea; Giannelli, Stefania; Castiello, Maria Carmina; Bosticardo, Marita; Evangelio, Costanza; Assanelli, Andrea; Casiraghi, Miriam; Di Nunzio, Sara; Callegaro, Luciano; Benati, Claudia; Rizzardi, Paolo; Pellin, Danilo; Di Serio, Clelia; Schmidt, Manfred; Von Kalle, Christof; Gardner, Jason; Mehta, Nalini; Neduva, Victor; Dow, David J.; Galy, Anne; Miniero, Roberto; Finocchi, Andrea; Metin, Ayse; Banerjee, Pinaki; Orange, Jordan; Galimberti, Stefania; Valsecchi, Maria Grazia; Biffi, Alessandra; Montini, Eugenio; Villa, Anna; Ciceri, Fabio; Roncarolo, Maria Grazia; Naldini, Luigi

    2015-01-01

    Wiskott-Aldrich Syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and re-infused the cells after reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical score. Vector integration analyses revealed highly polyclonal and multi-lineage haematopoiesis resulting from the gene corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes and no aberrant clonal expansion was observed after 20–32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS. PMID:23845947

  10. An insult-inducible vector system activated by hypoxia and oxidative stress for neuronal gene therapy.

    PubMed

    Cheng, Michelle Y; Lee, I-Ping; Jin, Michael; Sun, Guohua; Zhao, Heng; Steinberg, Gary K; Sapolsky, Robert M

    2011-03-01

    Gene therapy has demonstrated the protective potential of a variety of genes against stroke. However, conventional gene therapy vectors are limited due to the inability to temporally control their expression, which can sometimes lead to deleterious side effects. Thus, an inducible vector that can be temporally controlled and activated by the insult itself would be advantageous. Using hypoxia responsive elements (HRE) and antioxidant responsive elements (ARE), we have constructed an insult-inducible vector activated by hypoxia and reactive oxygen species (ROS). In COS7 cells, the inducible ARE-HRE-luciferase vectors are highly activated by oxygen deprivation, hydrogen peroxide treatment, and the ROS-induced transcription factor NF-E2-related factor 2 (Nrf2). Using a defective herpes virus, the neuroprotective potential of this inducible vector was tested by over-expressing the transcription factor Nrf2. In primary cortical cultures, expression of the inducible ARE-HRE-Nrf2 protects against oxygen glucose deprivation, similar to that afforded by the constitutively expressed Nrf2. This ARE+HRE vector system is advantageous in that it allows the expression of a transgene to be activated not only during hypoxia but also maintained after reperfusion, thus prolonging the transgene expression during an ischemic insult. This insult-inducible vector system will be a valuable gene therapy tool for activating therapeutic/protective genes in cerebrovascular diseases. PMID:21603078

  11. A review of therapeutic prospects of non-viral gene therapy in the retinal pigment epithelium

    PubMed Central

    Koirala, Adarsha; Conley, Shannon M.; Naash, Muna I.

    2013-01-01

    Ocular gene therapy has been extensively explored in recent years as a therapeutic avenue to target diseases of the cornea, retina and retinal pigment epithelium (RPE). Adeno-associated virus (AAV)-mediated gene therapy has shown promise in several RPE clinical trials but AAVs have limited payload capacity and potential immunogenicity. Traditionally however, non-viral alternatives have been plagued by low transfection efficiency, short-term expression and low expression levels. Recently, these drawbacks have begun to be overcome by the use of specialty carriers such as polylysine, liposomes, or polyethyleneimines, and by inclusion of suitable DNA elements to enhance gene expression and longevity. Recent advancements in the field have yielded non-viral vectors that have favorable safety profiles, lack immunogenicity, exhibit long-term elevated gene expression, and show efficient transfection in the retina and RPE, making them poised to transition to clinical applications. Here we discuss the advancements in nanotechnology and vector engineering that have improved the prospects for clinical application of non-viral gene therapy in the RPE. PMID:23796578

  12. A METHOD FOR EXTRACTING IMAGING CORRELATIONS WITH ALTERATIONS IN GLOBAL GENE EXPRESSION

    E-print Network

    De Micheli, Giovanni

    A METHOD FOR EXTRACTING IMAGING CORRELATIONS WITH ALTERATIONS IN GLOBAL GENE EXPRESSION C Nardini the correlation of imaging features with global gene expression and their significance. METHOD AND MATERIALS statistically significant correlation (pgene expression using our method. Interestingly, we were

  13. Evaluating Risks of Insertional Mutagenesis by DNA Transposons in Gene Therapy

    PubMed Central

    Hackett, Perry B.; Largaespada, David A.; Switzer, Kirsten C.; Cooper, Laurence J.N.

    2013-01-01

    Investigational therapy can be successfully undertaken using viral- and non-viral-mediated ex vivo gene transfer. Indeed, recent clinical trials have established the potential for genetically modified T cells to improve and restore health. Recently the Sleeping Beauty (SB) transposon/transposase system has been applied in clinical trials to stably insert a chimeric antigen receptor (CAR) to redirect T-cell specificity. We discuss the context in which the SB system can be harnessed for gene therapy and describe the human application of SB-modified CAR+ T cells. We have focused on theoretical issues relating to insertional mutagenesis in the context of human genomes that are naturally subjected to remobilization of transposons and the experimental evidence over the last decade of employing SB transposons for defining genes that induce cancer. These findings are put into the context of the use of SB transposons in the treatment of human disease. PMID:23313630

  14. A Conditionally Replicating Adenovirus for Nasopharyngeal Carcinoma Gene Therapy

    Microsoft Academic Search

    Marie C. Chia; Wei Shi; Jian-Hua Li; Otto Sanchez; Craig A. Strathdee; Dolly Huang; Pierre Busson; Henry J. Klamut; Fei-Fei Liu

    2004-01-01

    Successful attainment of tumor-specific gene expression was achieved in nasopharyngeal carcinoma (NPC) by exploiting the exclusive presence of the Epstein–Barr virus (EBV) genome in the cancer cells. In the current study, we have utilized an EBV-dependent transcriptional targeting strategy to construct a novel conditionally replicating adenovirus, adv.oriP.E1A. After treatment with adv.oriP.E1A, we observed extensive cell death in the EBV-positive NPC

  15. Adenovirus-Mediated mda-7 (IL24) Gene Therapy Suppresses Angiogenesis and Sensitizes NSCLC Xenograft Tumors to Radiation

    Microsoft Academic Search

    Takashi Nishikawa; Rajagopal Ramesh; Anupama Munshi; Sunil Chada; Raymond E. Meyn

    2004-01-01

    Melanoma differentiation-associated gene-7 (mda-7), recently classified as interleukin-24 (approved gene symbol IL24), is thought to be a tumor suppressor gene based on the loss of its expression in many different types of cancer. Gene therapy by adenovirus-mediated mda-7 (Ad-mda7) gene transfer has been shown to inhibit the growth of several different tumor cell lines, in vitro and in vivo. We

  16. Microarray Analysis of Gene Expression Reveals that Cyclo-oxygenase-2 Gene Therapy Up-regulates Hematopoiesis and Down-regulates Inflammation During Endochondral Bone Fracture Healing

    PubMed Central

    Lau, K.-H. William; Popa, Nicoleta L.

    2014-01-01

    Background Cyclo-oxygenase-2 (Cox-2) is an inflammatory mediator that is necessary for the tissue repair, including bone fracture healing. Although the application of Cox-2 gene therapy to a murine closed femoral fracture has accelerated bony union, but the beneficial effect was not observed until the endochondral stage of bone repair that is well after the inflammatory stage normally subsides. Methods To identify the molecular pathways through which Cox-2 regulates fracture healing, we examined gene expression profile in fracture tissues in response to Cox-2 gene therapy during the endochondral bone repair phase. Cox-2 gene therapy was applied to the closed murine femur fracture model. Microarray analysis was performed at 10 days post-fracture to examine global gene expression profile in the fracture tissues during the endochondral bone repair phase. The entire repertoire of significantly expressed genes was examined by gene set enrichment analysis, and the most up-regulated individual genes were evaluated further. Results The genes that normally promote inflammation were under-represented in the microarray analysis, and the expression of several inflammatory chemokines was significantly down-regulated. There was an up-regulation of two key transcription factor genes that regulate hematopoiesis and erythropoiesis. More surprisingly, there was no significant up-regulation in the genes that are normally involved in angiogenesis or bone formation. However, the expression of two tissue remodeling genes was up-regulated. Conclusions The down-regulation of the inflammatory genes in response to Cox-2 gene therapy was unexpected, given the pro-inflammatory role of prostaglandins. Cox-2 gene therapy could promote bony union through hematopoietic precursor proliferation during endochondral bone repair and thereby enhances subsequently fracture callus remodeling that leads to bony union of the fracture gap. PMID:25247155

  17. Using a magnetic field to redirect an oncolytic adenovirus complexed with iron oxide augments gene therapy efficacy.

    PubMed

    Choi, Joung-Woo; Park, Ji Won; Na, Youjin; Jung, Soo-Jung; Hwang, June Kyu; Choi, Dongho; Lee, Kyeong Geun; Yun, Chae-Ok

    2015-10-01

    Adenovirus (Ad) is a widely used vector for cancer gene therapy but its therapeutic efficacy is limited by low coxsackievirus and adenovirus receptor (CAR) expression in tumors and non-specifically targeted infection. Ad infectivity and specificity can be markedly improved by creating Ad-magnetic nanoparticles cluster complexes and directing their migration with an external magnetic field (MGF). We electrostatically complexed GFP-expressing, replication-incompetent Ad (dAd) with PEGylated and cross-linked iron oxide nanoparticles (PCION), generating dAd-PCION complexes. The dAd-PCION showed increased transduction efficiency, independent of CAR expression, in the absence or presence of an MGF. Cancer cell killing and intracellular oncolytic Ad (HmT)-PCION replication significantly increased with MGF exposure. Site-directed, magnetically-targeted delivery of the HmT-PCION elicited significantly greater therapeutic efficacy versus treatment with naked HmT or HmT-PCION without MGF in CAR-negative MCF7 tumors. Immunohistochemical tumor analysis showed increased oncolytic Ad replication in tumors following infection by HmT-PCION using an MGF. Whole-body bioluminescence imaging of tumor-bearing mice showed a 450-fold increased tumor-to-liver ratio for HmT-PCION with, versus without, MGF. These results demonstrate the feasibility and potential of external MGF-responsive PCION-coated oncolytic Ads as smart hybrid vectors for cancer gene therapy. PMID:26164117

  18. Interleukin 2 gene therapy for prostate cancer: phase I clinical trial and basic biology.

    PubMed

    Belldegrun, A; Tso, C L; Zisman, A; Naitoh, J; Said, J; Pantuck, A J; Hinkel, A; deKernion, J; Figlin, R

    2001-05-20

    Twenty-four patients with locally advanced prostate cancer (CaP) were enrolled in a phase I clinical trial using gene-based immunotherapy. A functional DNA-lipid complex encoding the interleukin 2 (IL-2) gene (Leuvectin; Vical, San Diego, CA) was administered intraprostatically into the hypoecogenic tumor lesion, using transrectal ultrasound guidance. Two groups of patients having locally advanced tumors were enrolled to receive a treatment regimen composed of two serial intraprostatic injections of the IL-2 gene agent administered 1 week apart. The first groups of patients included radical prostatectomy candidates who subsequently underwent surgery after the completion of the treatment regimen. The second group consisted of patients who had failed a prior therapy. Prostate specimens of the treated areas were attained after treatment and compared with the transrectal biopsies performed at baseline to assess for any responses. IL-2 gene therapy was well tolerated, with no grade 3 or 4 toxic reactions occurring. The most commonly reported symptoms were mild hematuria, transient rectal bleeding, and perineal discomfort that are likely attributable to the injection itself. During the entire course of treatment, there were no significant changes in American Urologic Association (AUA) symptom scores, in hematologic disturbances, electrolyte imbalances, or hepatic functions. Evidence of systemic immune activation was observed after IL-2 gene therapy, based on an increase in the intensity of T cell infiltration seen on immunohistochemical analysis of tissue samples from the injected tumor sites, and based on increased proliferation rates of peripheral blood lymphocytes that were cocultured with patient serum collected after treatment. Furthermore, transient decreases in serum prostate-specific antigen (PSA) (responders) were seen in 16 of 24 patients (67%) on day 1. Fourteen of the patients persisted in this decrease to day 8 (58%). In eight patients the PSA level rose (nonresponders). More patients (9 to 10) in the group that failed prior therapy responded to the IL-2 gene injections (chi-square test, p = 0.04), and 6 of the 9 also had lower than baseline PSA levels at week 10 after treatment. To the best of our knowledge, this is the first clinical study of its kind aimed at exploring the role of IL-2-based gene therapy in CaP patients. This phase I trial demonstrated the safety of intraprostatic Leuvectin injection, with transient PSA-based responses seen after therapy. PMID:11387054

  19. Aerosol delivery of programmed cell death protein 4 using polysorbitol-based gene delivery system for lung cancer therapy.

    PubMed

    Kim, You-Kyoung; Xing, Lei; Chen, Bao-An; Xu, Fengguo; Jiang, Hu-Lin; Zhang, Can

    2014-11-01

    The development of a safe and effective gene delivery system is the most challenging obstacle to the broad application of gene therapy in the clinic. In this study, we report the development of a polysorbitol-based gene delivery system as an alternative gene carrier for lung cancer therapy. The copolymer was prepared by a Michael addition reaction between sorbitol diacrylate (SD) and spermine (SPE); the SD-SPE copolymer effectively condenses with DNA on the nanoscale and protects it from nucleases. SD-SPE/DNA complexes showed excellent transfection with low toxicity both in vitro and in vivo, and aerosol delivery of SD-SPE complexes with programmed cell death protein 4 DNA significantly suppressed lung tumorigenesis in K-ras(LA1) lung cancer model mice. These results demonstrate that SD-SPE has great potential as a gene delivery system based on its excellent biocompatibility and high gene delivery efficiency for lung cancer gene therapy. PMID:24983766

  20. Isobel's Images--One Woman's Experience of Art Therapy

    ERIC Educational Resources Information Center

    White, Isobel; Bull, Stephanie; Beavis, Mary

    2009-01-01

    This paper explores the aims and purpose of long term art therapy. This is done by focusing on the experience of a woman with learning disabilities whom we have called Isobel White (pseudonym). In this paper we set out a theoretical context and then consider key aspects of the therapy process. We have included excerpts from reflective discussions…

  1. Oxidative stress-regulated lentiviral TK/GCV gene therapy for lung cancer treatment.

    PubMed

    Leinonen, Hanna M; Ruotsalainen, Anna-Kaisa; Määttä, Ann-Marie; Laitinen, Heidi M; Kuosmanen, Suvi M; Kansanen, Emilia; Pikkarainen, Jere T; Lappalainen, Jari P; Samaranayake, Haritha; Lesch, Hanna P; Kaikkonen, Minna U; Ylä-Herttuala, Seppo; Levonen, Anna-Liisa

    2012-12-01

    Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that regulates protection against a wide variety of toxic insults to cells, including cytotoxic cancer chemotherapeutic drugs. Many lung cancer cells harbor a mutation in either Nrf2 or its inhibitor Keap1 resulting in permanent activation of Nrf2 and chemoresistance. In this study, we sought to examine whether this attribute could be exploited in cancer suicide gene therapy by using a lentiviral (LV) vector expressing herpes simplex virus thymidine kinase (HSV-TK/GCV) under the regulation of antioxidant response element (ARE), a cis-acting enhancer sequence that binds Nrf2. In human lung adenocarcinoma cells in which Nrf2 is constitutively overexpressed, ARE activity was found to be high under basal conditions. In this setting, ARE-HSV-TK was more effective than a vector in which HSV-TK expression was driven by a constitutively active promoter. In a mouse xenograft model of lung cancer, suicide gene therapy with LV-ARE-TK/GCV was effective compared with LV-PGK-TK/GCV in reducing tumor size. We conclude that ARE-regulated HSV-TK/GCV therapy offers a promising approach for suicide cancer gene therapy in cells with high constitutive ARE activity, permitting a greater degree of therapeutic targeting to those cells. PMID:23041549

  2. Identification of Down's syndrome critical locus gene SIM2-s as a drug therapy target for solid tumors

    Microsoft Academic Search

    Maurice Phil Deyoung; Matthew Tress; Ramaswamy Narayanan

    2003-01-01

    We report here a cancer drug therapy use of a gene involved in Down's syndrome. Using bioinformatics approaches, we recently predicted Single Minded 2 gene (SIM2) from Down's syndrome critical region to be specific to certain solid tumors. Involvement of SIM2 in solid tumors has not previously been reported. Intrigued by a possible association between a Down's syndrome gene and

  3. AAV-mediated gene therapy in mouse models of recessive retinal degeneration

    PubMed Central

    Pang, Ji-jing; Lei, Lei; Dai, Xufeng; Shi, Wei; Liu, Xuan; Dinculescu, Astra; McDowell, J. Hugh

    2013-01-01

    In recent years, more and more mutant genes that cause retinal diseases have been detected. At the same time, many naturally occurring mouse models of retinal degeneration have also been found, which show similar changes to human retinal diseases. These, together with improved viral vector quality allow more and more traditionally incurable inherited retinal disorders to become potential candidates for gene therapy. Currently, the most common vehicle to deliver the therapeutic gene into target retinal cells is the adeno-associated viral vector (AAV). Following delivery to the immuno-priviledged subretinal space, AAV-vectors can efficiently target both retinal pigment epithelium and photoreceptor cells, the origin of most retinal degenerations. This review focuses on the AAV-based gene therapy in mouse models of recessive retinal degenerations, especially those in which delivery of the correct copy of the wild-type gene has led to significant beneficial effects on visual function, as determined by morphological, biochemical, electroretinographic and behavioral analysis. The past studies in animal models and ongoing successful LCA2 clinical trials, predict a bright future for AAV gene replacement treatment for inherited recessive retinal diseases. PMID:22300136

  4. Functional imaging for radiation treatment planning, response assessment, and adaptive therapy in head and neck cancer.

    PubMed

    Bhatnagar, Priya; Subesinghe, Manil; Patel, Chirag; Prestwich, Robin; Scarsbrook, Andrew F

    2013-01-01

    Patients with squamous cell carcinomas (SCCs) of the head and neck are increasingly treated nonsurgically. Imaging plays a critical role in helping define the targets for radiation therapy, especially intensity-modulated radiation therapy, in which the dose gradients are steep. Anatomic imaging with conventional modalities, particularly computed tomography (CT), has been used in patients with head and neck SCCs, but this approach has limitations. Functional imaging techniques, including positron emission tomography (PET) combined with CT or magnetic resonance (MR) imaging, offer complementary information and can be used noninvasively to assess a range of biomarkers in patients with head and neck SCCs, including hypoxia, cell proliferation and apoptosis, and epidermal growth factor receptor status. These biologic markers can be monitored before, during, and after treatment to improve patient selection for specific therapeutic strategies, guide adaptation of therapy, and potentially facilitate more accurate assessment of disease response. This article discusses the practical aspects of integrating functional imaging into head-and-neck radiation therapy planning and reviews the potential of molecular imaging biomarkers for response assessment and therapy adaptation. The uses of PET tracers for imaging cellular processes such as metabolism, proliferation, hypoxia, and cell membrane synthesis are explored, and applications for MR techniques such as dynamic contrast material-enhanced imaging, diffusion-weighted imaging, blood oxygenation level-dependent imaging, and MR spectroscopy are reviewed. The potential of integrated PET/CT perfusion imaging and hybrid PET/MR imaging also is highlighted. These developments may allow more individualized treatment planning in patients with head and neck SCCs in the emerging era of personalized medicine. PMID:24224586

  5. Gene discovery through imaging genetics: identification of two novel genes associated with schizophrenia

    PubMed Central

    Potkin, SG; Turner, JA; Fallon, JA; Lakatos, A; Keator, DB; Guffanti, G; Macciardi, F

    2012-01-01

    We have discovered two genes, RSRC1 and ARHGAP18, associated with schizophrenia and in an independent study provided additional support for this association. We have both discovered and verified the association of two genes, RSRC1 and ARHGAP18, with schizophrenia. We combined a genome-wide screening strategy with neuroimaging measures as the quantitative phenotype and identified the single nucleotide polymorphisms (SNPs) related to these genes as consistently associated with the phenotypic variation. To control for the risk of false positives, the empirical P-value for association significance was calculated using permutation testing. The quantitative phenotype was Blood-Oxygen-Level Dependent (BOLD) Contrast activation in the left dorsal lateral prefrontal cortex measured during a working memory task. The differential distribution of SNPs associated with these two genes in cases and controls was then corroborated in a larger, independent sample of patients with schizophrenia (n = 82) and healthy controls (n = 91), thus suggesting a putative etiological function for both genes in schizophrenia. Up until now these genes have not been linked to any neuropsychiatric illness, although both genes have a function in prenatal brain development. We introduce the use of functional magnetic resonance imaging activation as a quantitative phenotype in conjunction with genome-wide association as a gene discovery tool. PMID:19065146

  6. The ERBB3 receptor in cancer and cancer gene therapy

    PubMed Central

    Sithanandam, G; Anderson, LM

    2009-01-01

    ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma. PMID:18404164

  7. Gene Therapy in the Inner Ear Using Adenovirus Vectors

    PubMed Central

    Husseman, Jacob; Raphael, Yehoash

    2015-01-01

    Therapies for the protection and regeneration of auditory hair cells are of great interest given the significant monetary and lifestyle impact of hearing loss. The past decade has seen tremendous advances in the use of adenoviral vectors to achieve these aims. Preliminary data demonstrated the functional capacity of this technique as adenoviral-induced expression of neurotrophic and growth factors protected hair cells and spiral ganglion neurons from ototoxic insults. Subsequent efforts confirmed the feasibility of adenoviral transfection of cells in the auditory neuroepithelium via cochleostomy into the scala media. Most recently, efforts have focused on regeneration of depleted hair cells. Mammalian hearing loss is generally considered a permanent insult as the auditory epithelium lacks a basal layer capable of producing new hair cells. Recently, the transcription factor Atoh1 has been found to play a critical role in hair cell differentiation. Adenoviral-mediated overexpression of Atoh1 in culture and in vivo have shown the ability to regenerate auditory and vestibular hair cells by causing transdifferentiation of neighboring epithelial-supporting cells. Functional recovery of both the auditory and vestibular systems has been documented following adenoviral induced Atoh1 overexpression. PMID:19494571

  8. PET imaging of thymidine kinase gene expression in the liver of non-human primates following systemic delivery of an adenoviral vector

    Microsoft Academic Search

    A Fontanellas; S Hervas-Stubbs; A Sampedro; M Collantes; A Azpilicueta; I Mauleón; A Pañeda; G Quincoces; J Prieto; I Melero; I Peñuelas

    2009-01-01

    Non-invasive in vivo imaging of transgene expression is currently providing very important means to optimize gene therapy regimes. Results in non-human primates are considered the most predictive models for the outcome in patients. In this study, we have documented that tumour and primary cell lines from human and non-human primates are comparably gene-transduced in vitro by serotype 5 adenovirus expressing

  9. Nonviral in vivo gene therapy for tissue engineering of articular cartilage and tendon repair.

    PubMed

    Goomer, R S; Maris, T M; Gelberman, R; Boyer, M; Silva, M; Amiel, D

    2000-10-01

    Heretofore, nonviral methods have been used primarily for in vitro transfection of cultured cell lines. These methods were substantially less efficient when compared with the use of viruses, particularly when used in vivo. Herein a three-step, highly efficient method of nonviral gene delivery is presented. Using this method, genes have been delivered successfully into tissues of orthopaedic importance with high-efficiency by nonviral means. Transforming growth factor-beta 1, parathyroid hormone related protein, and a marker gene were transfected into primary perichondrium and cartilage cells with efficiencies in excess of 70%. They overexpressed their cognate gene products showing efficacy of expression in a rabbit model of osteochondral defect repair. Using the same method, a marker gene was delivered into a canine model for intrasynovial flexor tendon injury and repair. This was achieved by direct gene delivery during surgery. An estimated 5 additional minutes were required during surgery to complete the transfection steps. High efficiency gene delivery was achieved in the flexor tendons, tendon sheaths, tendon pulleys, surrounding tissues, and skin. The efficiency of transfection approached 100% in the exposed superficial tissue layers and transfected cells were found several layers below the exposed tissue surfaces. The data show the potential of direct nonviral gene therapy in orthopaedics for ex vivo and in vivo applications. PMID:11039769

  10. Coincident radiation imaging of iodine 125 for in vivo gene imaging in small animals

    Microsoft Academic Search

    A. G Weisenberger; S. Majewski; M. Saha; E. Bradley

    1997-01-01

    Progress has been made towards a novel in vivo gene imaging technology which take advantage of the emission properties of 125I as the label for a gene specific probe. The radioisotope 125I decays via electron capture emitting a 35 keV ?-ray with the prompt emission of several 27–32 keV K? and K? shell X-rays. Hence, a coincidence detection condition can

  11. Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data

    PubMed Central

    Waheed, Sarah; Mitchell, Alan; Usmani, Saad; Epstein, Joshua; Yaccoby, Shmuel; Nair, Bijay; van Hemert, Rudy; Angtuaco, Edgardo; Brown, Tracy; Bartel, Twyla; McDonald, James; Anaissie, Elias; van Rhee, Frits; Crowley, John; Barlogie, Bart

    2013-01-01

    Multiple myeloma causes major morbidity resulting from osteolytic lesions that can be detected by metastatic bone surveys. Magnetic resonance imaging and positron emission tomography can detect bone marrow focal lesions long before development of osteolytic lesions. Using data from patients enrolled in Total Therapy 3 for newly diagnosed myeloma (n=303), we analyzed associations of these imaging techniques with baseline standard laboratory variables assessed before initiating treatment. Of 270 patients with complete imaging data, 245 also had gene expression profiling data. Osteolytic lesions detected on metastatic bone surveys correlated with focal lesions detected by magnetic resonance imaging and positron emission tomography, although, in two-way comparisons, focal lesion counts based on both magnetic resonance imaging and positron emission tomography tended to be greater than those based on metastatic bone survey. Higher numbers of focal lesions detected by magnetic resonance imaging and positron emission tomography were positively linked to high serum concentrations of C-reactive protein, gene-expression-profiling–defined high risk, and the proliferation molecular subgroup. Positron emission tomography focal lesion maximum standardized unit values were significantly correlated with gene-expression-profiling–defined high risk and higher numbers of focal lesions detected by positron emission tomography. Interestingly, four genes associated with high-risk disease (related to cell cycle and metabolism) were linked to counts of focal lesions detected by magnetic resonance imaging and positron emission tomography. Collectively, our results demonstrate significant associations of all three imaging techniques with tumor burden and, especially, disease aggressiveness captured by gene-expression-profiling–risk designation. (Clinicaltrials.gov identifier: NCT00081939) PMID:22733020

  12. HEMATOPOIETIC STEM CELL GENE THERAPY: ASSESSING THE RELEVANCE OF PRE-CLINICAL MODELS

    PubMed Central

    Larochelle, Andre; Dunbar, Cynthia E.

    2013-01-01

    The modern laboratory mouse has become a central tool for biomedical research with a notable influence in the field of hematopoiesis. Application of retroviral-based gene transfer approaches to mouse hematopoietic stem cells (HSCs) has led to a sophisticated understanding of the hematopoietic hierarchy in this model. However, the assumption that gene transfer methodologies developed in the mouse could be similarly applied to human HSCs for the treatment of human diseases left the field of gene therapy in a decade-long quandary. It is not until more relevant humanized xenograft mouse models and phylogenetically related large animal species were used to optimize gene transfer methodologies that unequivocal clinical successes were achieved. However, the subsequent reporting of severe adverse events in these clinical trials casted doubts on the predictive value of conventional pre-clinical testing, and encouraged the development of new assays for assessing the relative genotoxicity of various vector designs. PMID:24014892

  13. An approach to achieve long-term expression in skin gene therapy.

    PubMed

    Therrien, Jean-Philippe; Pfützner, Wolfgang; Vogel, Jonathan C

    2008-01-01

    For gene therapy purposes, the skin is an attractive organ to target for systemic delivery of therapeutic proteins to treat systemic diseases, skin diseases, or skin cancer. To achieve long-term stable expression of a therapeutic gene in keratinocytes (KC), we have developed an approach using a bicistronic retroviral vector expressing the desired therapeutic gene linked to a selectable marker (multidrug resistant gene, MDR) that is then introduced into KC and fibroblasts (FB) to create genetically modified human skin equivalent (HSE). After grafting the HSE onto immunocompromised mice, topical colchicine treatment is used to select and enrich for genetically modified keratinocyte stem cells (KSC) that express MDR and are resistant to colchicine's antimitotic effects. Both the apparatus for topical colchicine delivery and the colchicine doses have been optimized for application to human skin. This approach can be validated by systemic delivery of therapeutic factors such as erythropoietin and the antihypertensive atrial natriuretic peptide. PMID:18337228

  14. ENTERVISION: Research Training in 3D Digital Imaging for Cancer Radiation Therapy

    E-print Network

    Dosanjh, M

    2013-01-01

    ENTERVISION, is a Marie Curie Initial Training Network project providing training for 12 Early - Stage Researchers and 4 Experienced Researchers in the field of online medical imaging for hadron therapy. It was established in response to the critical need for reinforcing research in online imaging and for training of highly skilled professionals, with the aim of early detection and more precise treatment of tumours.

  15. Rapid block matching based nonlinear registration on GPU for image guided radiation therapy

    Microsoft Academic Search

    An Wang; Brandon Disher; Greg Carnes; Terry M. Peters

    2010-01-01

    To compensate for non-uniform deformation due to patient motion within and between fractions in image guided radiation therapy, a block matching technique was adapted and implemented on a standard graphics processing unit (GPU) to determine the displacement vector field that maps the nonlinear transformation between successive CT images. Normalized cross correlation (NCC) was chosen as the similarity metric for the

  16. Roadmap: Radiologic Imaging Sciences Radiation Therapy (with certification and ATS Radiologic Technology) -

    E-print Network

    Sheridan, Scott

    Roadmap: Radiologic Imaging Sciences ­ Radiation Therapy ­ (with certification and ATS Radiologic Technology) - Bachelor of Radiologic Imaging Sciences Technology [RE-BRIT-RIS-RTHB] Regional College Catalog Hours] Note: Students must have graduated from a hospital-based certificate program in radiologic

  17. Imaging Modalities in Focal Therapy: Patient Selection, Treatment Guidance and Follow-up

    PubMed Central

    Muller, BG; van den Bos, W; Pinto, PA; de la Rosette, JJMCH

    2014-01-01

    Purpose of review Focal therapy for prostate cancer is emerging as a management option between active surveillance and radical treatments. In this article we present two of the most important imaging modalities in focal therapy, multiparametric MRI and Ultrasonography. We review recent advances within these two platforms. Recent findings State-of-the-art imaging in all phases of focal therapy is essential for treatment safety. In patient selection, treatment guidance and follow-up, different aspects of imaging are important. mpMRI is an imaging technology with high imaging resolution and contrast. This makes it an excellent technology for patient selection and treatment planning and follow-up. Ultrasound has the unique property of real time image acquisition. This makes it an excellent technology for real time treatment guidance. There are multiple novelties in these two platforms that have increased the accuracy considerably. Examples in ultrasound are: CEUS, elastography, shear-wave elastography and histoscanning. In mpMRI these advantages consist of multiple sequences combined to one image and MR thermometry. Summary Standardization of mpTRUS and mpMRI is of paramount importance. For targeted treatment and follow-up, a good negative predictive value of the test is important. There is much to gain both of these developing fields and imaging accuracy of the two platforms is comparable. Standardization in conduct and interpretation, 3D reconstruction and fusion of the two platforms can make focal therapy for prostate cancer standard of care. PMID:24637316

  18. Immune response against gene therapy vectors: influence of synovial fluid on adeno-associated virus mediated gene transfer to chondrocytes.

    PubMed

    Cottard, Virginie; Valvason, Chiara; Falgarone, Géraldine; Lutomski, Didier; Boissier, Marie-Christophe; Bessis, Natacha

    2004-03-01

    Intraarticular gene transfer with adeno-associated virus (AAV) vectors may allow efficient therapeutic transgene expression within the joint. In an effort to understand potential obstacles (particularly immunity against AAV vectors) to intraarticular gene therapy better, our objective was to determine whether synovial fluid (SF) influenced AAV-mediated gene transfer to chondrocytes. SF and sera from 21 patients with joint diseases were collected. Neutralizing activity against AAV/interleukin-4 (IL-4) was determined by assessing the ability of SF or serum to inhibit AAV/IL-4 transduction to the C20A4 chondrocytes. IgGs were purified from SF by salt-dependent chromatography. Anti-AAV IgG levels were determined by ELISA in the SF. SF and sera from all the patients inhibited AAV-mediated gene transfer to chondrocytes. Six SF out of 21 exerted a stronger inhibition. Serum from healthy patients were also inhibitory. Purified IgGs from SF exhibited inhibition patterns similar to those seen with whole SF. Anti-AAV IgG were found in SF from 13 patients out of 18. Moreover, in the SF, anti-AAV IgG level was correlated with the neutralizing activity (p < 0.001, r = 0.716). A correlation was observed between levels of inhibition by the SF and serum (P < 0.0001, r = 0.813). Inhibition of AAV/IL-4 infection of C20A4 cells by SF and sera was abolished by increasing the number of AAV/IL-4 particles. SF from patients with joint disease consistently inhibited AAV infection of chondrocytes in vitro. This effect was ascribable to IgG, most probably directed against AAV. In the future, these data may be useful for tailoring intraarticular AAV-mediated gene therapy to individual patients. PMID:15024183

  19. Cancer targeting Gene-Viro-Therapy of liver carcinoma by dual-regulated oncolytic adenovirus armed with TRAIL gene.

    PubMed

    Cao, X; Yang, M; Wei, R-C; Zeng, Y; Gu, J-F; Huang, W-D; Yang, D-Q; Li, H-L; Ding, M; Wei, N; Zhang, K-J; Xu, B; Liu, X-R; Qian, Q-J; Liu, X-Y

    2011-08-01

    Liver cancer is a common and aggressive malignancy, but available treatment approaches remain suboptimal. Cancer targeting Gene-Viro-Therapy (CTGVT) has shown excellent anti-tumor effects in a preclinical study. CTGVT takes advantage of both gene therapy and virotherapy by incorporating an anti-tumor gene into an oncolytic virus vector. Potent anti-tumor activity is achieved by virus replication and exogenous expression of the anti-tumor gene. A dual-regulated oncolytic adenoviral vector designated Ad·AFP·E1A·E1B (?55) (Ad·AFP·D55 for short thereafter) was constructed by replacing the native viral E1A promoter with the simian virus 40 enhancer/?-fetoprotein (AFP) composite promoter (AFPep) based on an E1B-55K-deleted construct, ZD55. Ad·AFP·D55 showed specific replication and cytotoxicity in AFP-positive hepatoma cells. It also showed enhanced safety in normal cells when compared with the mono-regulated vector ZD55. To improve the anti-hepatoma activities of the virus, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene was introduced into Ad·AFP·D55. Ad·AFP·D55-TRAIL exhibited remarkable anti-tumor activities in vitro and in vivo. Treatment with Ad·AFP·D55-TRAIL can induce both autophagy owing to the Ad·AFP·D55 vector and caspase-dependent apoptosis owing to the TRAIL protein. Therefore, Ad·AFP·D55-TRAIL could be a potential anti-hepatoma agent with anti-tumor activities due to AFP-specific replication and TRAIL-induced apoptosis. PMID:21412282

  20. Development of A Novel Image Guidance Alternative for Patient Localization using Topographic Images for TomoTherapy

    NASA Astrophysics Data System (ADS)

    Qi, X. Sharon; White, Benjamin; Low, Daniel A.

    2014-03-01

    To develop a faster and lower dose topogram based image registration for TomoTherapy as an alternative image guidance tool to volumetric megavoltage computed tomography (MVCT). Topogram procedures were performed for an anthropomorphic thorax phantom on a TomoTherapy HD unit (Accuray Inc., Sunnyvale, CA) using couch speeds from 1-4 cm/s and gantry angles of 0 and 90 degrees, other scanning parameters are: 1 mm imaging jaw, compression factor of 1, 30 seconds scanning duration with all multileaf collimators (MLCs) open. The raw exit detector data was exported after each scan. The topogram was reconstructed from a fan beam source for TomoTherapy beam and detector geometry at a SSD of 85 cm. A reference image, so called Digitally Reconstructed Topogram (DRT) was created by integrating the trajectories through the kVCT simulation with the topogram geometry. Image registration was performed by visually aligning the bony structure in topogram to the DRT. Image resolution was determined by the radius of curvature for the detector array, source to axis distance, source to detector distance, detector spacing, and number of detectors. The localization errors were 1.5, 2.5 mm in medio-lateral and anterior-posterior direction, larger errors in cranial-caudal direction was observed for faster couch speeds (i.e., >=3cm/s). The topographic imaging time was 30 sec (versus 3-5 minutes for MVCT thorax scan) with imaging dose less than 1% of MVCT scan. Topograms with appropriate couch speed provide reliable patient localization images while significantly reducing pre-treatment imaging time. Topogram can be used as an alternative and/or additional patient alignment tool to MVCT on TomoTherapy.

  1. Image-guided synergistic photothermal therapy using photoresponsive imaging agent-loaded graphene-based nanosheets.

    PubMed

    Miao, Wenjun; Shim, Gayong; Kim, Gunwoo; Lee, Soondong; Lee, Hee-Jung; Kim, Young Bong; Byun, Youngro; Oh, Yu-Kyoung

    2015-08-10

    We report the image-guided synergistic photothermal antitumor effects of photoresponsive near-infrared (NIR) imaging agent, indocyanine green (ICG), by loading onto hyaluronic acid-anchored, reduced graphene oxide (HArGO) nanosheets. Loading of ICG onto either rGO (ICG/rGO) or HArGO (ICG/HArGO) substantially improved the photostability of photoresponsive ICG upon NIR irradiation. After 1min of irradiation, the NIR absorption peak of ICG almost disappeared whereas the peak of ICG on rGO or HArGO was retained even after 5min of irradiation. Compared with plain rGO, HArGO provided greater cellular delivery of ICG and photothermal tumor cell-killing effects upon laser irradiation in CD44-positive KB cells. The temperature of cell suspensions treated with ICG/HArGO was 2.4-fold higher than that of cells treated with free ICG. Molecular imaging revealed that intravenously administered ICG/HArGO accumulated in KB tumor tissues higher than ICG/rGO or free ICG. Local temperatures in tumor tissues of laser-irradiated KB cell-bearing nude mice were highest in those intravenously administered ICG/HArGO, and were sufficient to trigger thermal-induced complete tumor ablation. Immunohistologically stained tumors also showed the highest percentages of apoptotic cells in the group treated with ICG/HArGO. These results suggest that photoresponsive ICG-loaded HArGO nanosheets could serve as a potential theranostic nano-platform for image-guided and synergistic photothermal antitumor therapy. PMID:26003041

  2. Polymeric Micelles in Anticancer Therapy: Targeting, Imaging and Triggered Release

    Microsoft Academic Search

    Chris Oerlemans; Wouter Bult; Mariska Bos; Gert Storm; J. Frank W. Nijsen; Wim E. Hennink

    2010-01-01

    Micelles are colloidal particles with a size around 5–100 nm which are currently under investigation as carriers for hydrophobic\\u000a drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of\\u000a which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be\\u000a improved in different ways. Targeting ligands can

  3. Clinical utility of recombinant adenoviral human p53 gene therapy: current perspectives.

    PubMed

    Chen, Guang-Xia; Zhang, Shu; He, Xiao-Hua; Liu, Shi-Yu; Ma, Chao; Zou, Xiao-Ping

    2014-01-01

    Gene therapy has promised to be a highly effective antitumor treatment by introducing a tumor suppressor gene or the abrogation of an oncogene. Among the potential therapeutic transgenes, the tumor suppressor gene p53 serves as an attractive target. Restoration of wild-type p53 function in tumors can be achieved by introduction of an intact complementary deoxyribonucleic acid copy of the p53 gene using a suitable viral vector, in most cases an adenoviral vector (Adp53). Preclinical in vitro and in vivo studies have shown that Adp53 triggers a dramatic tumor regression response in various cancers. These viruses are engineered to lack certain early proteins and are thus replication defective, including Gendicine, SCH-58500, and Advexin. Several types of tumor-specific p53-expressing conditionally replicating adenovirus vectors (known as replication-competent CRAdp53 vectors) have been developed, such as ONYX 015, AdDelta24-p53, SG600-p53, OBP-702, and H101. Various clinical trials have been conducted to investigate the safety and efficiency of these adenoviral vectors. In this review we will talk about the biological mechanisms, clinical utility, and therapeutic potentials of the replication-deficient Adp53-based and replication-competent CRAdp53-based gene therapy. PMID:25364261

  4. Endosomal pH responsive polymers for efficient cancer targeted gene therapy.

    PubMed

    Shi, Bingyang; Zhang, Hu; Bi, Jingxiu; Dai, Sheng

    2014-07-01

    Treatment of human diseases at gene level is always limited by effective gene delivery vectors. In this study, we designed and developed an endosomal pH sensitive targeted gene delivery system, folic acid functionalized Schiff-base linked imidazole chitosan (FA-SLICS), for cancer therapy. The FA-SLICS is able to self-assemble plasmid DNA (pDNA) into nano-scaled polyplexes under a neutral condition and to release the loaded pDNA in the endosomal microenvironment due to the presence of pH sensitive Schiff-base moieties along chitosan backbones. The FA-SLICS has negligible cytotoxicity to normal cells (CHO), but displays slight toxicity to cancer cells (HeLa and HepG2). In addition, FA-SLICS can selectively and efficiently transfect FR (folate receptor) positive cells (HeLa cells) as a gene carrier. Therefore, the FA-SLICS should be a promising delivery vector in cancer gene therapy based on its cell targeting capability and intracellular microenvironment controlled delivery mechanism. PMID:24880229

  5. Computational Design and Application of Endogenous Promoters for Transcriptionally Targeted Gene Therapy for Rheumatoid Arthritis

    PubMed Central

    Geurts, Jeroen; Joosten, Leo AB; Takahashi, Nozomi; Arntz, Onno J; Glück, Anton; Bennink, Miranda B; van den Berg, Wim B; van de Loo, Fons AJ

    2009-01-01

    The promoter regions of genes that are differentially regulated in the synovial membrane during the course of rheumatoid arthritis (RA) represent attractive candidates for application in transcriptionally targeted gene therapy. In this study, we applied an unbiased computational approach to define proximal-promoters from a gene expression profiling study of murine experimental arthritis. Synovium expression profiles from progressing stages of collagen-induced arthritis (CIA) were classified into six distinct groups using k-means clustering. Using an algorithm based on local over-representation and comparative genomics, we identified putatively functional transcription factor–binding sites (TFBS) in TATA-dependent proximal-promoters. Applying a filter based on spacing between TATA box and transcription start site (TSS) combined with the presence of over-represented nuclear factor ?B (NF?B), AP-1, or CCAAT/enhancer-binding protein ? (C/EBP?) sites, 382 candidate murine and human promoters were reduced to 66, corresponding to 45 genes. In vitro, 9 out of 10 computationally defined promoter regions conferred cytokine-inducible expression in murine cells and human synovial fibroblasts. Under these conditions, the serum amyloid A3 (Saa3) promoter showed the strongest transcriptional induction and strength. We applied this promoter for driving therapeutically efficacious levels of the interleukin-1 receptor antagonist (Il1rn) in a disease-regulated fashion. These results demonstrate the value of bioinformatics for guiding the selection of endogenous promoters for transcriptionally targeted gene therapy. PMID:19690516

  6. The Na(+)/glucose cotransporters: from genes to therapy.

    PubMed

    Sabino-Silva, R; Mori, R C; David-Silva, A; Okamoto, M M; Freitas, H S; Machado, U F

    2010-11-01

    Glucose enters eukaryotic cells via two types of membrane-associated carrier proteins, the Na(+)/glucose cotransporters (SGLT) and the facilitative glucose transporters (GLUT). The SGLT family consists of six members. Among them, the SGLT1 and SGLT2 proteins, encoded by the solute carrier genes SLC5A1 and SLC5A2, respectively, are believed to be the most important ones and have been extensively explored in studies focusing on glucose fluxes under both physiological and pathological conditions. This review considers the regulation of the expression of the SGLT promoted by protein kinases and transcription factors, as well as the alterations determined by diets of different compositions and by pathologies such as diabetes. It also considers congenital defects of sugar metabolism caused by aberrant expression of the SGLT1 in glucose-galactose malabsorption and the SGLT2 in familial renal glycosuria. Finally, it covers some pharmacological compounds that are being currently studied focusing on the interest of controlling glycemia by antagonizing SGLT in renal and intestinal tissues. PMID:21049241

  7. Gene expression profiling in vaccine therapy and immunotherapy for cancer

    PubMed Central

    Bedognetti, Davide; Wang, Ena; Sertoli, Mario Roberto; Marincola, Francesco M

    2012-01-01

    The identification of tumor antigens (TA) recognized by T cells led to the design of therapeutic strategies aimed at eliciting adaptive-immune responses. The last decade experience has shown that, although active immunization can induce enhancement of anti-cancer T cell precursors (easily detectable in standard assays), most often they are unable to induce tumor regression and, consequently, have scarce impact on overall survival. Moreover, in the few occasions when tumor rejection occurs, the mechanisms determining this phenomenon remain poorly understood, and data derived from in vivo human observations are rare. The advent of high-throughput gene expression analysis (microarrays) has cast new lights on unrecognized mechanisms that are now deemed as central for the development of an efficient immune-mediated tumor rejection. The aim of this article is to review the data about the molecular signature associated with this process. We believe that the description of how the mechanism of immune-mediated tissue destruction occurs would contribute to understand why it happens, thereby allowing to develop more effective immune-therapeutic strategies. PMID:20518712

  8. Neural-targeted gene therapy for rodent and primate hemiparkinsonism.

    PubMed

    Anton, R; Kordower, J H; Maidment, N T; Manaster, J S; Kane, D J; Rabizadeh, S; Schueller, S B; Yang, J; Rabizadeh, S; Edwards, R H

    1994-06-01

    Expression of the rate-limiting enzyme for catecholamine biosynthesis, tyrosine hydroxylase (TH), via retroviral and plasmid expression vectors improved the efficacy of conditionally immortalized nigral neural cells in ameliorating rodent and nonhuman primate models of Parkinson's disease through neural transplantation. No improvement in rotational behavior occurred when sham transplants or nondopaminergic transplants were performed. Transplantation of the temperature-sensitive immortalized parental nigral neural line with a TH expression vector resulted in improvement for at least 2 months. Improvement was accompanied by HPLC evidence of increased L-DOPA production and immunocytochemical evidence of TH in the transfected cells increased over that of the parental line. No tumor formation was detected. These results suggest that: (1) temperature-sensitive immortalized neural cells may be genetically engineered successfully to improve their efficacy for the treatment of parkinsonism; and (2) a change in L-DOPA production, as opposed to growth factor production or other factors, is likely to account for the observed improvement, since the parental and derived lines differ by a single gene. PMID:7518394

  9. Current translational and clinical practices in hematopoietic cell and gene therapy

    PubMed Central

    DiGiusto, David L.; Kiem, Hans-Peter

    2013-01-01

    Clinical trials over the last 15 years have demonstrated that cell and gene therapy for cancer, monogenic and infectious disease is feasible and can lead to long-term benefit for patients (1). These trials however have been limited to proof of principle and were conducted on modest numbers of patients or over long periods of time. In order for these studies to move towards standard practice and commercialization, scalable technologies for the isolation, ex vivo manipulation and delivery of these cells to patients must be developed. Additionally, regulatory strategies and clinical protocols for the collection, creation and delivery of cell products must be generated. In this article we will review recent progress in hematopoietic cell and gene therapy, describe some of the current issues facing the field and discuss clinical, technical and regulatory approaches used to navigate the road to product development. PMID:22799276

  10. Advanced targeted, cell and gene-therapy approaches for pediatric hematological malignancies: results and future perspectives.

    PubMed

    Magnani, Chiara F; Tettamanti, Sarah; Maltese, Francesca; Turazzi, Nice; Biondi, Andrea; Biagi, Ettore

    2013-01-01

    Despite the survival of pediatric patients affected by hematological malignancies being improved in the last 20?years by chemotherapy and hematopoietic stem cell transplantation, a significant amount of patients still relapses. Treatment intensification is limited by toxic side effects and is constrained by the plateau of efficacy, while the pipeline of new chemotherapeutic drugs is running short. Therefore, novel therapeutic strategies are essential and researchers around the world are testing in clinical trials immune and gene-therapy approaches as second-line treatments. The aim of this review is to give a glance at these novel promising strategies of advanced medicine in the field of pediatric leukemias. Results from clinical protocols using new targeted "smart" drugs, immunotherapy, and gene therapy are summarized, and important considerations regarding the combination of these novel approaches with standard treatments to promote safe and long-term cure are discussed. PMID:23641364

  11. Advanced Targeted, Cell and Gene-Therapy Approaches for Pediatric Hematological Malignancies: Results and Future Perspectives

    PubMed Central

    Magnani, Chiara F.; Tettamanti, Sarah; Maltese, Francesca; Turazzi, Nice; Biondi, Andrea; Biagi, Ettore

    2013-01-01

    Despite the survival of pediatric patients affected by hematological malignancies being improved in the last 20?years by chemotherapy and hematopoietic stem cell transplantation, a significant amount of patients still relapses. Treatment intensification is limited by toxic side effects and is constrained by the plateau of efficacy, while the pipeline of new chemotherapeutic drugs is running short. Therefore, novel therapeutic strategies are essential and researchers around the world are testing in clinical trials immune and gene-therapy approaches as second-line treatments. The aim of this review is to give a glance at these novel promising strategies of advanced medicine in the field of pediatric leukemias. Results from clinical protocols using new targeted “smart” drugs, immunotherapy, and gene therapy are summarized, and important considerations regarding the combination of these novel approaches with standard treatments to promote safe and long-term cure are discussed. PMID:23641364

  12. Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts

    PubMed Central

    Zhu, Yin; Cheng, Ming; Yang, Zhen; Zeng, Chun-Yan; Chen, Jiang; Xie, Yong; Luo, Shi-Wen; Zhang, Kun-He; Zhou, Shu-Feng; Lu, Nong-Hua

    2014-01-01

    Mesenchymal stem cells (MSCs) have been recognized as promising delivery vehicles for gene therapy of tumors. Gastric cancer is the third leading cause of worldwide cancer mortality, and novel treatment modalities are urgently needed. NK4 is an antagonist of hepatocyte growth factor receptors (Met) which are often aberrantly activated in gastric cancer and thus represent a useful candidate for targeted therapies. This study investigated MSC-delivered NK4 gene therapy in nude mice bearing gastric cancer xenografts. MSCs were transduced with lentiviral vectors carrying NK4 complementary DNA or enhanced green fluorescent protein (GFP). Such transduction did not change the phenotype of MSCs. Gastric cancer xenografts were established in BALB/C nude mice, and the mice were treated with phosphate-buffered saline (PBS), MSCs-GFP, Lenti-NK4, or MSCs-NK4. The tropism of MSCs toward gastric cancer cells was determined by an in vitro migration assay using MKN45 cells, GES-1 cells and human fibroblasts and their presence in tumor xenografts. Tumor growth, tumor cell apoptosis and intratumoral microvessel density of tumor tissue were measured in nude mice bearing gastric cancer xenografts treated with PBS, MSCs-GFP, Lenti-NK4, or MSCs-NK4 via tail vein injection. The results showed that MSCs migrated preferably to gastric cancer cells in vitro. Systemic MSCs-NK4 injection significantly suppressed the growth of gastric cancer xenografts. MSCs-NK4 migrated and accumulated in tumor tissues after systemic injection. The microvessel density of tumor xenografts was decreased, and tumor cellular apoptosis was significantly induced in the mice treated with MSCs-NK4 compared to control mice. These findings demonstrate that MSC-based NK4 gene therapy can obviously inhibit the growth of gastric cancer xenografts, and MSCs are a better vehicle for NK4 gene therapy than lentiviral vectors. Further studies are warranted to explore the efficacy and safety of the MSC-based NK4 gene therapy in animals and cancer patients. PMID:25525335

  13. Experimental gene therapy in mammary and urinary bladder cancer using electrogene transfer.

    PubMed

    Shibata, Masa-Aki; Morimoto, Junji; Ito, Yuko; Kusakabe, Ken; Otsuki, Yoshinori

    2004-12-01

    We investigated the effectiveness of in vivo electrogene transfer as a means of therapy in rat urinary bladder carcinoma and in mammary carcinoma models in both athymic and syngeneic mice using the herpes simplex virus 1 thymidine kinase (HSVtk) or IL-12 genes in combination with ganciclovir (GCV). A significant increase in the levels of tissue apoptosis and necrosis was induced with a single injection of HSVtk vector directly into bladder and mammary tumors followed by in vivo transfection and a regimen of intraperitoneal GCV injection. This procedure induced significant selective tumor cell death, characterized by marked inflammation and peripheral macrophage influx. Active caspase-3 was also strongly expressed in areas of cell death, indicating the initiation of apoptosis. This result was confirmed in corollary in vitro studies on a mouse bladder carcinoma cell line in which elevated caspase-3, -8, and -9 activities and decreased mitochondrial membrane potential were observed as a result of transfection with HSVtk and addition of GCV to the medium. In the syngeneic mouse mammary cancer model, we additionally found both tumor volume and metastasis to lymph nodes and lungs to be significantly reduced throughout the 2-month experiment. However, in contrast to their syngeneic counterparts, HSVtk/GCV therapy did not effectively inhibit mammary tumor growth/metastasis in an athymic mouse model, leading us to believe that T-cell-mediated immune responses may participate via the bystander effect in HSVtk/GCV experimental therapy. We subsequently evaluated the antitumor activity of IL-12, which can activate T-cell-mediated immune responses involving macrophages, in the syngeneic mammary tumors and found that IL-12 also significantly suppressed mammary tumor growth and metastasis. We thus suggest that in vivo electrogene transfer is a useful transfection tool in cancer gene therapy and, in addition, we show that T-cell-mediated immune responses may be a critical factor in cancer gene therapy using HSVtk/GCV and IL-12. PMID:15614446

  14. Adipose Tissue-Derived Human Mesenchymal Stem Cells Mediated Prodrug Cancer Gene Therapy

    Microsoft Academic Search

    Lucia Kucerova; Veronika Altanerova; Miroslava Matuskova; Silvia Tyciakova; Cestmir Altaner

    2007-01-01

    Human adipose tissue-derived mesenchymal stem cells (AT- MSC) are considered to be a promising source of autologous stem cells in personalized cell-based therapies.Tumor tracking properties of MSC provide an attractive opportunity for targeted transgene delivery into the sites of tumor formation.In the present study, we addressed whether the suicide gene introduction into human AT-MSC could produce a tumor-specific prodrug converting

  15. The Effect of Interleukin 36 Gene Therapy in the Regression of Tumor

    PubMed Central

    Solahaye-Kahnamouii, Shiva; Farhadi, Farrokh; Rahkare-Farshi, Mahni; Pakdel, Farzaneh; Kashefimehr, Atabak; Pouralibaba, Firouz; Shirani, Gholamreza; Bayat, Mohammad; Karimi, Abbas

    2014-01-01

    Background Cancer immunotherapy attempts to stimulate the immune system to reject and destroy tumors and is one of the cancer treatment strategies. Recently, interluekin36 (IL36) has been used as immunotherapeutic agents in cancer gene therapy. Present study investigated that the IL36 gene therapy effects on the regression of tumor masses in mouse model. Aim of this study is determination of the gene therapy effects by IL36 in the regression of tumor masses in mouse model. Methods To study the therapeutic efficacy of this cytokine, WEHI-164 tumor cells were transected with mIL36 plasmids. ELISA test was used to check cytokine production by transected cells. To establish fibro sarcoma mouse model, Tumoral transfected cells were injected subcutaneously to inoculate tumor in BALB/C mice. Tumor volumes were measured by caliper. Mice were sacrificed and tumors were extracted. The expression of IL36 and IFN-? was studied with Real-time PCR and immunoblotting. The expression of Ki-67 (a tumor proliferation marker) in tumor masses was studied by immunohistochemistry staining. In this study we had 2 groups which are treated with IL-36 and Untreated with IL-36 as a blank. Results The group treated with IL36 indicated decrease of tumor mass volume (p<0.001). The results of western blotting and real-time PCR showed the IL36 expression increased in the group treated with IL36 (with relative expression of 1.9). Conclusion Immunohistochemistry staining indicated that the Ki-67expression has been reduced in the group interfered with IL36. IL36 gene therapy has therapeutic effects on the regression of tumor masses in fibro sarcoma mouse model. PMID:25628840

  16. Optimization of Ultrasound-mediated Anti-angiogenic Cancer Gene Therapy.

    PubMed

    Fujii, Hiroko; Matkar, Pratiek; Liao, Christine; Rudenko, Dmitriy; Lee, Paul Jh; Kuliszewski, Michael A; Prud'homme, Gerald J; Leong-Poi, Howard

    2013-01-01

    Ultrasound-targeted microbubble destruction (UTMD) can be used to deliver silencing gene therapy to tumors. We hypothesized that UTMD would be effective in suppressing angiogenesis within tumors, and that modulation of the ultrasound pulsing intervals (PI) during UTMD would affect the magnitude of target knockdown. We performed UTMD of vascular endothelial growth factor receptor-2 (VEGFR2) short hairpin (sh)RNA plasmid in an heterotopic mammary adenocarcinoma model in rats, evaluating PIs of 2, 5, 10, and 20 seconds. We demonstrated that UTMD with a PI of 10 seconds resulted in the greatest knockdown of VEGFR2 by PCR, immunostaining, western blotting, smaller tumor volumes and perfused areas, and lower tumor microvascular blood volume (MBV) and flow by contrast-enhanced ultrasound (CEU) compared with UTMD-treated tumors at 2, 5, and 20 seconds, control tumors, tumors treated with intravenous shRNA plasmid and scrambled plasmid. CEU perfusion assessment using the therapeutic probe demonstrated that tumors were fully replenished with microbubbles within 10 seconds, but incompletely replenished at PI-2 and PI-5 seconds. In conclusion, for anti-VEGFR2 cancer gene therapy by UTMD, PI of 10 seconds results in higher target knockdown and a greater anti-angiogenic effect. Complete replenishment of tumor vasculature with silencing gene-bearing microbubbles in between destructive pulses of UTMD is required to maximize the efficacy of anti-angiogenic cancer gene therapy.Molecular Therapy - Nucleic Acids (2013) 2, e94; doi:10.1038/mtna.2013.20; published online 21 May 2013. PMID:23695537

  17. Bioluminescence Reporter Gene Imaging Characterize Human Embryonic Stem Cell-Derived Teratoma Formation

    PubMed Central

    Su, Weijun; Zhou, Manqian; Zheng, Yizhou; Fan, Yan; Han, Zhongchao; Kong, Deling; Wu, Joseph C.; Xiang, Rong; Li, Zongjin

    2011-01-01

    Human embryonic stem (hES) cells are capable of differentiation into virtually all cell types and hold tremendous potential as cell sources for regenerative therapies. However, teratoma formation can be the main obstacle for hES cells therapy. In order to understand the biology and physiology of hES cells teratoma formation, we investigated the angiogenic process within teratomas and characterized teratoma cells. In this study, hES cells transduced with double fusion reporter gene that consists of firefly luciferase and enhanced green fluorescent protein (Fluc-eGFP) were injected into hind limbs of SCID mice and performed longitudinal bioluminescence imaging on these animals. To test angiogenic contribution of teratoma from host or hES cells, human and mouse endothelial cells marker CD31 was stained respectively. To further explore the characterization of teratoma derived cells, flow cytometry analysis was carried out and GFP+/SSEA-4+ cells were isolated and subcultured. Then, we re-injected the isolated GFP+/SSEA-4+ teratoma cells into SCID mice and observed by imaging. Our results show that the reporter gene imaging is an ideal technology for monitoring long-term stem cell viability, death, and proliferation. Teratomas contained vasculatures are from hES cells and host. hESCs derived teratomas express a high level of undifferentiated marker SSEA-4 and CD56, and subcultured GFP+/SSEA-4+ cells had similar expression pattern comparing to undifferentiated hES cells, except for a very high level of CD56 and a little lower expression of undifferentiated markers, such as SSEA-3, SSEA-4, TRA-1-60, and TRA-1-81. Moreover, the SSEA-4+ teratoma cells can form teratomas in SCID mice, and this type teratomas grow at a lower rate compared to teratomas derived from hES cells, and are more differentiated. PMID:21328457

  18. Enhancement of Aerosol Cisplatin Chemotherapy with Gene Therapy Expressing ABC10 protein in Respiratory System

    PubMed Central

    Hohenforst-Schmidt, Wolfgang; Zarogoulidis, Paul; Linsmeier, Bernd; Kioumis, Ioannis; Li, Qiang; Huang, Haidong; Sachpatzidou, Despoina; Lampaki, Sofia; Organtzis, John; Domvri, Kalliopi; Sakkas, Leonidas; Zachariadis, George A.; Archontas, Konstantinos N.; Kallianos, Anastasios; Rapti, Aggeliki; Yarmus, Lonny; Zarogoulidis, Konstantinos; Brachmann, Johannes

    2014-01-01

    Inhaled therapy for lung cancer is a local form of treatment. Currently inhaled non-specific cytotoxic agents have been evaluated as a future treatment for local disease control and distant metastasis control. There are few information regarding the influence of local transporters and gene expression of the respiratory epithelium to the absorption of administered drugs. In the current work we used adenoviral-type 5(dE1/E3) (Cytomegalovirus promoter) with human ABCA10 transgene (Ad-h-ABCA10) purchased from Vector Labs® in order to investigate whether gene therapy can be used as a pre-treatment to enhance the efficiency of inhaled cisplatin. We included the following groups to our work: a) control, b) aerosol vector, c) aerosol vector plus cisplatin, d) aerosol cisplatin, e) intratumoral cisplatin administration, f) intratumoral vector plus cisplatin administration. The results indicate that the aerosol cisplatin group had a long term survival with the intratumoral cisplatin group following. The enhancement of the ABCA family locally to the respiratory system prior to the aerosol cisplatin administration can be used safely and efficiently. Future treatment design of local therapies should include the investigation of local transporters and genes. PMID:24723977

  19. Patterns of HER2 Gene Amplification and Response to Anti-HER2 Therapies

    PubMed Central

    Morancho, Beatriz; Zacarias-Fluck, Mariano; Zhang, Junjie; Martínez-Barriocanal, Águeda; Navarro Jiménez, Alexandra; Aura, Claudia; Burgues, Octavio; Lluch, Ana; Cortés, Javier; Nuciforo, Paolo; Rubio, Isabel T.; Marangoni, Elisabetta; Deeds, James; Boehm, Markus; Schlegel, Robert; Tabernero, Josep; Mosher, Rebecca; Arribas, Joaquín

    2015-01-01

    A chromosomal region that includes the gene encoding HER2, a receptor tyrosine kinase (RTK), is amplified in 20% of breast cancers. Although these tumors tend to respond to drugs directed against HER2, they frequently become resistant and resume their malignant progression. Gene amplification in double minutes (DMs), which are extrachromosomal entities whose number can be dynamically regulated, has been suggested to facilitate the acquisition of resistance to therapies targeting RTKs. Here we show that ~30% of HER2-positive tumors show amplification in DMs. However, these tumors respond to trastuzumab in a similar fashion than those with amplification of the HER2 gene within chromosomes. Furthermore, in different models of resistance to anti-HER2 therapies, the number of DMs containing HER2 is maintained, even when the acquisition of resistance is concomitant with loss of HER2 protein expression. Thus, both clinical and preclinical data show that, despite expectations, loss of HER2 protein expression due to loss of DMs containing HER2 is not a likely mechanism of resistance to anti-HER2 therapies. PMID:26075403

  20. Complete regression of glioblastoma by mesenchymal stem cells mediated prodrug gene therapy simulating clinical therapeutic scenario.

    PubMed

    Altaner, Cestmir; Altanerova, Veronika; Cihova, Marina; Ondicova, Katarina; Rychly, Boris; Baciak, Ladislav; Mravec, Boris

    2014-03-15

    Suicide gene therapy mediated by mesenchymal stem cells with their ability to engraft into tumors makes these therapeutic stem cells an attractive tool to activate prodrugs directly within the tumor mass. In this study, we evaluated the therapeutic efficacy of human mesenchymal stem cells derived from bone marrow and from adipose tissue, engineered to express the suicide gene cytosine deaminase::uracil phosphoribosyltransferase to treat intracerebral rat C6 glioblastoma in a simulated clinical therapeutic scenario. Intracerebrally grown glioblastoma was treated by resection and subsequently with single or repeated intracerebral inoculations of therapeutic stem cells followed by a continuous intracerebroventricular delivery of 5-fluorocytosine using an osmotic pump. Kaplan-Meier survival curves revealed that surgical resection of the tumor increased the survival time of the resected animals depending on the extent of surgical intervention. However, direct injections of therapeutic stem cells into the brain tissue surrounding the postoperative resection cavity led to a curative outcome in a significant number of treated animals. Moreover, the continuous supply of therapeutic stem cells into the brain with growing glioblastoma by osmotic pumps together with continuous prodrug delivery also proved to be therapeutically efficient. We assume that observed curative therapy of glioblastoma by stem cell-mediated prodrug gene therapy might be caused by the destruction of both tumor cells and the niche where glioblastoma initiating cells reside. PMID:24038033

  1. Enhancement of Aerosol Cisplatin Chemotherapy with Gene Therapy Expressing ABC10 protein in Respiratory System.

    PubMed

    Hohenforst-Schmidt, Wolfgang; Zarogoulidis, Paul; Linsmeier, Bernd; Kioumis, Ioannis; Li, Qiang; Huang, Haidong; Sachpatzidou, Despoina; Lampaki, Sofia; Organtzis, John; Domvri, Kalliopi; Sakkas, Leonidas; Zachariadis, George A; Archontas, Konstantinos N; Kallianos, Anastasios; Rapti, Aggeliki; Yarmus, Lonny; Zarogoulidis, Konstantinos; Brachmann, Johannes

    2014-01-01

    Inhaled therapy for lung cancer is a local form of treatment. Currently inhaled non-specific cytotoxic agents have been evaluated as a future treatment for local disease control and distant metastasis control. There are few information regarding the influence of local transporters and gene expression of the respiratory epithelium to the absorption of administered drugs. In the current work we used adenoviral-type 5(dE1/E3) (Cytomegalovirus promoter) with human ABCA10 transgene (Ad-h-ABCA10) purchased from Vector Labs(®) in order to investigate whether gene therapy can be used as a pre-treatment to enhance the efficiency of inhaled cisplatin. We included the following groups to our work: a) control, b) aerosol vector, c) aerosol vector plus cisplatin, d) aerosol cisplatin, e) intratumoral cisplatin administration, f) intratumoral vector plus cisplatin administration. The results indicate that the aerosol cisplatin group had a long term survival with the intratumoral cisplatin group following. The enhancement of the ABCA family locally to the respiratory system prior to the aerosol cisplatin administration can be used safely and efficiently. Future treatment design of local therapies should include the investigation of local transporters and genes. PMID:24723977

  2. The use of neural stem cells in cancer gene therapy: Predicting the path to the clinic

    PubMed Central

    Ahmed, Atique U; Alexiades, Nikita G; Lesniak, Maciej S

    2010-01-01

    Gene therapy is a novel means of anticancer treatment that has led to preliminary positive results in the preclinical setting, as well as in clinical trials; however, successful clinical application of this approach has been hampered by the inability of gene delivery systems to target tumors and to deliver a therapeutic payload to disseminated tumor foci efficiently. Along with viral vector systems, various mammalian cells with tropism for tumor cells have been considered as vehicles for delivery of anticancer therapeutics. The discovery of the inherent tumor-tropic properties of neural stem cells (NSCs) has provided a unique opportunity to develop targeted therapies that use NSCs as a vehicle to track invasive tumor cells and deliver anticancer agents selectively to diseased areas. Many in vivo and in vitro studies have demonstrated that the targeted migration of NSCs to infiltrative brain tumors, including malignant glioma, provides a potential therapeutic approach. In this review, the development of NSCs as targeted carriers for anticancer gene therapy is discussed, and barriers in the path to the clinic, as well as approaches to overcoming such barriers are presented. PMID:20886386

  3. Parkinson's Disease Gene Therapy: Success by Design Meets Failure by Efficacy

    PubMed Central

    Bartus, Raymond T; Weinberg, Marc S; Samulski, R. Jude

    2014-01-01

    Over the past decade, nine gene therapy clinical trials for Parkinson's disease (PD) have been initiated and completed. Starting with considerable optimism at the initiation of each trial, none of the programs has yet borne sufficiently robust clinical efficacy or found a clear path toward regulatory approval. Despite the immediately disappointing nature of the efficacy outcomes in these trials, the clinical data garnered from the individual studies nonetheless represent tangible and significant progress for the gene therapy field. Collectively, the clinical trials demonstrate that we have overcome the major safety hurdles previously suppressing central nervous system (CNS) gene therapy, for none produced any evidence of untoward risk or harm after administration of various vector-delivery systems. More importantly, these studies also demonstrated controlled, highly persistent generation of biologically active proteins targeted to structures deep in the human brain. Therefore, a renewed, focused emphasis must be placed on advancing clinical efficacy by improving clinical trial design, patient selection and outcome measures, developing more predictive animal models to support clinical testing, carefully performing retrospective analyses, and most importantly moving forward—beyond our past limits. PMID:24356252

  4. SERCA2a gene therapy in heart failure: an anti-arrhythmic positive inotrope

    PubMed Central

    Sikkel, Markus B; Hayward, Carl; MacLeod, Kenneth T; Harding, Sian E; Lyon, Alexander R

    2014-01-01

    Therapeutic options that directly enhance cardiomyocyte contractility in chronic heart failure (HF) therapy are currently limited and do not improve prognosis. In fact, most positive inotropic agents, such as ?-adrenoreceptor agonists and PDE inhibitors, which have been assessed in HF patients, cause increased mortality as a result of arrhythmia and sudden cardiac death. Cardiac sarcoplasmic reticulum Ca2+-ATPase2a (SERCA2a) is a key protein involved in sequestration of Ca2+ into the sarcoplasmic reticulum (SR) during diastole. There is a reduction of SERCA2a protein level and function in HF, which has been successfully targeted via viral transfection of the SERCA2a gene into cardiac tissue in vivo. This has enhanced cardiac contractility and reduced mortality in several preclinical models of HF. Theoretical concerns have been raised regarding the possibility of arrhythmogenic adverse effects of SERCA2a gene therapy due to enhanced SR Ca2+ load and induction of SR Ca2+ leak as a result. Contrary to these concerns, SERCA2a gene therapy in a wide variety of preclinical models, including acute ischaemia/reperfusion, chronic pressure overload and chronic myocardial infarction, has resulted in a reduction in ventricular arrhythmias. The potential mechanisms for this unexpected beneficial effect, as well as mechanisms of enhancement of cardiac contractile function, are reviewed in this article. PMID:24138023

  5. Sustained normalization of neurological disease after intracranial gene therapy in a feline model.

    PubMed

    McCurdy, Victoria J; Johnson, Aime K; Gray-Edwards, Heather L; Randle, Ashley N; Brunson, Brandon L; Morrison, Nancy E; Salibi, Nouha; Johnson, Jacob A; Hwang, Misako; Beyers, Ronald J; Leroy, Stanley G; Maitland, Stacy; Denney, Thomas S; Cox, Nancy R; Baker, Henry J; Sena-Esteves, Miguel; Martin, Douglas R

    2014-04-01

    Progressive debilitating neurological defects characterize feline G(M1) gangliosidosis, a lysosomal storage disease caused by deficiency of lysosomal ?-galactosidase. No effective therapy exists for affected children, who often die before age 5 years. An adeno-associated viral vector carrying the therapeutic gene was injected bilaterally into two brain targets (thalamus and deep cerebellar nuclei) of a feline model of G(M1) gangliosidosis. Gene therapy normalized ?-galactosidase activity and storage throughout the brain and spinal cord. The mean survival of 12 treated G(M1) animals was >38 months, compared to 8 months for untreated animals. Seven of the eight treated animals remaining alive demonstrated normalization of disease, with abrogation of many symptoms including gait deficits and postural imbalance. Sustained correction of the G(M1) gangliosidosis disease phenotype after limited intracranial targeting by gene therapy in a large animal model suggests that this approach may be useful for treating the human version of this lysosomal storage disorder. PMID:24718858

  6. Combining cell transplants or gene therapy with deep brain stimulation for Parkinson's disease.

    PubMed

    Rowland, Nathan C; Starr, Philip A; Larson, Paul S; Ostrem, Jill L; Marks, William J; Lim, Daniel A

    2015-02-01

    Cell transplantation and gene therapy each show promise to enhance the treatment of Parkinson's disease (PD). However, because cell transplantation and gene therapy generally require direct delivery to the central nervous system, clinical trial design involves unique scientific, ethical, and financial concerns related to the invasive nature of the procedure. Typically, such biologics have been tested in PD patients who have not received any neurosurgical intervention. Here, we suggest that PD patients undergoing deep brain stimulation (DBS) device implantation are an ideal patient population for the clinical evaluation of cell transplantation and gene therapy. Randomizing subjects to an experimental group that receives the biologic concurrently with the DBS implantation-or to a control group that receives the DBS treatment alone-has several compelling advantages. First, this study design enables the participation of patients likely to benefit from DBS, many of whom simultaneously meet the inclusion criteria of biologic studies. Second, the need for a sham neurosurgical procedure is eliminated, which may reduce ethical concerns, promote patient recruitment, and enhance the blinding of surgical trials. Third, testing the biologic by "piggybacking" onto an established, reimbursable procedure should reduce the cost of clinical trials, which may allow a greater number of biologics to reach this critical stage of research translation. Finally, this clinical trial design may lead to combinatorial treatment strategies that provide PD patients with more durable control over disabling motor symptoms. By combining neuromodulation with biologics, we may also reveal important treatment paradigms relevant to other diseases of the brain. PMID:25521796

  7. LDLR-Gene therapy for familial hypercholesterolaemia: problems, progress, and perspectives

    PubMed Central

    2010-01-01

    Coronary artery diseases (CAD) inflict a heavy economical and social burden on most populations and contribute significantly to their morbidity and mortality rates. Low-density lipoprotein receptor (LDLR) associated familial hypercholesterolemia (FH) is the most frequent Mendelian disorder and is a major risk factor for the development of CAD. To date there is no cure for FH. The primary goal of clinical management is to control hypercholesterolaemia in order to decrease the risk of atherosclerosis and to prevent CAD. Permanent phenotypic correction with single administration of a gene therapeutic vector is a goal still needing to be achieved. The first ex vivo clinical trial of gene therapy in FH was conducted nearly 18 years ago. Patients who had inherited LDLR gene mutations were subjected to an aggressive surgical intervention involving partial hepatectomy to obtain the patient's own hepatocytes for ex vivo gene transfer with a replication deficient LDLR-retroviral vector. After successful re-infusion of transduced cells through a catheter placed in the inferior mesenteric vein at the time of liver resection, only low-level expression of the transferred LDLR gene was observed in the five patients enrolled in the trial. In contrast, full reversal of hypercholesterolaemia was later demonstrated in in vivo preclinical studies using LDLR-adenovirus mediated gene transfer. However, the high efficiency of cell division independent gene transfer by adenovirus vectors is limited by their short-term persistence due to episomal maintenance and the cytotoxicity of these highly immunogenic viruses. Novel long-term persisting vectors derived from adeno-associated viruses and lentiviruses, are now available and investigations are underway to determine their safety and efficiency in preparation for clinical application for a variety of diseases. Several novel non-viral based therapies have also been developed recently to lower LDL-C serum levels in FH patients. This article reviews the progress made in the 18 years since the first clinical trial for gene therapy of FH, with emphasis on the development, design, performance and limitations of viral based gene transfer vectors used in studies to ameliorate the effects of LDLR deficiency. PMID:21144047

  8. Pilot assessment of HIV gene therapy-hematopoietic stem cell clinical trial acceptability among minority patients and their advisors.

    PubMed

    King, William Douglas; Wyatt, Gail E; Liu, Honghu; Williams, John K; DiNardo, Anthony D; Mitsuyasu, Ronald T

    2010-12-01

    Clinical trials involving technologically involved novel treatments such as gene therapy delivered through hematopoietic stem cells as human immunodeficiency virus (HIV) treatment will need to recruit ethnically diverse patients to ensure the acceptance among broad groups of individuals and generalizability of research findings. Five focus groups of 47 HIV-positive men and women, religious and community leaders and health providers, mostly from African American and low-income communities, were conducted to examine knowledge about gene therapy and stem cell research and to assess the moral and ethical beliefs that might influence participation in clinical trials. Three themes emerged from these groups: (1) the need for clarification of terminology and the ethics of understanding gene therapy-stem cell research, (2) strategies to avoid mistrust of medical procedures and provider mistrust, and (3) the conflict between science and religious beliefs as it pertains to gene therapy-stem cell research. PMID:21287892

  9. Method and system to synchronize acoustic therapy with ultrasound imaging

    NASA Technical Reports Server (NTRS)

    Owen, Neil (Inventor); Bailey, Michael R. (Inventor); Hossack, James (Inventor)

    2009-01-01

    Interference in ultrasound imaging when used in connection with high intensity focused ultrasound (HIFU) is avoided by employing a synchronization signal to control the HIFU signal. Unless the timing of the HIFU transducer is controlled, its output will substantially overwhelm the signal produced by ultrasound imaging system and obscure the image it produces. The synchronization signal employed to control the HIFU transducer is obtained without requiring modification of the ultrasound imaging system. Signals corresponding to scattered ultrasound imaging waves are collected using either the HIFU transducer or a dedicated receiver. A synchronization processor manipulates the scattered ultrasound imaging signals to achieve the synchronization signal, which is then used to control the HIFU bursts so as to substantially reduce or eliminate HIFU interference in the ultrasound image. The synchronization processor can alternatively be implemented using a computing device or an application-specific circuit.

  10. Gene therapy of B-cell lymphoma with cytokine gene-modified trioma cells.

    PubMed

    Strehl, J; Selmayr, M; Kremer, J P; Hültner, L; Lindhofer, H; Mocikat, R

    1999-09-24

    The trioma approach is a new immunotherapeutic strategy for treating B-cell lymphomas. It is based on converting the tumour idiotype to a bispecific immunoglobulin that redirects the idiotype to antigen-presenting cells. We show here that even pre-existing tumours can be eradicated by trioma vaccination, that the trioma approach is superior to vaccination with cytokine gene-modified autologous tumour cells and that there is a synergism between trioma immunisation and GM-CSF gene transfer. Furthermore, we show that the immunising potential of GM-CSF gene-modified autologous lymphoma cells is not as dependent on the cytokine expression level as described for other tumour models, such that even minute expression rates are effective. IL-4 gene transfer in the lymphoma model is considerably less efficient or even ineffective when more sensitive systems are used. Remarkably, trioma-mediated effects are extinguished when IL-4 is expressed by the trioma cell. PMID:10449617

  11. Inhibition of Tumor Angiogenesis and Growth by Nanoparticle-Mediated p53 Gene Therapy in Mice

    PubMed Central

    Prabha, Swayam; Sharma, Blanka; Labhasetwar, Vinod

    2012-01-01

    Mutation of the p53 tumor suppressor gene, the most common genetic alteration in human cancers, results in more aggressive disease and increased resistance to conventional therapies. Aggressiveness may be related to the increased angiogenic activity of cancer cells containing mutant p53. To restore wild-type p53 function in cancer cells, we developed polymeric nanoparticles (NPs) for p53 gene delivery. Previous in vitro and in vivo studies demonstrated the ability of these NPs to provide sustained intracellular release of DNA, thus sustained gene transfection and decreased tumor cell proliferation. We investigated in vivo mechanisms involved in NP-mediated p53 tumor inhibition, with focus on angiogenesis. We hypothesize that sustained p53 gene delivery will help decrease tumor angiogenic activity and thus reduce tumor growth and improve animal survival. Xenografts of p53 mutant tumors were treated with a single intratumoral injection of p53NPs. We observed intratumoral p53 gene expression corresponding to tumor growth inhibition, over 5 weeks. Treated tumors showed upregulation of thrombospondin-1, a potent antiangiogenic factor, and a decrease in microvessel density vs. controls (saline, p53 DNA alone, and control NPs). Greater levels of apoptosis were also observed in p53NP-treated tumors. Overall, this led to significantly improved survival in p53NP-treated animals. NP-mediated p53 gene delivery slowed cancer progression and improved survival in an in vivo cancer model. One mechanism by which this is accomplished is disruption of tumor angiogenesis. We conclude that the NP-mediated sustained tumor p53 gene therapy can effectively be used for tumor growth inhibition. PMID:22595792

  12. Improving the safety of cell therapy with the TK-suicide gene

    PubMed Central

    Greco, Raffaella; Oliveira, Giacomo; Stanghellini, Maria Teresa Lupo; Vago, Luca; Bondanza, Attilio; Peccatori, Jacopo; Cieri, Nicoletta; Marktel, Sarah; Mastaglio, Sara; Bordignon, Claudio; Bonini, Chiara; Ciceri, Fabio

    2015-01-01

    While opening new frontiers for the cure of malignant and non-malignant diseases, the increasing use of cell therapy poses also several new challenges related to the safety of a living drug. The most effective and consolidated cell therapy approach is allogeneic hematopoietic stem cell transplantation (HSCT), the only cure for several patients with high-risk hematological malignancies. The potential of allogeneic HSCT is strictly dependent on the donor immune system, particularly on alloreactive T lymphocytes, that promote the beneficial graft-versus-tumor effect (GvT), but may also trigger the detrimental graft-versus-host-disease (GvHD). Gene transfer technologies allow to manipulate donor T-cells to enforce GvT and foster immune reconstitution, while avoiding or controlling GvHD. The suicide gene approach is based on the transfer of a suicide gene into donor lymphocytes, for a safe infusion of a wide T-cell repertoire, that might be selectively controlled in vivo in case of GvHD. The herpes simplex virus thymidine kinase (HSV-TK) is the suicide gene most extensively tested in humans. Expression of HSV-TK in donor lymphocytes confers lethal sensitivity to the anti-herpes drug, ganciclovir. Progressive improvements in suicide genes, vector technology and transduction protocols have allowed to overcome the toxicity of GvHD while preserving the antitumor efficacy of allogeneic HSCT. Several phase I-II clinical trials in the last 20 years document the safety and the efficacy of HSV-TK approach, able to maintain its clear value over the last decades, in the rapidly progressing horizon of cancer cellular therapy. PMID:25999859

  13. Imaging Primary Mouse Sarcomas After Radiation Therapy Using Cathepsin-Activatable Fluorescent Imaging Agents

    SciTech Connect

    Cuneo, Kyle C. [Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina (United States)] [Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina (United States); Mito, Jeffrey K.; Javid, Melodi P. [Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina (United States)] [Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina (United States); Ferrer, Jorge M. [Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts (United States)] [Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts (United States); Kim, Yongbaek [Department of Clinical Pathology, College of Veterinary Medicine, Seoul National University, Seoul (Korea, Republic of)] [Department of Clinical Pathology, College of Veterinary Medicine, Seoul National University, Seoul (Korea, Republic of); Lee, W. David [The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts (United States)] [The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts (United States); Bawendi, Moungi G. [Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts (United States)] [Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts (United States); Brigman, Brian E. [Department of Orthopedic Surgery, Duke University School of Medicine, Durham, North Carolina (United States)] [Department of Orthopedic Surgery, Duke University School of Medicine, Durham, North Carolina (United States); Kirsch, David G., E-mail: david.kirsch@duke.edu [Department of Radiation Oncology, Duke University School of Medicine, Durham, North Carolina (United States); Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina (United States)

    2013-05-01

    Purpose: Cathepsin-activated fluorescent probes can detect tumors in mice and in canine patients. We previously showed that these probes can detect microscopic residual sarcoma in the tumor bed of mice during gross total resection. Many patients with soft tissue sarcoma (STS) and other tumors undergo radiation therapy (RT) before surgery. This study assesses the effect of RT on the ability of cathepsin-activated probes to differentiate between normal and cancerous tissue. Methods and Materials: A genetically engineered mouse model of STS was used to generate primary hind limb sarcomas that were treated with hypofractionated RT. Mice were injected intravenously with cathepsin-activated fluorescent probes, and various tissues, including the tumor, were imaged using a hand-held imaging device. Resected tumor and normal muscle samples were harvested to assess cathepsin expression by Western blot. Uptake of activated probe was analyzed by flow cytometry and confocal microscopy. Parallel in vitro studies using mouse sarcoma cells were performed. Results: RT of primary STS in mice and mouse sarcoma cell lines caused no change in probe activation or cathepsin protease expression. Increasing radiation dose resulted in an upward trend in probe activation. Flow cytometry and immunofluorescence showed that a substantial proportion of probe-labeled cells were CD11b-positive tumor-associated immune cells. Conclusions: In this primary murine model of STS, RT did not affect the ability of cathepsin-activated probes to differentiate between tumor and normal muscle. Cathepsin-activated probes labeled tumor cells and tumor-associated macrophages. Our results suggest that it would be feasible to include patients who have received preoperative RT in clinical studies evaluating cathepsin-activated imaging probes.

  14. Ferritin as a Novel Reporter Gene for Photoacoustic Molecular Imaging

    PubMed Central

    Ha, Seung Han; Carson, Andrew R.; Kim, Kang

    2013-01-01

    Reporter genes may serve as endogenous contrast agents in the field of photoacoustic (PA) molecular imaging (PMI), enabling greater characterization of detailed cellular processes and disease progression. To demonstrate the feasibility of using ferritin as a reporter gene, human melanoma SK-24 (SK-MEL-24) cells were co-transfected with plasmid expressing human heavy chain ferritin (H-FT) and plasmid expressing enhanced green fluorescent protein (pEGFP-C1) using lipofectamine™ 2000. Non-transfected SK-MEL-24 cells served as a negative control. Fluorescent imaging of GFP confirmed transfection and transgene expression in co-transfected cells. To detect iron accumulation due to ferritin overexpression in SK-MEL-24 cells, a focused high-frequency ultrasonic transducer (60 MHz, f/1.5), synchronized to a pulsed laser (fluence < 5 mJ/cm2) was used to scan the PA signal at a wide range NIR wavelengths (850–950 nm). PA signal intensity from H-FT transfected SK-MEL-24 cells was about 5–9 dB higher than nontransfected SK-MEL-24 cells at 850–950 nm. Immunofluorescence and RT-PCR analysis both indicate high levels of ferritin expression in H-FT transfected SK-MEL24 cells, with little ferritin expression in nontransfected SK-MEL-24 cells. In this study, the feasibility of using ferritin as a reporter gene for PMI has been demonstrated in vitro. The use of ferritin as a reporter gene represents a novel concept for PMI using an endogenous contrast agent and may provide various opportunities for molecular imaging and basic science research. PMID:22949299

  15. Gene Therapy: Charting a Future Course—Summary of a National Institutes of Health Workshop, April 12, 2013

    PubMed Central

    O'Reilly, Marina; Federoff, Howard J.; Fong, Yuman; Kohn, Donald B.; Patterson, Amy P.; Ahmed, Nabil; Asokan, Aravind; Boye, Shannon E.; Crystal, Ronald G.; De Oliveira, Satiro; Gargiulo, Linda; Harper, Scott Q.; Ikeda, Yasuhiro; Jambou, Robert; Montgomery, Maureen; Prograis, Lawrence; Rosenthal, Eugene; Sterman, Daniel H.; Vandenberghe, Luk H.; Zoloth, Laurie; Abedi, Mehrdad; Adair, Jennifer; Adusumilli, Prasad S.; Goins, William F.; Gray, Jhanelle; Monahan, Paul; Popplewell, Leslie; Sena-Esteves, Miguel; Tannous, Bakhos; Weber, Thomas; Wierda, William; Gopal-Srivastava, Rashmi; McDonald, Cheryl L.; Rosenblum, Daniel

    2014-01-01

    Abstract Recently, the gene therapy field has begun to experience clinical successes in a number of different diseases using various approaches and vectors. The workshop Gene Therapy: Charting a Future Course, sponsored by the National Institutes of Health (NIH) Office of Biotechnology Activities, brought together early and mid-career researchers to discuss the key scientific challenges and opportunities, ethical and communication issues, and NIH and foundation resources available to facilitate further clinical advances. PMID:24773122

  16. Public, Experts, and Acceptance of Advanced Medical Technologies: The Case of Organ Transplant and Gene Therapy in Japan

    Microsoft Academic Search

    Hajime Sato; Akira Akabayashi; Ichiro Kai

    2006-01-01

    In 1997, after long social debates, the Japanese government enacted a law on organ transplantation from brain-dead bodies.\\u000a Since 1993, on gene therapy, administrative agencies have issued a series of guidelines. This study seeks to elucidate when\\u000a people became aware of the issues and when they formed their opinions on organ transplant and gene therapy. At the same time,\\u000a it

  17. Intra-articular IL4 gene therapy in arthritis: anti-inflammatory effect and enhanced Th2activity

    Microsoft Academic Search

    D L Boyle; K H Y Nguyen; S Zhuang; Y Shi; J E McCormack; S Chada; G S Firestein

    1999-01-01

    Gene therapy has been explored as a potential method for treating chronic inflammatory diseases such as rheumatoid arthritis. To determine the efficacy of intra-articular IL-4 gene therapy in an animal model of arthritis using a retroviral vector, a retrovirus encoding rat IL-4 (DA-IL-4) was engineered, purified and concentrated to high titer (?109 CFU\\/ml). Infectivity and expression levels were demonstrated in

  18. Deformable image registration of CT and truncated cone-beam CT for adaptive radiation therapy

    NASA Astrophysics Data System (ADS)

    Zhen, Xin; Yan, Hao; Zhou, Linghong; Jia, Xun; Jiang, Steve B.

    2013-11-01

    Truncation of a cone-beam computed tomography (CBCT) image, mainly caused by the limited field of view (FOV) of CBCT imaging, poses challenges to the problem of deformable image registration (DIR) between computed tomography (CT) and CBCT images in adaptive radiation therapy (ART). The missing information outside the CBCT FOV usually causes incorrect deformations when a conventional DIR algorithm is utilized, which may introduce significant errors in subsequent operations such as dose calculation. In this paper, based on the observation that the missing information in the CBCT image domain does exist in the projection image domain, we propose to solve this problem by developing a hybrid deformation/reconstruction algorithm. As opposed to deforming the CT image to match the truncated CBCT image, the CT image is deformed such that its projections match all the corresponding projection images for the CBCT image. An iterative forward-backward projection algorithm is developed. Six head-and-neck cancer patient cases are used to evaluate our algorithm, five with simulated truncation and one with real truncation. It is found that our method can accurately register the CT image to the truncated CBCT image and is robust against image truncation when the portion of the truncated image is less than 40% of the total image. Part of this work was presented at the 54th AAPM Annual Meeting (Charlotte, NC, USA, 29 July-2 August 2012).

  19. Expression of Human Factor IX in Rabbit Hepatocytes by Retrovirus-Mediated Gene Transfer: Potential for Gene Therapy of Hemophilia B

    Microsoft Academic Search

    Donna Armentano; Arthur R. Thompson; Gretchen Darlington; Savio L. C. Woo

    1990-01-01

    Hemophilia B (Christmas disease) is a chromosome X-linked blood clotting disorder which results when factor IX is deficient or functionally defective. The enzyme is synthesized in the liver, and the existence of animal models for this genetic disease will permit the development of somatic gene therapy protocols aimed at transfer of the functional gene into the liver. We report the

  20. Adenovirus-mediated hypoxia-targeted gene therapy using HSV thymidine kinase and bacterial nitroreductase prodrug-activating genes in vitro and in vivo

    Microsoft Academic Search

    T J Harvey; I M Hennig; S D Shnyder; P A Cooper; N Ingram; G D Hall; P J Selby; J D Chester

    2011-01-01

    Hypoxia is an important factor in tumor growth. It is associated with resistance to conventional anticancer treatments. Gene therapy targeting hypoxic tumor cells therefore has the potential to enhance the efficacy of treatment of solid tumors. Transfection of a panel of tumor cell lines with plasmid constructs containing hypoxia-responsive promoter elements from the genes, vascular endothelial growth factor (VEGF) and