Sample records for gene therapy images

  1. Genes and Gene Therapy

    MedlinePLUS

    ... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  2. The Application of Nanoparticles in Gene Therapy and Magnetic Resonance Imaging

    PubMed Central

    HERRANZ, FERNANDO; ALMARZA, ELENA; RODRÍGUEZ, IGNACIO; SALINAS, BEATRIZ; ROSELL, YAMILKA; DESCO, MANUEL; BULTE, JEFF W.; RUIZ-CABELLO, JESÚS

    2012-01-01

    The combination of nanoparticles, gene therapy, and medical imaging has given rise to a new field known as gene theranostics, in which a nanobioconjugate is used to diagnose and treat the disease. The process generally involves binding between a vector carrying the genetic information and a nanoparticle, which provides the signal for imaging. The synthesis of this probe generates a synergic effect, enhancing the efficiency of gene transduction and imaging contrast. We discuss the latest approaches in the synthesis of nanoparticles for magnetic resonance imaging, gene therapy strategies, and their conjugation and in vivo application. PMID:21484943

  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. Development and Assessment of Gene Therapies for

    E-print Network

    Kolstad, Kathleen Durgin

    2009-01-01

    eyes caused by RPE65 mutations: Prerequisite for human gene therapyThe eye is an attractive organ for targeted gene therapy aseye is transparent, it is simple to image and conduct intraocular injections. In addition, gene therapy

  6. MRI-guided gene therapy Xiaoming Yanga

    E-print Network

    Atalar, Ergin

    Minireview MRI-guided gene therapy Xiaoming Yanga , Ergin Atalara,b,* a Department of Radiology gene expression. This review summarizes the current status of MRI- guided gene therapy. Ã? 2006 resonance imaging; MRI-guided therapy; Gene therapy 1. Introduction Gene therapy is an exciting frontier

  7. Gamma camera imaging of HSV-tk gene expression with [131I]-FIAU: Clinical applications in gene therapy

    SciTech Connect

    Tjuvajev, J.; Joshi, R.; Kennedy, J. [Memorial Sloan Kettering Cancer Center, NY (United States)] [and others

    1996-05-01

    Develop a method to image gene expression that can be used to monitor successful gene transduction in patients. Currently there are no noninvasive ways to define the extent and spatial location of gene transduction or the level of gene expression in targeted organs or tumors. Wild-type RF2 s.c. tumors were produced by implantation of 10{sup 6} cells into both flanks of Sprague Dawley R-Nu rats. Following a 46 day growth period, the left and right flank tumors reached a 5x4x3 and 3x2x1 cm size. The left tumor was inoculated with 10{sup 6} gp-STK-A2 retroviral vector-producer cells (10{sup 6}-10{sup 7} cfu/ml) in 100 {mu}l of media to induce in vivo transduction with HSV-tk gene. No carrier added 2`-fluoro-1-{beta}-D-arabinofuranosyl-5-[131I]-iodo-uracil [131I]-FIAU was synthesized and 2.8 mCi was injected i.v. 14 days after gp-STK-A2 cell inoculation. Gamma camera imaging was performed in vivo at 4,24 and 36 hours post [131I]-FIAU injection with a dual-headed gamma camera. The 24 and 36 hour images showed specific localization of retained radioactivity only in the transduced tumors. These results were confirmed using quantitative autoradiography (QAR) of the same tumors. QAR also showed significantly higher levels of retained radioactivity (>1% dose/g) in the transduced tumor than in other nontransduced areas (<0.03 %dose/g). The transduced tumor tissue had microscopic features typical of subcutaneously growing RG2 glioma and non vector-producer cells could be identified. Gene therapy trials in patients would benefit greatly from a noninvasive measure and image that could define the location, magnitude and persistence of gene expression overtime. HSV-tk and FIAU can be used as a {open_quotes}marker gene{close_quotes} - {open_quotes}marker substrate{close_quotes} combination for PET ([124-I]) or possibly SPECT ([123-I]) imaging.

  8. In vivo molecular imaging of adenoviral versus lentiviral gene therapy in two bone formation models.

    PubMed

    Feeley, Brian T; Conduah, Augustine H; Sugiyama, Osamu; Krenek, Lucie; Chen, Irvin S Y; Lieberman, Jay R

    2006-08-01

    Regional gene therapy techniques are promising methods to enhance bone formation in large bone defects that would be difficult to treat with allograft or autograft bone stock. In this study, we compared in vivo temporal expression patterns of adenoviral- and lentiviral-mediated gene therapy in two bone formation models. Primary rat bone marrow cells (RBMC) were transduced with lentiviral or adenoviral vectors containing luciferase (Luc) or BMP-2 cDNA, or cotransduced with vectors containing Luc and bone morphogenetic protein 2 (BMP-2). In vitro protein production was determined with luciferase assay or ELISA (for BMP-2 production) weekly for 12 weeks. Two bone formation models were used -- a hind limb muscle pouch or radial defect -- in SCID mice. A cooled charged-coupled device (CCD) camera was used to image in vivo luciferase expression weekly for 12 weeks. In vitro, adenoviral expression of BMP-2 and luciferase was detected by ELISA or luciferase assay, respectively, for 4 weeks. Lentiviral expression of BMP-2 and luciferase was sustained in culture for 3 months. Using the CCD camera, we found that adenoviral vectors expressed luciferase expression for up to 21 days, but lentiviral vectors expressed target gene expression for 3 months in vivo in both bone formation models. There was no detectable difference in the amount of bone formed between the adenoviral and lentiviral groups. Lentiviral-mediated delivery of BMP-2 can induce long term in vitro and in vivo gene expression, which may be beneficial when developing tissue engineering strategies to heal large bone defects or defects with a compromised biologic environment. PMID:16788987

  9. Gene therapies for osteoarthritis

    Microsoft Academic Search

    Christopher H. Evans

    2004-01-01

    Osteoarthritis (OA) is a major health problem in urgent need of better treatment. Gene therapy offers to meet this need. Of\\u000a the different strategies for using gene therapy in OA, local gene transfer to synovium is in the most advanced stage of development.\\u000a Local gene transfer brings several advantages, including a focused, local therapy that promises greater efficacy with reduced

  10. The Sodium Iodide Symporter (NIS) as an Imaging Reporter for Gene, Viral, and Cell-based Therapies

    PubMed Central

    Penheiter, Alan R; Russell, Stephen J; Carlson, Stephanie K

    2012-01-01

    Preclinical and clinical tomographic imaging systems increasingly are being utilized for non-invasive imaging of reporter gene products to reveal the distribution of molecular therapeutics within living subjects. Reporter gene and probe combinations can be employed to monitor vectors for gene, viral, and cell-based therapies. There are several reporter systems available; however, those employing radionuclides for positron emission tomography (PET) or singlephoton emission computed tomography (SPECT) offer the highest sensitivity and the greatest promise for deep tissue imaging in humans. Within the category of radionuclide reporters, the thyroidal sodium iodide symporter (NIS) has emerged as one of the most promising for preclinical and translational research. NIS has been incorporated into a remarkable variety of viral and non-viral vectors in which its functionality is conveniently determined by in vitro iodide uptake assays prior to live animal imaging. This review on the NIS reporter will focus on 1) differences between endogenous NIS and heterologously-expressed NIS, 2) qualitative or comparative use of NIS as an imaging reporter in preclinical and translational gene therapy, oncolytic viral therapy, and cell trafficking research, and 3) use of NIS as an absolute quantitative reporter. PMID:22263922

  11. History of gene therapy.

    PubMed

    Wirth, Thomas; Parker, Nigel; Ylä-Herttuala, Seppo

    2013-08-10

    Two decades after the initial gene therapy trials and more than 1700 approved clinical trials worldwide we not only have gained much new information and knowledge regarding gene therapy in general, but also learned to understand the concern that has persisted in society. Despite the setbacks gene therapy has faced, success stories have increasingly emerged. Examples for these are the positive recommendation for a gene therapy product (Glybera) by the EMA for approval in the European Union and the positive trials for the treatment of ADA deficiency, SCID-X1 and adrenoleukodystrophy. Nevertheless, our knowledge continues to grow and during the course of time more safety data has become available that helps us to develop better gene therapy approaches. Also, with the increased understanding of molecular medicine, we have been able to develop more specific and efficient gene transfer vectors which are now producing clinical results. In this review, we will take a historical view and highlight some of the milestones that had an important impact on the development of gene therapy. We will also discuss briefly the safety and ethical aspects of gene therapy and address some concerns that have been connected with gene therapy as an important therapeutic modality. PMID:23618815

  12. Corneal gene therapy

    Microsoft Academic Search

    Eytan A. Klausner; Dan Peer; Robert L. Chapman; Richard F. Multack; Shridhar V. Andurkar

    2007-01-01

    Gene therapy to the cornea can potentially correct inherited and acquired diseases of the cornea. Factors that facilitate corneal gene delivery are the accessibility and transparency of the cornea, its stability ex vivo and the immune privilege of the eye. Initial corneal gene delivery studies characterized the relationship between intraocular modes of administration and location of reporter gene expression. The

  13. Gene therapy for newborns

    Microsoft Academic Search

    DONALD B. KOHN; ROBERTSON PARKMAN

    Application of gene therapy to treat genetic and infectious diseases may have several ad- vantages if performed in newborns. Because of the minimal adverse effect of the underlying disease on cells of the newborn, the relatively small size of in- fants, and the large amount of future growth, gene therapy may be more successful in newborns than in older children

  14. Gene therapy progress and prospects: the eye

    Microsoft Academic Search

    J W B Bainbridge; M H Tan; R R Ali

    2006-01-01

    The eye has unique advantages as a target organ for gene therapy of both inherited and acquired ocular disorders and offers a valuable model system for gene therapy. The eye is readily accessible to phenotypic examination and investigation of therapeutic effects in vivo by fundus imaging and electrophysiological techniques. Considerable progress has been made in the development of gene replacement

  15. Antitumor gene therapy

    Microsoft Academic Search

    C. Cirielli; M. C. Capogrossi; A. Passaniti

    1997-01-01

    Gene therapy as an anti-tumor strategy is becoming a powerful tool for cytokine delivery to inhibit the growth of many tumors. Several delivery systems are being utilized and designed for the expression of specific genes to achieve a therapeutic result. Liposomes, retroviral vectors, and adenoviral vectors have all been used and eventual clinical application may depend on the type of

  16. Gene therapy for restenosis

    Microsoft Academic Search

    Roy C. Smith; Kenneth Walsh

    2000-01-01

    This review provides an overview of candidate genes that are currently being evaluated for genetic strategies in vascular\\u000a gene therapy. We discuss treatment strategies that have proven efficacious in limiting postinterventional restenosis through\\u000a evaluation with in vivo model systems. The candidate strategies utilize genes that are either cytotoxic, regulate vascular\\u000a smooth muscle cell differentiation or proliferation. In addition, we review

  17. The use of high-frequency ultrasound imaging and biofluorescence for in vivo evaluation of gene therapy vectors

    PubMed Central

    2013-01-01

    Background Non-invasive imaging of the biodistribution of novel therapeutics including gene therapy vectors in animal models is essential. Methods This study assessed the utility of high-frequency ultrasound (HF-US) combined with biofluoresence imaging (BFI) to determine the longitudinal impact of a Herpesvirus saimiri amplicon on human colorectal cancer xenograft growth. Results HF-US imaging of xenografts resulted in an accurate and informative xenograft volume in a longitudinal study. The volumes correlated better with final ex vivo volume than mechanical callipers (R2 = 0.7993, p = 0.0002 vs. R2 = 0.7867, p = 0.0014). HF-US showed that the amplicon caused lobe formation. BFI demonstrated retention and expression of the amplicon in the xenografts and quantitation of the fluorescence levels also correlated with tumour volumes. Conclusions The use of multi-modal imaging provided useful and enhanced insights into the behaviour of gene therapy vectors in vivo in real-time. These relatively inexpensive technologies are easy to incorporate into pre-clinical studies. PMID:24219244

  18. 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

  19. DNA Micelle Flares for Intracellular mRNA Imaging and Gene Therapy

    PubMed Central

    Chen, Tao; Sam Wu, Cuichen; Jimenez, Elizabeth; Zhu, Zhi; Dajac, Joshua G.; You, Mingxu; Han, Da

    2013-01-01

    Multifunctional DNA micelles: Molecular beacon micelle flares (MBMFs), based on diacyllipid-molecular beacon conjugate (L-MB) self-assembly, have been developed for combined mRNA detection and gene therapy. The advantages of these micelle flares include easy probe synthesis, efficient cellular uptake, enhanced enzymatic stability, high signal-to-background ratio, excellent target selectivity, and superior biocompatibility. In addition, these probes possess a hydrophobic cavity that can be used for additional hydrophobic agents, holding great promise for constructing an all-in-one nucleic acid probe. PMID:23319350

  20. [Gene therapy in The Netherlands].

    PubMed

    Schenk-Braat, E A M; van Mierlo, M M K B; Hospers, G A P; Wagemaker, G; Bangma, C H; Kaptein, L C M

    2007-09-01

    Extensive research is ongoing worldwide on the clinical utility of gene therapy, particularly for the treatment of cancer and genetic disorders. Two gene therapy products have already been approved recently in China. Clinical experience with gene therapy has also been accumulating in the Netherlands: over 200 Dutch patients have now been treated in clinical trials. Published results indicate that gene therapy is generally safe. Gene therapy appears to be effective for some genetic disorders, such as severe combined immune deficiency and haemophilia B. The efficacy of gene therapy, particularly in the treatment of cancer, appears to be limited up till now. PMID:17953170

  1. Cell and Gene Therapy

    Microsoft Academic Search

    Robbie Norville

    \\u000a Cell and Gene therapies are novel additions to the current multimodal approach of chemotherapy, radiation, surgery, and hematopoietic\\u000a stem cell transplant (HSCT) for the treatment of pediatric cancers. The manipulation of genes and the immune system can treat\\u000a cancer and prevent genetic diseases as well as increase the body's ability to receive intense treatment that would be impossible\\u000a otherwise. Humans

  2. Switching on the Lights for Gene Therapy

    Microsoft Academic Search

    Alexandra Winkeler; Miguel Sena-Esteves; Leonie E. M. Paulis; Hongfeng Li; Yannic Waerzeggers; Benedikt Rückriem; Uwe Himmelreich; Markus Klein; Parisa Monfared; Maria A. Rueger; Michael Heneka; Stefan Vollmar; Mathias Hoehn; Cornel Fraefel; Rudolf Graf; Klaus Wienhard; Wolf D. Heiss; Andreas H. Jacobs; Karen Aboody

    2007-01-01

    Strategies for non-invasive and quantitative imaging of gene expression in vivo have been developed over the past decade. Non-invasive assessment of the dynamics of gene regulation is of interest for the detection of endogenous disease-specific biological alterations (e.g., signal transduction) and for monitoring the induction and regulation of therapeutic genes (e.g., gene therapy). To demonstrate that non-invasive imaging of regulated

  3. The ethics of gene therapy.

    PubMed

    Chan, Sarah; Harris, John

    2006-10-01

    Recent developments have progressed in areas of science that pertain to gene therapy and its ethical implications. This review discusses the current state of therapeutic gene technologies, including stem cell therapies and genetic modification, and identifies ethical issues of concern in relation to the science of gene therapy and its application, including the ethics of embryonic stem cell research and therapeutic cloning, the risks associated with gene therapy, and the ethics of clinical research in developing new therapeutic technologies. Additionally, ethical issues relating to genetic modification itself are considered: the significance of the human genome, the distinction between therapy and enhancement, and concerns regarding gene therapy as a eugenic practice. PMID:17078379

  4. A silica-polymer composite nano system for tumor-targeted imaging and p53 gene therapy of lung cancer.

    PubMed

    Wu, Hongbo; Zhao, Yanqiu; Mu, Xiaoqian; Wu, Huijuan; Chen, Lijuan; Liu, Wenjing; Mu, Yu; Liu, Jie; Wei, Xudong

    2015-04-01

    In our study, a silica-polymer composite nano system (MB-NSi-p53-CS ternary complexes) composed of methylene blue-encapsulated amine-terminated silica nanoparticles (MB-NSi) and chondroitin sulfate (CS) were successfully developed for tumor-targeted imaging and p53 gene therapy of lung cancer. MB was employed as a NIR probe for in vivo imaging, MB-NSi nanoparticles were served as gene vector, while CS was applied to be a coating and targeting polymer. MB-NSi-p53-CS ternary complexes displayed nanosized diameter, effective p53 condensation ability, efficient p53 protection profile, and superior bovine serum albumin stability in vitro. Experiments on A549 cell line further revealed low cytotoxicity, high p53 transfection, and anticancer efficacy of MB-NSi-p53-CS ternary complexes. In vivo imaging and tumor targetability assays demonstrated that MB-NSi-p53-CS ternary complexes were a preferable system with desirable imaging and tumor-targeting properties. PMID:25624096

  5. Nanoparticles for retinal gene therapy

    Microsoft Academic Search

    Shannon M. Conley; Muna I. Naash

    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

  6. Angiogenic and antiangiogenic gene therapy

    Microsoft Academic Search

    M Malecki; P Kolsut; R Proczka

    2005-01-01

    Gene therapy is thought to be a promising method for the treatment of various diseases. One gene therapy strategy invloves the manipulations on a process of formation of new vessels, commonly defined as angiogenesis. Angiogenic and antiangiogenic gene therapy is a new therapeutic approach to the treatment of cardiovascular and cancer patients, respectively. So far, preclinical and clinical studies are

  7. 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

  8. Genetics Home Reference: What is gene therapy?

    MedlinePLUS

    ... Work Mutations and Health Inheritance Consultation Testing Therapy Human Genome Project Genomic Research Next Handbook > Gene Therapy > What is ... offers a list of links to information about genes and gene therapy . Educational resources related to gene therapy are available ...

  9. Noninvasive Imaging of Herpes Virus Thymidine Kinase Gene Transfer and Expression: A Potential Method for Monitoring Clinical Gene Therapy

    Microsoft Academic Search

    Jun G. TJuvajev; Ronald Finn; Kyoichi Watanabe; Revathi Joshi; Takamitsu Oku; John Kennedy; Bradley Beattie; Jason Koutcher; Steven Larson; Ronald G. Blasberg

    Noninvasive imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk)gene expression is possible with a clinical gamma camera and by single-photon emission tomography (SPECT) using ‘3t1-labeled 2'- ftuo@2'deoxy-1-@-D-arabinofuranosyl-5-iodo-uradil (FIAU). Studies were performed in rats bearing s.c. tumors. Tumors were produced by injection of wild-typeRG2gliomaor W256mammary carcinomacells into one flank and RG2TK+ glioma or W256TK+ mammary carcinoma cells (that had

  10. Gene Therapy for Autoimmune Disorders

    Microsoft Academic Search

    C. H. Evans; S. C. Ghivizzani; T. J. Oligino; P. D. Robbins

    2000-01-01

    Although many autoimmune disorders do not have a strong genetic basis, their treatment may nevertheless be improved by gene therapies. Most strategies seek to transfer genes encoding immunomodulatory products that will alter host immune responses in a beneficial manner. Used in this fashion, genes serve as biological delivery vehicles for the products they encode. By this means gene therapy overcomes

  11. GENIS: Gene Expression of Sodium Iodide Symporter for Noninvasive Imaging of Gene Therapy Vectors and Quantification of Gene Expression in Vivo

    Microsoft Academic Search

    Kenneth N. Barton; Donald Tyson; Hans Stricker; Young S. Lew; Gregory Heisey; Sweaty Koul; Alberto de la Zerda; Fang-Fang Yin; Hui Yan; Tavarekere N. Nagaraja; Kelly Ann Randall; Guk Kim Jin; Joseph D. Fenstermacher; Sissy Jhiang; Jae Ho Kim; Svend O. Freytag; Stephen L. Brown

    2003-01-01

    With the goal of optimizing adenovirus-mediated suicide gene therapy for prostate cancer, we have developed a method based on the human sodium iodide symporter (hNIS) that allows for noninvasive monitoring of adenoviral vectors and quantification of gene expression magnitude and volume within the prostate. A replication-competent adenovirus (Ad5-yCD\\/mutTKSR39rep-hNIS) coexpressing a therapeutic yeast cytosine deaminase (yCD)\\/mutant herpes simplex virus thymidine kinase

  12. 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

  13. Gene therapy of liver cancer

    PubMed Central

    Hernandez-Alcoceba, Ruben; Sangro, Bruno; Prieto, Jesus

    2006-01-01

    The application of gene transfer technologies to the treatment of cancer has led to the development of new experimental approaches like gene directed enzyme/pro-drug therapy (GDEPT), inhibition of oncogenes and restoration of tumor-suppressor genes. In addition, gene therapy has a big impact on other fields like cancer immunotherapy, anti-angiogenic therapy and virotherapy. These strategies are being evaluated for the treatment of primary and metastatic liver cancer and some of them have reached clinical phases. We present a review on the basis and the actual status of gene therapy approaches applied to liver cancer. PMID:17036377

  14. 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.

  15. Gene therapy in the CNS

    Microsoft Academic Search

    L C Costantini; J C Bakowska; X O Breakefield; O Isacson

    2000-01-01

    Gene therapy for neurological disorder is currently an experimental concept. The goals for clinical utilization are the relief of symptoms, slowing of disease progression, and correction of genetic abnormalities. Experimental studies are realizing these goals in the development of gene therapies in animal models. Discoveries of the molecular basis of neurological disease and advances in gene transfer systems have allowed

  16. 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

  17. Gene therapy in keratoconus.

    PubMed

    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

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

    E-print Network

    Buschmann, Michael

    original article© The American Society of Gene & Cell Therapy Molecular Therapy 1 The transfection a critical impediment to successful clinical translation of gene therapy. Polyplexes formed by combining DNA decondensation/unpacking kinetics. Major barriers to nonviral gene transfer were studied by image

  19. Gene Therapy for Chronic Pain

    Microsoft Academic Search

    William R. Lariviere; Doris K. Cope

    \\u000a Gene therapy shows great potential to assist numerous patients with inadequate relief of inflammatory or neuropathic pain,\\u000a or intractable pain associated with advanced cancer. A brief overview is provided of the methods of gene therapy and of preclinical\\u000a findings in animal models of prolonged inflammatory, neuropathic and cancer pain. Preclinical findings demonstrate no efficacy\\u000a of gene therapy on basal thermal

  20. Radiation therapy imaging apparatus

    SciTech Connect

    Chou, T.J.; Shoenfeld, H.; Greenway, W.C.

    1991-02-19

    This patent describes a radiation therapy imaging apparatus for providing images in a patient being treated on a radiation therapy apparatus for verification and monitoring of patient positioning and verification of alignment and shaping of the radiation field of the radiation therapy apparatus. It comprises: a high-energy treatment head for applying a radiation dose to a patient positioned on a treatment table, and a gantry rotatable about an isocentric axis and carrying the treatment head for permitting the radiation dose to be applied to the patient from any of a range of angles about the isocentric axis; the radiation therapy imaging apparatus including a radiation therapy image detector which comprises a video camera mounted on the gantry diametrically opposite the treat head, an elongated light-excluding enclosure enveloping the camera to exclude ambient light from the camera, a fluoroscopic plate positioned on a distal end of the enclosure remote from the camera and aligned with the head to produce a fluoroscopic image in response to radiation applied from the head through the patient, mirror means in the enclosure and oriented for reflecting the image to the camera to permit monitoring on a viewing screen of the position of the radiation field in respect to the patient, and means for retracting at least the distal end of the enclosure from a position in which the fluoroscopic plate is disposed opposite the treatment head without disturbing the position of the camera on the gantry, so that the enclosure can be collapsed and kept from projecting under the treatment table when the patient is being positioned on the treatment table.

  1. Human Gene Therapy: Genes without Frontiers?

    ERIC Educational Resources Information Center

    Simon, Eric J.

    2002-01-01

    Describes the latest advancements and setbacks in human gene therapy to provide reference material for biology teachers to use in their science classes. Focuses on basic concepts such as recombinant DNA technology, and provides examples of human gene therapy such as severe combined immunodeficiency syndrome, familial hypercholesterolemia, and…

  2. Pompe disease gene therapy

    PubMed Central

    Byrne, Barry J.; Falk, Darin J.; Pacak, Christina A.; Nayak, Sushrusha; Herzog, Roland W.; Elder, Melissa E.; Collins, Shelley W.; Conlon, Thomas J.; Clement, Nathalie; Cleaver, Brian D.; Cloutier, Denise A.; Porvasnik, Stacy L.; Islam, Saleem; Elmallah, Mai K.; Martin, Anatole; Smith, Barbara K.; Fuller, David D.; Lawson, Lee Ann; Mah, Cathryn S.

    2011-01-01

    Pompe disease is an autosomal recessive metabolic myopathy caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase and results in cellular lysosomal and cytoplasmic glycogen accumulation. A wide spectrum of disease exists from hypotonia and severe cardiac hypertrophy in the first few months of life due to severe mutations to a milder form with the onset of symptoms in adulthood. In either condition, the involvement of several systems leads to progressive weakness and disability. In early-onset severe cases, the natural history is characteristically cardiorespiratory failure and death in the first year of life. Since the advent of enzyme replacement therapy (ERT), the clinical outcomes have improved. However, it has become apparent that a new natural history is being defined in which some patients have substantial improvement following ERT, while others develop chronic disability reminiscent of the late-onset disease. In order to improve on the current clinical outcomes in Pompe patients with diminished clinical response to ERT, we sought to address the cause and potential for the treatment of disease manifestations which are not amenable to ERT. In this review, we will focus on the preclinical studies that are relevant to the development of a gene therapy strategy for Pompe disease, and have led to the first clinical trial of recombinant adeno-associated virus-mediated gene-based therapy for Pompe disease. We will cover the preliminary laboratory studies and rationale for a clinical trial, which is based on the treatment of the high rate of respiratory failure in the early-onset patients receiving ERT. PMID:21518733

  3. Gene therapy for Parkinson's disease

    Microsoft Academic Search

    Philippe Horellou; Jacques Mallet

    1997-01-01

    Gene therapy is a potentially powerful approach to the treatment of neurological diseases. The discovery of neurotrophic factors\\u000a inhibiting neurodegenerative processes and neurotransmitter-synthesizing enzymes provides the basis for current gene therapy\\u000a strategies for Parkinson's disease. Genes can be transferred by viral or nonviral vectors. Of the various possible vectors,\\u000a recombinant retroviruses are the most efficient for genetic modification of cells

  4. Gene therapy in the cornea

    Microsoft Academic Search

    Rajiv R. Mohan; Ajay Sharma; Marcelo V. Netto; Sunilima Sinha; Steven E. Wilson

    2005-01-01

    Technological advances in the field of gene therapy has prompted more than three hundred phase I and phase II gene-based clinical trials for the treatment of cancer, AIDS, macular degeneration, cardiovascular, and other monogenic diseases. Besides treating diseases, gene transfer technology has been utilized for the development of preventive and therapeutic vaccines for malaria, tuberculosis, hepatitis A, B and C

  5. 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

  6. Gene therapy for retinal diseases.

    PubMed

    Samiy, Nasrollah

    2014-01-01

    Gene therapy has a growing research potential particularly in the field of ophthalmic and retinal diseases owing to three main characteristics of the eye; accessibility in terms of injections and surgical interventions, its immune-privileged status facilitating the accommodation to the antigenicity of a viral vector, and tight blood-ocular barriers which save other organs from unwanted contamination. Gene therapy has tremendous potential for different ocular diseases. In fact, the perspective of gene therapy in the field of eye research does not confine to exclusive monogenic ophthalmic problems and it has the potential to include gene based pharmacotherapies for non-monogenic problems such as age related macular disease and diabetic retinopathy. The present article has focused on how gene transfer into the eye has been developed and used to treat retinal disorders with no available therapy at present. PMID:25709778

  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.

  8. Gene Therapy for Parkinson's Disease

    PubMed Central

    Denyer, Rachel; Douglas, Michael R.

    2012-01-01

    Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field. PMID:22619738

  9. 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

  10. Gene therapy on the move.

    PubMed

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

    2013-11-01

    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

  11. Gene Silencing Therapy Against Cancer

    Microsoft Academic Search

    Chao-Zhong Song

    Over the past 25 yr, gene silencing therapy derived from nucleic acid-based molecules has evolved from bench research to clinical\\u000a therapy. The recent discovery of RNA interference (RNAi), a mechanism by which double stranded RNAs mediate sequence-specific\\u000a gene silencing, provided a new tool in the fight against cancer. The application of RNAi technology in basic cancer research\\u000a will facilitate the

  12. RNAi: A New Paradigm in Cancer Gene Therapy

    Microsoft Academic Search

    Edna M. Mora; Selanere L. Mangala; Gabriel Lopez-Berestein; Anil K. Sood

    \\u000a RNA interference (RNAi) has revolutionized the field of gene therapy and opened up new opportunities for personalized treatments.\\u000a However, several challenges remain for gene therapy. Therefore, new approaches for gene regulatory therapies are needed to\\u000a overcome these challenges. In this chapter, we discuss the clinical significance of the RNAi machinery, clinical applications,\\u000a delivery systems, off-target effects, imaging, and clinical trials.

  13. Progress toward Human Gene Therapy

    Microsoft Academic Search

    Theodore Friedmann

    1989-01-01

    Current therapies for most human genetic diseases are inadequate. In response to the need for effective treatments, modern molecular genetics is providing tools for an unprecedented new approach to disease treatment through an attack directly on mutant genes. Recent results with several target organs and gene transfer techniques have led to broad medical and scientific acceptance of the feasibility of

  14. Gene therapy for cystic fibrosis.

    PubMed

    Johnson, L G

    1995-02-01

    Following the cloning of the cystic fibrosis (CF) gene, in vitro studies rapidly established the feasibility of gene therapy for this disease. Unlike ex vivo approaches that have been utilized for other genetic diseases such as adenosine deaminase deficiency, gene therapy for CF will likely require direct in vivo delivery of gene transfer vectors to the airways of patients with CF. Hence, major research efforts have been directed at the development of efficient gene transfer vectors that are safe for use in human subjects. Several vectors have now emerged from the laboratory for evaluation in clinical safety and efficacy trials in the United States and in the United Kingdom. Adenovirus-mediated gene transfer has been utilized for initial clinical safety and efficacy trials in the United States, while liposome-mediated gene transfer has been chosen for initial clinical safety and efficacy trials in the United Kingdom. The rationale and laboratory studies are reviewed leading to initial clinical safety and efficacy trials. Also reviewed are the currently available vectors for potential use in clinical studies, their advantages and disadvantages, and the promises and pitfalls of current gene therapy efforts for CF in the United States focusing on adenovirus vectors in current clinical trials. PMID:7842818

  15. Gene therapy for retinal disease

    PubMed Central

    McClements, Michelle E; MacLaren, Robert E

    2013-01-01

    Gene therapy strategies for the treatment of inherited retinal diseases have made major advances in recent years. This review focuses on adeno-associated viral (AAV) vector approaches to treat retinal degeneration and thus prevent or delay the onset of blindness. Data from human clinical trials of gene therapy for retinal disease show encouraging signs of safety and efficacy from AAV vectors. Recent progress in enhancing cell-specific targeting and transduction efficiency of the various retinal layers plus the use of AAV-delivered growth factors to augment the therapeutic effect and limit cell death suggest even greater success in future human trials is possible. PMID:23305707

  16. PET imaging of adoptive progenitor cell therapies

    Microsoft Academic Search

    Gelovani; Juri G

    2008-01-01

    Objectives. ;\\u000aThe 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

  17. Ethics of Gene Therapy Debated.

    ERIC Educational Resources Information Center

    Borman, Stu

    1991-01-01

    Presented are the highlights of a press conference featuring biomedical ethicist LeRoy Walters of Georgetown University and attorney Andrew Kimbrell of the Foundation on Economic Trends. The opposing points of view of these two speakers serve to outline the pros and cons of the gene therapy issue. (CW)

  18. Ocular Gene Therapy: Quo Vadis?

    Microsoft Academic Search

    William W. Hauswirth; Laurent Beaufrere

    2000-01-01

    he question of where gene therapy is going has almost as many answers as there are practitioners in the field. Narrowing our focus to diseases of the eye, this diver- sity of opinions does not contract proportionately. Therefore, rather than forecasting the future, it is more useful to assess the field today, including a consideration of where problems re- main

  19. 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

  20. Gene therapy and uterine leiomyoma: a review.

    PubMed

    Al-Hendy, Ayman; Salama, Salama

    2006-01-01

    Leiomyomas (fibroids) are common estrogen-dependent uterine tumours that cause significant morbidity for women and a substantial economic impact on health delivery systems. Currently, there is no effective medical treatment option for this condition-hysterectomy is the mainstay of management. This is not an attractive choice for many women, especially patients desiring to preserve their fertility potential. Gene therapy is becoming a clinical reality, with more than 600 clinical trials worldwide. Researchers have recently attempted to develop a gene-therapy-based approach for the ablation of uterine fibroids. The localized nature of this condition and its accessibility using different imaging or endoscopic techniques make it an attractive target for direct delivery of gene-based vectors. Recent work from our laboratory suggests the potential use of a dominant-negative form of estrogen receptor (ER) to inactivate estrogen signalling in leiomyoma cells and induce apoptosis. Our in vivo data in a mouse model demonstrate the ability of an adenovirus-expressing dominant-negative ER to arrest leiomyoma growth. We and others also have described the utility of the herpes simplex virus-thymidine kinase (HSV-TK) plus ganciclovir (GCV) suicide gene-therapy system to effectively eradicate leiomyoma cells by utilizing the bystandard effect phenomena and the high expression of gap-junction protein in these tumours. Further work on rat models will pave the way for future leiomyoma gene-therapy clinical trials and allow the realization of gene therapy as a viable non-surgical option for this common problem in women's health. PMID:16603566

  1. Current strategies in cancer gene therapy

    Microsoft Academic Search

    Anas El-Aneed

    2004-01-01

    Cancer gene therapy is the most studied application of gene therapy. Many genetic alterations are involved in the transformation of a normal cell into a neoplastic one. The two main gene groups involved in cancer development are oncogenes and tumor suppressor genes. While the latter eliminates cancerous cells via apoptosis, the former enhances cell proliferation. Therefore, apoptotic genes and anti-oncogenes

  2. Encapsulation for somatic gene therapy.

    PubMed

    Chang, P L

    1999-06-18

    With the human genome project approaching its completion date of 2005, gene-based technology will play an increasingly important role in health-care delivery. Non-autologous somatic gene therapy is a novel application in which non-autologous cell lines engineered to secrete a recombinant protein are enclosed within immunoisolation devices and implanted into all patients requiring the same product for therapy. The development of this technology requires a multi-disciplinary effort towards optimization of the biomaterial used to manufacture the implantable devices and selection of the appropriate cell lines for enclosure. The efficacy of this technology is illustrated in the treatment of dwarfism and lysosomal storage disease in murine models. The potential of a safe and cost-effective gene-based delivery method should have wide applications in treating both classical genetic disorders and non-Mendelian diseases. PMID:10415564

  3. Gene Therapy for Bone Engineering

    PubMed Central

    Balmayor, Elizabeth Rosado; van Griensven, Martijn

    2015-01-01

    Bone has an intrinsic healing capacity that may be exceeded when the fracture gap is too big or unstable. In that moment, osteogenic measures need to be taken by physicians. It is important to combine cells, scaffolds and growth factors, and the correct mechanical conditions. Growth factors are clinically administered as recombinant proteins. They are, however, expensive and needed in high supraphysiological doses. Moreover, their half-life is short when administered to the fracture. Therefore, gene therapy may be an alternative. Cells can constantly produce the protein of interest in the correct folding, with the physiological glycosylation and in the needed amounts. Genes can be delivered in vivo or ex vivo by viral or non-viral methods. Adenovirus is mostly used. For the non-viral methods, hydrogels and recently sonoporation seem to be promising means. This review will give an overview of recent advancements in gene therapy approaches for bone regeneration strategies. PMID:25699253

  4. 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

  5. Gene therapy in the Cornea: 2005–present

    Microsoft Academic Search

    Rajiv R. Mohan; Jonathan C. K. Tovey; Ajay Sharma; Ashish Tandon

    Successful restoration of vision in human patients with gene therapy affirmed its promise to cure ocular diseases and disorders. The efficacy of gene therapy is contingent upon vector and mode of therapeutic DNA introduction into targeted cells\\/tissues. The cornea is an ideal tissue for gene therapy due to its ease of access and relative immune-privilege. Considerable progress has been made

  6. Is pituitary gene therapy realistic?

    PubMed

    Davis, J R; McNeilly, A S

    2001-10-01

    Current therapies for pituitary tumours are moderately successful in many cases but still suffer from significant limitations, with relatively poor long-term rates of endocrine cure from surgery, and long-term hypopituitarism after radiotherapy. Even in the case of the most readily treatable tumours, prolactinomas, medical therapy with dopamine agonists is limited by lack of response or side-effects in up to 10% of patients. This has led to increasing interest in the application of our knowledge of pituitary cell and molecular biology to evaluate the potential of gene therapy. Various vectors are available to facilitate gene delivery, and recombinant adenoviruses have been studied in detail because of their ability to transduce the postmitotic, nondividing cells of the pituitary gland. Various studies with reporter genes such as beta-galactosidase have demonstrated high efficiency and long lasting expression of adenoviral transgenes in cultured pituitary cells in vitro. The feasibility of high level transgene expression has also been shown in vivo, but so far this requires stereotaxic intrapituitary injection to achieve adequate transduction. Ablation of pituitary cells has been demonstrated in cultured cell lines and in subcutaneous tumours in nude mice, though alternative animal models will be required to evaluate efficacy in more slowly proliferating tumours as found in man. Inflammatory responses have been documented in the pituitary gland as in other tissues, and this will require the evaluation of modified vectors to avoid significant adverse effects before human applications can be considered. In summary, gene therapy for pituitary disease is likely to be feasible in the future, but will require careful and extensive evaluation of efficacy and safety, using a variety of possible methods of gene delivery. PMID:11678822

  7. Phoenix rising: gene therapy makes a comeback.

    PubMed

    Limberis, Maria P

    2012-08-01

    Despite the first application of gene therapy in 1990, gene therapy has until recently failed to meet the huge expectations set forth by researchers, clinicians, and patients, thus dampening enthusiasm for an imminent cure for many life-threatening genetic diseases. Nonetheless, in recent years we have witnessed a strong comeback for gene therapy, with clinical successes in young and adult subjects suffering from inherited forms of blindness or from X-linked severe combined immunodeficiency disease. In this review, various gene therapy vectors progressing into clinical development and pivotal advances in gene therapy trials will be discussed. PMID:22623503

  8. Muscle Gene Therapy for Hemophilia

    PubMed Central

    Sabatino, Denise E.; Arruda, Valder R.

    2013-01-01

    Muscle-directed gene therapy for hemophilia is an attractive strategy for expression of therapeutic levels of clotting factor as evident from preclinical studies and an early phase clinical trial. Notably, local FIX expression by AAV-mediated direct intramuscular injection to skeletal muscle persists for years. Development of intravascular delivery of AAV vector approaches to skeletal muscle resulted in vector in widespread areas of the limb and increased expression of FIX in hemophilia B dogs. The use of FIX variants with improved biological activity may provide the opportunity to increase the efficacy of these approaches. Studies for hemophilia A are less developed at this point, but utilizing transgenes that improve hemostasis independent of FIX and FVIII has potential therapeutic application for both hemophilia A and B. Continuous monitoring of humoral and T cell responses to the transgene and AAV capsid in human trials will be critical for the translation of these promising approaches for muscle gene therapy for hemophilia. PMID:24883231

  9. Gene therapy for ovarian cancer

    Microsoft Academic Search

    Kristopher J. Kimball; T. Michael Numnum; Rodney P. Rocconi; Ronald D. Alvarez

    2006-01-01

    Ovarian cancer remains the leading cause of death due to gynecologic cancer in women in the United States. Gene and viral-based\\u000a therapies represent novel therapeutic approaches for cancer. The manipulation of genetic content of tumor cells toward a therapeutic\\u000a end has been divided into several general strategies, including molecular chemotherapy, mutation compensation, immunopotentiation,\\u000a and virotherapy. Improvements in delivery vehicles and

  10. 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

  11. Image-Guided Hydrodynamic Gene Delivery

    NASA Astrophysics Data System (ADS)

    Liu, Dexi

    2009-03-01

    Gene delivery by rapid injection of a large volume of DNA solution into a blood vessel, commonly called hydrodynamic gene delivery, has become a common method for gene therapy studies in rodents. In this presentation, I will focus on our recent work aiming at establishment of an image-guided hydrodynamic procedure for gene delivery in humans. Our study employed swine as an animal model and the procedure developed includes image-guided insertion of a balloon catheter into the selected blood vessel of the targeted organ from the jugular vein and hydrodynamic injection of plasmid DNA in saline. The talk will cover the rationale of our approach, the effectiveness of procedure for gene delivery to liver and muscle, and the impact of the procedure on physiological functions and serum chemistry of the animals. The results will be discussed with respect to potential applications of the hydrodynamic gene delivery to human gene therapy.

  12. Gene therapy in cardiac arrhythmias.

    PubMed

    Praveen, S V; Francis, Johnson; Venugopal, K

    2006-01-01

    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 the left bundle branch can provide stable heart rates. Genetic modification of the AV node mimicking beta blockade can be therapeutic in the management of atrial fibrillation. G protein overexpression to modify the AV node also is experimental. Modification and expression of potassium channel genes altering the delayed rectifier potassium currents may permit better management of congenital long QT syndromes. Arrhythmias in a failing heart are due to abnormal calcium cycling. Potential targets for genetic modulation include the sarcoplasmic reticulum calcium pump, calsequestrin and sodium calcium exchanger. Lastly the ethical concerns need to be addressed. PMID:16943902

  13. 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

  14. Gene Therapy in the Cornea: 2005-present

    PubMed Central

    Mohan, Rajiv R.; Tovey, Jonathan C.K.; Sharma, Ajay; Tandon, Ashish

    2011-01-01

    Successful restoration of vision in human patients with gene therapy affirmed its promise to cure ocular diseases and disorders. The efficacy of gene therapy is contingent upon vector and mode of therapeutic DNA introduction into targeted cells/tissues. The cornea is an ideal tissue for gene therapy due to its ease of access and relative immune-privilege. Considerable progress has been made in the field of corneal gene therapy in last 5 years. Several new gene transfer vectors, techniques and approaches have evolved. Although corneal gene therapy is still in its early stages of development, the potential of gene-based interventions to treat corneal abnormalities have begun to surface. Identification of next generation viral and nanoparticle vectors, characterization of delivered gene levels, localization, and duration in the cornea, and significant success in controlling corneal disorders, particularly fibrosis and angiogenesis, in experimental animal disease models, with no major side effects have propelled gene therapy a step closer towards establishing gene-based therapies for corneal blindness. Recently, researchers have assessed the delivery of therapeutic genes for corneal diseases and disorders due to trauma, infections, chemical, mechanical, and surgical injury, and/or abnormal wound healing. This review provides an update on the developments in gene therapy for corneal diseases and discusses the barriers that hinder its utilization for delivering genes in the cornea. PMID:21967960

  15. Cellular Targeting for Cochlear Gene Therapy

    PubMed Central

    Ryan, Allen F.; Mullen, Lina M.; Doherty, Joni K.

    2015-01-01

    Gene therapy has considerable potential for the treatment of disorders of the inner ear. Many forms of inherited hearing loss have now been linked to specific locations in the genome, and for many of these the genes and specific mutations involved have been identified. This information provides the basis for therapy based on genetic approaches. However, a major obstacle to gene therapy is the targeting of therapy to the cells and the times that are required. The inner ear is a very complex organ, involving dozens of cell types that must function in a coordinated manner to result in the formation of the ear, and in hearing. Mutations that result in hearing loss can affect virtually any of these cells. Moreover, the genes involved are active during particular times, some for only brief periods of time. In order to be effective, gene therapy must be delivered to the appropriate cells, and at the appropriate times. In many cases, it must also be restricted to these cells and times. This requires methods with which to target gene therapy in space and time. Cell-specific gene promoters offer the opportunity to direct gene therapy to a desired cell type. Moreover, conditional promoters allow gene expression to be turned off and on at desired times. Theoretically, these technologies offer a mechanism by which to deliver gene therapy to any cell, at any given time. This chapter will examine the potential for such targeting to deliver gene therapy to the inner ear in a precisely controlled manner. PMID:19494575

  16. Gene therapy for optic nerve disease

    Microsoft Academic Search

    K R G Martin; H A Quigley

    2004-01-01

    Purpose There has been recent interest in the potential use of gene therapy techniques to treat ocular disease. In this article, we consider the optic nerve diseases that are potentially most amenable to gene therapy.Methods We discuss the recent success of gene transfer experiments in animal models of glaucoma, optic neuritis, Leber's hereditary optic neuropathy (LHON), and optic nerve transection,

  17. LSUHSC Gene Therapy Program External Grant Awards

    E-print Network

    LSUHSC Gene Therapy Program External Grant Awards FEDERAL AWARDS: $25,422,433 · CFTR expression generated dendritic cells · Adult stem cell mediated gene therapy for cystic fibrosis STATE AWARDS: $15 Center · Lacrimal gland bioinformatics: a neural connection of dry eye and aging · Gene and Stem Cell

  18. The emerging fields of suicide gene therapy and virotherapy

    Microsoft Academic Search

    David Kirn; Ion Niculescu-Duvaz; Gunnel Hallden; Caroline J Springer

    2002-01-01

    Gene therapy is defined as a technology aimed at modifying the genetic component of cells for therapeutic benefit. ‘Suicide genes’ can be introduced into cancer cells to make them more sensitive to chemotherapeutics or toxins. Chemotherapeutic suicide gene therapy approaches are known as gene-directed enzyme prodrug therapy or gene-prodrug activation therapy. Other approaches include replacement gene therapy, antisense strategies and

  19. Targeting Herpetic Keratitis by Gene Therapy

    PubMed Central

    Elbadawy, Hossein Mostafa; Gailledrat, Marine; Desseaux, Carole; Ponzin, Diego; Ferrari, Stefano

    2012-01-01

    Ocular gene therapy is rapidly becoming a reality. By November 2012, approximately 28 clinical trials were approved to assess novel gene therapy agents. Viral infections such as herpetic keratitis caused by herpes simplex virus 1 (HSV-1) can cause serious complications that may lead to blindness. Recurrence of the disease is likely and cornea transplantation, therefore, might not be the ideal therapeutic solution. This paper will focus on the current situation of ocular gene therapy research against herpetic keratitis, including the use of viral and nonviral vectors, routes of delivery of therapeutic genes, new techniques, and key research strategies. Whereas the correction of inherited diseases was the initial goal of the field of gene therapy, here we discuss transgene expression, gene replacement, silencing, or clipping. Gene therapy of herpetic keratitis previously reported in the literature is screened emphasizing candidate gene therapy targets. Commonly adopted strategies are discussed to assess the relative advantages of the protective therapy using antiviral drugs and the common gene therapy against long-term HSV-1 ocular infections signs, inflammation and neovascularization. Successful gene therapy can provide innovative physiological and pharmaceutical solutions against herpetic keratitis. PMID:23326647

  20. Gene Technology Based Therapies in the Brain

    Microsoft Academic Search

    T. Wirth; S. Ylä-Herttuala

    Gene therapy potentially represents one of the most important developments in modern medicine. Gene therapy, especially of\\u000a cancer, has created exciting and elusive areas of therapeutic research in the past decade. In fact, the first gene therapy\\u000a performed in a human was not against cancer but was performed to a 14 year old child suffering from adenosine deaminase (ADA)\\u000a deficiency.

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

    PubMed

    Wirth, Thomas

    2011-12-20

    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

  2. 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

  3. Multimodality Imaging of Gene Transfer with a Receptor-Based Reporter Gene

    E-print Network

    Larson-Prior, Linda

    Multimodality Imaging of Gene Transfer with a Receptor-Based Reporter Gene Ron Chen1, Jesse J, Missouri Gene therapy trials have traditionally used tumor and tissue biopsies for assessing the efficacy of gene transfer. Non- invasive imaging techniques offer a distinct advantage over tissue biopsies

  4. Gene Therapy Progress and Prospects: Nonviral vectors

    Microsoft Academic Search

    T Niidome; L Huang

    2002-01-01

    The success of gene therapy is largely dependent on the development of the gene delivery vector. Recently, gene transfection into target cells using naked DNA, which is a simple and safe approach, has been improved by combining several physical techniques, for example, electroporation, gene gun, ultrasound and hydrodynamic pressure. Chemical approaches have been utilized to improve the efficiency and cell

  5. 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

  6. LSUHSC NEW ORLEANS GENE THERAPY PUBLICATIONS

    E-print Network

    - mediated and cell-based therapies for treatment of cystic fibrosis. Molecular Therapy 15. Cancer Gene Therapy 15(2):73-84. 2007 Bahner, I., T. Sumiyoshi, M. Kagoda, R. Swartout, K. Pepper, D Cancer Cell Lines. Molecular Cancer, 6:34. #12;Kawana, K., Quayle, A. J., Ficarra, M., Ibana, J. A., Shen

  7. Gene therapy for adenosine deaminase deficiency.

    PubMed

    Cappelli, Barbara; Aiuti, Alessandro

    2010-05-01

    In the last decade, gene therapy for adenosine deaminase deficiency has been developed as a successful alternative strategy to allogeneic bone marrow transplant and enzyme replacement therapy. Infusion of autologous hematopoietic stem cells, corrected ex vivo by retroviral vectors and combined to low-intensity conditioning regimen, has resulted in immunologic improvement, metabolic correction, and long-term clinical benefits. These findings have opened the way to applications of gene therapy in other primary immune deficiencies using novel vector technology. PMID:20493400

  8. 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.

  9. Gene Therapy Strategies for Cardiac Electrical Dysfunction

    PubMed Central

    Greener, Ian; Donahue, J. Kevin

    2010-01-01

    Cardiac disease is frequently associated with abnormalities in electrical function that can severely impair cardiac performance with potentially fatal consequences. The available therapeutic options have some efficacy but are far from perfect. The curative potential of gene therapy makes it an attractive approach for the treatment of cardiac arrhythmias. To date, gene therapy research strategies have targeted three major classes of cardiac arrhythmias: 1) ventricular arrhythmias, 2) atrial fibrillation, and 3) bradyarrhythmias. Various vehicles for gene transfer have been employed with adeno-associated viral gene delivery being the preferred choice for long-term gene expression, and adenoviral gene delivery for short-term proof of concept work. In combination with the development of novel delivery methods, gene therapy may prove to be an effective strategy to eliminate the most debilitating of arrhythmias. PMID:20696170

  10. Development of Biomaterials for Gene Therapy

    Microsoft Academic Search

    Sang-oh Han; Ram I. Mahato; Yong Kiel Sung; Sung Wan Kim

    2000-01-01

    Novel biocompatible polymeric gene carriers have been examined for their potential in treating various genetic and acquired diseases. The use of polymeric gene carriers may overcome the cur- rent problems associated with viral vectors in safety, immunogenicity, and mutagenesis. However, effective polymer-based gene therapy requires the control of cellular access and uptake, intracel- lular trafficking, and nuclear retention of plasmid

  11. In vivo imaging and radioiodine therapy following sodium iodide symporter gene transfer in animal model of intracerebral gliomas

    Microsoft Academic Search

    J-Y Cho; D HY Shen; W Yang; B Williams; T LF Buckwalter; G Hinkle; R Pozderac; R Kloos; H N Nagaraja; R F Barth; S M Jhiang

    2002-01-01

    Radioactive iodide uptake (RAIU) in thyroid follicular epithelial cells, mediated by the sodium iodide symporter (NIS), is the first rate-limiting step in iodide accumulation which provides a mechanism for effective radioiodide treatment for patients with thyroid cancer. We hypothesize that NIS gene transfer to non-thyroid tumor cells will enhance intracellular radioiodide accumulation and result in better tumor control. Here, we

  12. [Gene therapy for severe combined immunodeficiency].

    PubMed

    Petersen, Line Barrett; Jensen, Thomas G

    2010-06-01

    New results with gene therapy for severe combined immunodeficiency due to adenosine deaminase deficiency are promising. We review a clinical project in which ten children were treated with gene modified autologous haematopoietic stem cells. After treatment, eight patients were able to do without enzyme-replacement therapy, and nine patients showed improved immune function and sustained low concentration of toxic metabolites. No clonal outgrow was observed indicating a limited risk for future malignant development. Despite these promising results, the safety of gene therapy can still be improved. PMID:20534204

  13. Parkinson’s Disease: Gene Therapies

    PubMed Central

    Coune, Philippe G.; Schneider, Bernard L.; Aebischer, Patrick

    2012-01-01

    With the recent development of effective gene delivery systems, gene therapy for the central nervous system is finding novel applications. Here, we review existing viral vectors and discuss gene therapy strategies that have been proposed for Parkinson’s disease. To date, most of the clinical trials were based on viral vectors to deliver therapeutic transgenes to neurons within the basal ganglia. Initial trials used genes to relieve the major motor symptoms caused by nigrostriatal degeneration. Although these new genetic approaches still need to prove more effective than existing symptomatic treatments, there is a need for disease-modifying strategies. The investigation of the genetic factors implicated in Parkinson’s disease is providing precious insights in disease pathology that, combined with innovative gene delivery systems, will hopefully offer novel opportunities for gene therapy interventions to slow down, or even halt disease progression. PMID:22474617

  14. Gene Therapy Techniques for Peripheral Arterial Disease

    SciTech Connect

    Manninen, Hannu I. [Department of Clinical Radiology, Kuopio University Hospital, Puijonlaaksontie 2, FIN-70210 Kuopio (Finland); Maekinen, Kimmo [Departmentof Surgery, and Gene Therapy Unit, Kuopio University Hospital, Puijonlaaksontie 2, FIN-70210 Kuopio (Finland)

    2002-03-15

    Somatic gene therapy is the introduction of new genetic material into selective somatic cells with resulting therapeutic benefits. Vascular wall and, subsequently, cardiovascular diseases have become an interesting target for gene therapy studies.Arteries are an attractive target for gene therapy since vascular interventions, both open surgical and endovascular, are well suited for minimally invasive, easily monitored gene delivery. Promising therapeutic effects have been obtained in animal models in preventing post-angioplasty restenosis and vein graft thickening, as well as increasing blood flow and collateral development in ischemic limbs.First clinical trials suggest a beneficial effect of vascular endothelial growth factor in achieving therapeutic angiogenesis in chronic limb ischemia and the efficacy of decoy oligonucleotides to prevent infrainguinal vein graft stenosis. However, further studies are mandatory to clarify the safety issues, to develop better gene delivery vectors and delivery catheters, to improve transgene expression, as well as to find the most effective and safe treatment genes.

  15. Targeted gene therapies: tools, applications, optimization.

    PubMed

    Humbert, Olivier; Davis, Luther; Maizels, Nancy

    2012-01-01

    Many devastating human diseases are caused by mutations in a single gene that prevent a somatic cell from carrying out its essential functions, or by genetic changes acquired as a result of infectious disease or in the course of cell transformation. Targeted gene therapies have emerged as potential strategies for treatment of such diseases. These therapies depend upon rare-cutting endonucleases to cleave at specific sites in or near disease genes. Targeted gene correction provides a template for homology-directed repair, enabling the cell's own repair pathways to erase the mutation and replace it with the correct sequence. Targeted gene disruption ablates the disease gene, disabling its function. Gene targeting can also promote other kinds of genome engineering, including mutation, insertion, or gene deletion. Targeted gene therapies present significant advantages compared to approaches to gene therapy that depend upon delivery of stably expressing transgenes. Recent progress has been fueled by advances in nuclease discovery and design, and by new strategies that maximize efficiency of targeting and minimize off-target damage. Future progress will build on deeper mechanistic understanding of critical factors and pathways. PMID:22530743

  16. Ultrasound for molecular imaging and therapy in cancer

    PubMed Central

    Kaneko, Osamu F.

    2012-01-01

    Over the past decade, molecularly-targeted contrast enhanced ultrasound (ultrasound molecular imaging) has attracted significant attention in preclinical research of cancer diagnostic and therapy. Potential applications for ultrasound molecular imaging run the gamut from early detection and characterization of malignancies to monitoring treatment responses and guiding therapies. There may also be a role for ultrasound contrast agents for improved delivery of chemotherapeutic drugs and gene therapies across biological barriers. Currently, a first Phase 0 clinical trial in patients with prostate cancer assesses toxicity and feasibility of ultrasound molecular imaging using contrast agents targeted at the angiogenic marker vascular endothelial growth factor receptor type 2 (VEGFR2). This mini-review highlights recent advances and potential applications of ultrasound molecular imaging and ultrasound-guided therapy in cancer. PMID:23061039

  17. Human Studies of Angiogenic Gene Therapy

    PubMed Central

    Gupta, Rajesh; Tongers, Jörn; Losordo, Douglas W.

    2009-01-01

    Despite significant advances in medical, interventional, and surgical therapy for coronary and peripheral arterial disease, the burden of these illnesses remains high. To address this unmet need, the science of therapeutic angiogenesis has been evolving for almost two decades. Early pre-clinical studies and phase I clinical trials achieved promising results with growth factors administered as recombinant proteins or as single-agent gene therapies, and data accumulated through 10 years of clinical trials indicate that gene therapy has an acceptable safety profile. However, more rigorous phase II and phase III clinical trials have failed to unequivocally demonstrate that angiogenic agents are beneficial under the conditions and in the patients studied to date. Investigators have worked to understand the biology of the vascular system and to incorporate their findings into new treatments for patients with ischemic disease. Recent gene- and cell-therapy trials have demonstrated the bioactivity of several new agents and treatment strategies. Collectively, these observations have renewed interest in the mechanisms of angiogenesis and deepened our understanding of the complexity of vascular regeneration. Gene therapy that incorporates multiple growth factors, approaches that combine cell and gene therapy, and the administration of "master switch" agents that activate numerous downstream pathways are among the credible and plausible steps forward. In this review, we will examine the clinical development of angiogenic therapy, summarize several of the lessons learned during the conduct of these trials, and suggest how this prior experience may guide the conduct of future preclinical investigations and clinical trials. PMID:19815827

  18. Strategies in Gene Therapy for Glioblastoma

    PubMed Central

    Kwiatkowska, Aneta; Nandhu, Mohan S.; Behera, Prajna; Chiocca, E. Antonio; Viapiano, Mariano S.

    2013-01-01

    Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses) as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy. PMID:24202446

  19. Gene therapy for primary immunodeficiencies: Part 1.

    PubMed

    Cavazzana-Calvo, Marina; Fischer, Alain; Hacein-Bey-Abina, Salima; Aiuti, Alessandro

    2012-10-01

    Over 60 patients affected by SCID due to IL2RG deficiency (SCID-X1) or adenosine deaminase (ADA)-SCID have received hematopoietic stem cell gene therapy in the past 15 years using gammaretroviral vectors, resulting in immune reconstitution and clinical benefit in the majority of them. However, the occurrence of insertional oncogenesis in the SCID-X1 trials has led to the development of new clinical trials based on integrating vectors with improved safety design as well as investigation on new technologies for highly efficient gene targeting and site-specific gene editing. Here we will present the experience and perspectives of gene therapy for SCID-X1 and ADA-SCID and discuss the pros and cons of gene therapy in comparison to allogeneic transplantation. PMID:22981681

  20. Progress in gene therapy for neurological disorders

    PubMed Central

    Simonato, Michele; Bennett, Jean; Boulis, Nicholas M.; Castro, Maria G.; Fink, David J.; Goins, William F.; Gray, Steven J.; Lowenstein, Pedro R.; Vandenberghe, Luk H.; Wilson, Thomas J.; Wolfe, John H.; Glorioso, Joseph C.

    2013-01-01

    Diseases of the nervous system have devastating effects and are widely distributed among the population, being especially prevalent in the elderly. These diseases are often caused by inherited genetic mutations that result in abnormal nervous system development, neurodegeneration, or impaired neuronal function. Other causes of neurological diseases include genetic and epigenetic changes induced by environmental insults, injury, disease-related events or inflammatory processes. Standard medical and surgical practice has not proved effective in curing or treating these diseases, and appropriate pharmaceuticals do not exist or are insufficient to slow disease progression. Gene therapy is emerging as a powerful approach with potential to treat and even cure some of the most common diseases of the nervous system. Gene therapy for neurological diseases has been made possible through progress in understanding the underlying disease mechanisms, particularly those involving sensory neurons, and also by improvement of gene vector design, therapeutic gene selection, and methods of delivery. Progress in the field has renewed our optimism for gene therapy as a treatment modality that can be used by neurologists, ophthalmologists and neurosurgeons. In this Review, we describe the promising gene therapy strategies that have the potential to treat patients with neurological diseases and discuss prospects for future development of gene therapy. PMID:23609618

  1. What is Gene Therapy? Rafael Yez

    E-print Network

    Royal Holloway, University of London

    Dystrophy Sickle-cell disease #12;Dealing with inherited disease: a pending subject · We now knowWhat is Gene Therapy? Rafael Yáñez rafael.yanez@rhul.ac.uk Rare Disease Day @ Royal Holloway 28th protein or no protein #12;Genetic (aka inherited) diseases come from faulty genes Duchenne Muscular

  2. Optimizing Ribozymes for Somatic Cell Gene Therapy

    Microsoft Academic Search

    Andrea D. Branch; Paul E. Klotman

    1998-01-01

    Therapeutic ribozymes are created through a multistep process that requires trial and error. There are few established rules governing ribozyme design, but guidelines are emerging. It is not yet known whether hammerheads and hairpins, the two ribozymes most widely studied as potential gene therapy agents, have the inherent capability to ablate single genes. Their capacity for specificity and selectivity remains

  3. Recent developments in ocular gene therapy

    Microsoft Academic Search

    Teresa Borrás

    2003-01-01

    The past two to three years have witnessed a remarkable increase in the number of gene therapy studies to treat almost every disease of the eye. All types of delivery systems, viral and non-viral, have been used. Experiments have begun to move from the use of reporters, to genes with potential therapeutic value. In this paper, rather than giving an

  4. Novel Cell and Gene Therapies for HIV

    PubMed Central

    Hoxie, James A.; June, Carl H.

    2012-01-01

    Highly active antiretroviral therapy dramatically improves survival in HIV-infected patients. However, persistence of HIV in reservoirs has necessitated lifelong treatment that can be complicated by cumulative toxicities, incomplete immune restoration, and the emergence of drug-resistant escape mutants. Cell and gene therapies offer the promise of preventing progressive HIV infection by interfering with HIV replication in the absence of chronic antiviral therapy. Individuals homozygous for a deletion in the CCR5 gene (CCR5?32) are largely resistant to infection from R5-topic HIV-1 strains, which are most commonly transmitted. A recent report that an HIV-infected patient with relapsed acute myelogenous leukemia was effectively cured from HIV infection after transplantation of hematopoietic stem/progenitor cells (HSC) from a CCR5?32 homozygous donor has generated renewed interest in developing treatment strategies that target viral reservoirs and generate HIV resistance in a patient’s own cells. Although the development of cell-based and gene transfer therapies has been slow, progress in a number of areas is evident. Advances in the fields of gene-targeting strategies, T-cell-based approaches, and HSCs have been encouraging, and a series of ongoing and planned trials to establish proof of concept for strategies that could lead to successful cell and gene therapies for HIV are under way. The eventual goal of these studies is to eliminate latent viral reservoirs and the need for lifelong antiretroviral therapy. PMID:23028130

  5. 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.

  6. Gene therapy method targets tumor blood vessels

    Cancer.gov

    Working in mice, researchers at Washington University School of Medicine in St. Louis (home of the Alvin J. Siteman Cancer Center) report developing a gene delivery method long sought in the field of gene therapy: a deactivated virus carrying a gene of interest that can be injected into the bloodstream and make its way to the right cells. In this early proof-of-concept study, the scientists have shown that they can target tumor blood vessels in mice without affecting healthy tissues.

  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. Nuclear Imaging of Cancer Cell Therapies

    Microsoft Academic Search

    Vladimir Ponomarev

    2009-01-01

    A promising role of cellular therapies in cancer treatment is reflected by the constantly growing number of clinical trials with adoptively transferred cells. Direct and indirect cell labeling for the nuclear imaging of transferred cells has been proven reliable for imaging adoptive cellular therapies. Both methods show their advantages andlimitations. Direct labeling is arelatively easy,in- expensive, and well-established methodology. Indirect

  9. Physical Principles of Microbubbles for Ultrasound Imaging and Therapy

    Microsoft Academic Search

    Eleanor Stride

    2009-01-01

    Microbubble ultrasound contrast agents have been in clinical use for more than two decades, during which time their range of applications has increased to encompass echocardiography, Doppler enhancement, perfusion studies and molecular imaging, as well as a number of therapeutic applications including drug delivery, gene therapy, high-intensity focused ultrasound treatments and sonothrombolysis. The aim of this article is to review

  10. 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

  11. 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

  12. The American Society of Gene Therapy original article

    E-print Network

    Ponder, Katherine P.

    year. Gene therapy has been successfully used to treat MPS in animal models.10 HSC-directed gene© The American Society of Gene Therapy original article Molecular Therapy vol. 15 no. 5, 889 Therapy with Immunomodulation Xiucui Ma1 , Yuli Liu1 , Mindy Tittiger1 , Anne Hennig1 , Attila Kovacs1

  13. 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

  14. Development of Gene Therapy for Thalassemia

    PubMed Central

    Nienhuis, Arthur W.; Persons, Derek A.

    2012-01-01

    Retroviral vector–mediated gene transfer into hematopoietic stem cells provides a potentially curative therapy for severe ?-thalassemia. Lentiviral vectors based on human immunodeficiency virus have been developed for this purpose and have been shown to be effective in curing thalassemia in mouse models. One participant in an ongoing clinical trial has achieved transfusion independence after gene transfer into bone marrow stem cells owing, in part, to a genetically modified, dominant clone. Ongoing efforts are focused on improving the efficiency of lentiviral vector–mediated gene transfer into stem cells so that the curative potential of gene transfer can be consistently achieved. PMID:23125203

  15. Recent advances in gene therapy for thalassemia

    PubMed Central

    Raja, J. V.; Rachchh, M. A.; Gokani, R. H.

    2012-01-01

    Thalassemias are genetically transmitted disorders. Depending upon whether the genetic defects or deletion lies in transmission of ? or ? globin chain gene, thalassemias are classified into ? and ?-thalassemias. Thus, thalassemias could be cured by introducing or correcting a gene into the hematopoietic compartment or a single stem cell. Initial attempts at gene transfer have proved unsuccessful due to limitations of available gene transfer vectors. The present review described the newer approaches to overcome these limitations, includes the introduction of lentiviral vectors. New approaches have also focused on targeting the specific mutation in the globin genes, correcting the DNA sequence or manipulating the development in DNA translocation and splicing to restore globin chain synthesis. This review mainly discusses the gene therapy strategies for the thalassemias, including the use of lentiviral vectors, generation of induced pluripotent stem (iPS) cells, gene targeting, splice-switching and stop codon readthrough. PMID:22923960

  16. Cell and Gene Therapies for Refractory Epilepsy

    PubMed Central

    Detlev, Boison

    2007-01-01

    Despite recent advances in the development of antiepileptic drugs, refractory epilepsy remains a major clinical problem affecting up to 35% of patients with partial epilepsy. Currently, there are few therapies that affect the underlying disease process. Therefore, novel therapeutic concepts are urgently needed. The recent development of experimental cell and gene therapies may offer several advantages compared to conventional systemic pharmacotherapy: (i) Specificity to underlying pathogenetic mechanisms by rational design; (ii) specificity to epileptogenic networks by focal delivery; and (iii) avoidance of side effects. A number of naturally occurring brain substances, such as GABA, adenosine, and the neuropeptides galanin and neuropeptide Y, may function as endogenous anticonvulsants and, in addition, may interact with the process of epileptogenesis. Unfortunately, the systemic application of these compounds is compromised by limited bioavailability, poor penetration of the blood-brain barrier, or the widespread systemic distribution of their respective receptors. Therefore, in recent years a new field of cell and gene-based neuropharmacology has emerged, aimed at either delivering endogenous anticonvulsant compounds by focal intracerebral transplantation of bioengineered cells (ex vivo gene therapy), or by inducing epileptogenic brain areas to produce these compounds in situ (in vivo gene therapy). In this review, recent efforts to develop GABA-, adenosine-, galanin-, and neuropeptide Y- based cell and gene therapies are discussed. The neurochemical rationales for using these compounds are discussed, the advantages of focal applications are highlighted and preclinical cell transplantation and gene therapy studies are critically evaluated. Although many promising data have been generated recently, potential problems, such as long-term therapeutic efficacy, long-term safety, and efficacy in clinically relevant animal models, need to be addressed before clinical applications can be contemplated. PMID:18615179

  17. Human gene therapy in coming months

    SciTech Connect

    Marwick, C.

    1990-07-18

    According to the Human Gene Therapy Subcommittee, the first clinical trial of true gene therapy may begin in the fall. The main hurdles are expected to have been jumped by the end of this month, when the subcommittee meets again. The subcommittee's parent body, the Recombinant DNA Advisory Committee, is meeting at the same time and is expected to approve the subcommittee's recommendation. The study will still require approval by the Food and Drug Administration and by the acting director of the National Institutes of Health, William Raub.

  18. ORIGINAL ARTICLE Retinoschisin gene therapy in photoreceptors, Mller glia

    E-print Network

    Schaffer, David V.

    ORIGINAL ARTICLE Retinoschisin gene therapy in photoreceptors, Müller glia or all retinal cells to the importance of cell targeting and appropriate vector choice in the success of retinal gene therapies. Gene of this recessive monogenic disease is well understood, it is an excellent candidate for gene augmenta- tion therapy

  19. Gene therapy could begin next month

    SciTech Connect

    Marwick, C.

    1990-09-05

    The clinical application of gene therapy could begin as early as next month. As predicted the Recombinant DNA Committee of the National Institutes of Health has approved, with only one dissenting vote, the protocol intended to correct a rare congenital immune disorder, adenosine deaminase deficiency. The study involves inserting the gene that codes for this missing enzyme into cells obtained from 10 children with the disorder, then returning the cells to the patients.

  20. Nonviral Vector Systems for Cancer Gene Therapy

    Microsoft Academic Search

    Greg F. Walker; Ernst Wagner

    There is increasing interest in nonviral systems for the delivery of genes for cancer therapy. Nonviral gene delivery has\\u000a been considered an alternative to the intensely researched viral systems, although nonviral systems have several advantages.\\u000a First, they are nonimmunogenic and therefore can be applied to the patient more than once; there is no limitation to the size\\u000a of the deoxyribonucleic

  1. MOLECULAR THERAPY Vol. 4, No. 2, August 2001 Copyright The American Society of Gene Therapy

    E-print Network

    Ford, James

    expression may be an effective gene therapy vector design, if the target cells are dividing. The efficacy is to maintain the gene therapy vector extrachromosomally in the mammalian cell. Adenoviral vectors remainMOLECULAR THERAPY Vol. 4, No. 2, August 2001 Copyright © The American Society of Gene Therapy 1525

  2. Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy Design Principles

    E-print Network

    Schaffer, David V.

    Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy Design Principles Sharon States of America Abstract Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs between gene and standard antiretroviral therapies, and identify key factors that impact long-term viral

  3. MOLECULAR THERAPY Vol. 4, No. 3, September 2001 Copyright The American Society of Gene Therapy

    E-print Network

    Hemminki, Akseli

    MOLECULAR THERAPY Vol. 4, No. 3, September 2001 Copyright © The American Society of Gene Therapy. Barnes,5 Jesus Gomez-Navarro,1 David T. Curiel,1 and Ronald D. Alvarez5 1 The Gene Therapy Center, Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, 2 Department of Radiology

  4. Advances in ultrasound mediated gene therapy using microbubble contrast agents.

    PubMed

    Sirsi, Shashank R; Borden, Mark A

    2012-01-01

    Microbubble ultrasound contrast agents have the potential to dramatically improve gene therapy treatments by enhancing the delivery of therapeutic DNA to malignant tissue. The physical response of microbubbles in an ultrasound field can mechanically perturb blood vessel walls and cell membranes, enhancing drug permeability into malignant tissue. In this review, we discuss literature that provided evidence of specific mechanisms that enhance in vivo gene delivery utilizing microbubble contrast agents, namely their ability to 1) improving cell membrane permeability, 2) modulate vascular permeability, and 3) enhance endocytotic uptake in cells. Additionally, we review novel microbubble vectors that are being developed in order to exploit these mechanisms and deliver higher gene payloads with greater target specificity. Finally, we discuss some future considerations that should be addressed in the development of next-generation microbubbles in order to improve in vivo microbubble gene delivery. Overall, microbubbles are rapidly gaining popularity as efficient gene carriers, and combined with their functionality as imaging contrast agents, they represent powerful theranostic tools for image guided gene therapy applications. PMID:23382777

  5. Radiopharmaceutical and Gene Therapy Program

    SciTech Connect

    Buchsbaum, Donald J.

    2006-02-09

    The objective of our research program was to determine whether novel receptors can be induced in solid cancers as a target for therapy with radiolabeled unmodified peptides that bind to the receptors. The hypothesis was that induction of a high number of receptors on the surface of these cancer cells would result in an increased uptake of the radiolabeled monomeric peptides as compared to published results with radiolabeled antibodies or peptides to naturally expressed antigens or receptors, and therefore a better therapeutic outcome. The following is a summary of published results.

  6. Gene Therapy and Targeted Toxins for Glioma

    PubMed Central

    Castro, Maria G.; Candolfi, Marianela; Kroeger, Kurt; King, Gwendalyn D.; Curtin, James F.; Yagiz, Kader; Mineharu, Yohei; Assi, Hikmat; Wibowo, Mia; Muhammad, AKM Ghulam; Foulad, David; Puntel, Mariana; Lowenstein, Pedro R.

    2011-01-01

    The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors. PMID:21453286

  7. Extracellular barriers in respiratory gene therapy

    Microsoft Academic Search

    Niek Sanders; Carsten Rudolph; Kevin Braeckmans; Stefaan C. De Smedt; Joseph Demeester

    2009-01-01

    Respiratory gene therapy has been considered for the treatment of a broad range of pulmonary disorders. However, respiratory secretions form an important barrier towards the pulmonary delivery of therapeutic nucleic acids. In this review we will start with a brief description of the biophysical properties of respiratory mucus and alveolar fluid. This must allow the reader to gain insights into

  8. Gene transfer therapy of gaucher disease

    Microsoft Academic Search

    J. T. R. Clarke; D. Mahuran; J. W. Callahan; P. Thorner

    1996-01-01

    Gaucher disease is a hereditary disorder of glycosphingolipid metabolism caused by deficiency of lysosomal glucocerebrosidase (GBA) and characterized by accumulation of glucocerebroside in macrophages of the mononuclear phagocyte system (MPS; also called the reticuloendothelial system). Enzyme replacement treatment of the disease is highly effective; however, it is extremely expensive and inconvenient. Attempts at genetic correction by gene transfer therapy in

  9. 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

  10. Gene therapy and uterine leiomyoma: a review

    Microsoft Academic Search

    Ayman Al-Hendy; Salama Salama

    2006-01-01

    Leiomyomas (fibroids) are common estrogen-dependent uterine tumours that cause significant morbidity for women and a substantial economic impact on health delivery systems. Currently, there is no effective medical treatment option for this condition—hysterectomy is the mainstay of management. This is not an attractive choice for many women, especially patients desiring to preserve their fertility potential. Gene therapy is becoming a

  11. The Dangerous Promise of Gene Therapy

    NSDL National Science Digital Library

    Sophia Kolehmainen (Council for Responsible Genetics; )

    2000-02-01

    The issue-focused, peer-reviewed article investigates the first death of a participant in a gene therapy experiment. It reveals: lack of informed consent by participants, questionable use of volunteer types for trials, inadequate governmental and institutional controls, and doctors with conflict-of-interest agendas.

  12. Foamy Virus Vectors for HIV Gene Therapy

    PubMed Central

    Olszko, Miles E.; Trobridge, Grant D.

    2013-01-01

    Highly active antiretroviral therapy (HAART) has vastly improved outcomes for patients infected with HIV, yet it is a lifelong regimen that is expensive and has significant side effects. Retroviral gene therapy is a promising alternative treatment for HIV/AIDS; however, inefficient gene delivery to hematopoietic stem cells (HSCs) has so far limited the efficacy of this approach. Foamy virus (FV) vectors are derived from non-pathogenic viruses that are not endemic to the human population. FV vectors have been used to deliver HIV-inhibiting transgenes to human HSCs, and they have several advantages relative to other retroviral vectors. These include an attractive safety profile, broad tropism, a large transgene capacity, and the ability to persist in quiescent cells. In addition, the titers of FV vectors are not reduced by anti-HIV transgenes that affect the production of lentivirus (LV) vectors. Thus FV vectors are very promising for anti-HIV gene therapy. This review covers the advantages of FV vectors and describes their preclinical development for anti-HIV gene therapy. PMID:24153061

  13. Musings on genome medicine: gene therapy.

    PubMed

    Nathan, David G; Orkin, Stuart H

    2009-01-01

    Though the field has moved with glacial speed, gene therapies have been carried out successfully in patients with bone marrow disorders including immune deficiencies. The field may be poised to move forward more rapidly, but many barriers have yet to be surmounted. PMID:19435468

  14. Musings on genome medicine: gene therapy

    PubMed Central

    2009-01-01

    Though the field has moved with glacial speed, gene therapies have been carried out successfully in patients with bone marrow disorders including immune deficiencies. The field may be poised to move forward more rapidly, but many barriers have yet to be surmounted. PMID:19435468

  15. Nanoparticle applications in ocular gene therapy

    Microsoft Academic Search

    Xue Cai; Shannon Conley; Muna Naash

    2008-01-01

    The use of nanoparticles as carriers for the delivery of therapeutic materials to target tissues has became popular in recent years and has demonstrated great potentials for the treatments of a wide range of diseases. In this review, we summarize the advantages of nanotechnology as a common gene delivery strategy with emphasis on ocular therapy. Particular attention is paid to

  16. Gene Tests May Improve Therapy for Endometrial Cancer

    MedlinePLUS

    ... External link, please review our exit disclaimer . Subscribe Gene Tests May Improve Therapy for Endometrial Cancer By analyzing genes in hundreds of endometrial tumors, scientists identified details ...

  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 hemoglobinopathies: progress and challenges

    PubMed Central

    Dong, Alisa; Rivella, Stefano; Breda, Laura

    2013-01-01

    Hemoglobinopathies are genetic inherited conditions that originate from the lack or malfunction of the hemoglobin (Hb) protein. Sickle cell disease (SCD) and thalassemia are the most common forms of these conditions. The severe anemia combined with complications that arise in the most affected patients raises the necessity for a cure to restore hemoglobin function. The current routine therapies for these conditions, namely transfusion and iron chelation, have significantly improved the quality of life in patients over the years, but still fail to address the underlying cause of the diseases. A curative option, allogeneic bone marrow transplantation is available, but limited by the availability of suitable donors and graft-vs-host disease. Gene therapy offers an alternative approach to cure patients with hemoglobinopathies and aims at the direct recovery of the hemoglobin function via globin gene transfer. In the last 2 decades, gene transfer tools based on lentiviral vector development have been significantly improved and proven curative in several animal models for SCD and thalassemia. As a result, clinical trials are in progress and 1 patient has been successfully treated with this approach. However, there are still frontiers to explore that might improve this approach: the stoichiometry between the transgenic hemoglobin and endogenous hemoglobin with respect to the different globin genetic mutations; donor cell sourcing, such as the use of induced pluripotent stem cells (iPSCs); and the use of safer gene insertion methods to prevent oncogenesis. With this review we will provide insights about (1) the different lentiviral gene therapy approaches in mouse models and human cells; (2) current and planned clinical trials; (3) hurdles to overcome for clinical trials, such as myeloablation toxicity, insertional oncogenesis, and high vector expression; and (4) future perspectives for gene therapy, including safe harbors and iPSCs technology. PMID:23337292

  19. Gene Therapy: Implications for Craniofacial Regeneration

    PubMed Central

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

    2011-01-01

    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 over 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 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 twenty years the emerging field of craniofacial tissue engineering has adopted these techniques to enhance regeneration of mineralized tissues, salivary gland, periodontium, and to reduce tumor burden of head and neck squamous cell carcinoma. Studies are currently pursuing research on both biomaterial-mediated gene delivery as well as more clinically efficacious, though potentially more hazardous, viral methods. Though hundreds of gene therapy clinical trials have taken place in the past twenty 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

  20. Microfluidic approaches for gene delivery and gene therapy Jungkyu Kim,a

    E-print Network

    Sun, Yu

    Microfluidic approaches for gene delivery and gene therapy Jungkyu Kim,a Inseong Hwang,b Derek for gene delivery and therapy. The micro-scaled environment within microfluidic systems enables precise are producing increased efficiency in gene delivery and promise improved gene therapy results. Introduction Many

  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. Proton Therapy Verification with PET Imaging

    PubMed Central

    Zhu, Xuping; Fakhri, Georges El

    2013-01-01

    Proton therapy is very sensitive to uncertainties introduced during treatment planning and dose delivery. PET imaging of proton induced positron emitter distributions is the only practical approach for in vivo, in situ verification of proton therapy. This article reviews the current status of proton therapy verification with PET imaging. The different data detecting systems (in-beam, in-room and off-line PET), calculation methods for the prediction of proton induced PET activity distributions, and approaches for data evaluation are discussed. PMID:24312147

  3. Transcriptional Targeting for Ovarian Cancer Gene Therapy E. Casado,*,

    E-print Network

    Hemminki, Akseli

    /Gynecology; §Department of Pathology, Department of Cell Biology, and Department of Surgery; Gene Therapy CenterREVIEW Transcriptional Targeting for Ovarian Cancer Gene Therapy E. Casado,*, D. M. Nettelbeck. Alvarez,,¶ and D. T. Curiel*, ,1 *Division of Human Gene Therapy, Department of Medicine, Department

  4. The American Society of Gene Therapy original article

    E-print Network

    Cai, Long

    © The American Society of Gene Therapy original article Molecular Therapy vol. 15 no. 12, 2107 the way for HR-based strategies in gene therapy.8 On the basis of the achievements and setbacks in some gene through its endogenous promoter. We have developed a novel system based on integrase

  5. Retinal Gene Therapy Coming of Age Connie L. Cepko1

    E-print Network

    Cepko, Connie

    Commentary Retinal Gene Therapy Coming of Age Connie L. Cepko1 and Luk H. Vandenberghe2 About 5 years ago, results were made public from three independent early phase clinical gene therapy trials., 2008). These studies were arguably a first for an in vivo gene therapy approach to convincingly deliver

  6. Gene therapy in the treatment of ocular inflammation

    Microsoft Academic Search

    Karl Csaky; Robert Nussenblatt

    1999-01-01

    Gene therapy may become a powerful therapeutic modality in the treatment of both ocular inflammatory disease and as a means of preventing rejection following tissue transplantation. By directly introducing into ocular cells genes that encode proteins capable of down-regulating the immune response, gene therapy has potential for both therapy and as a method for studying mechanisms of disease. While marked

  7. RNAi as a gene therapy approach.

    PubMed

    Caplen, Natasha J

    2003-07-01

    RNA duplexes of 21 - 23 nucleotides (nts), with approximately 2 nt 3' overhangs (called small interfering RNAs or siRNAs), have recently been shown to mediate sequence-specific inhibition of gene expression in mammalian cells via a post-transcriptional gene silencing (PTGS) mechanism termed RNA interference (RNAi). RNAi has been rapidly adopted as a functional genomics tool in a wide range of species, has been adapted to allow for the transient or stable knockdown of gene expression generation in cell lines and animals, and has been developed for high-throughput analysis of gene function in Caenorhabditis elegans. With an increasing list of genes successfully knocked-down by RNAi in mammalian cells and improvements in the delivery of siRNAs to cells, including in vivo delivery to mice, attention is now turning to assessing the potential RNAi has as a gene therapy approach. RNAi is likely to have the greatest impact as a therapeutic tool in two key clinical areas, cancer and infectious disease, but it also has the potential as a therapy for other disorders including some dominant genetic diseases. This review will describe the status of the science behind this novel mechanism and will illustrate the therapeutic potential of RNAi-based technologies, using examples from these critical clinical research areas. PMID:12831363

  8. Gene Therapy and Wound Healing

    PubMed Central

    Eming, Sabine A.; Krieg, Thomas; Davidson, Jeffrey M

    2007-01-01

    Wound repair involves the sequential interaction of various cell types, extracellular matrix molecules, and soluble mediators. During the past 10 years, much new information on signals controlling wound cell behavior has emerged. This knowledge has led to a number of novel_therapeutic strategies. In particular, the local delivery of pluripotent growth factor molecules to the injured tissue has been intensively investigated over the past decade. Limited success of clinical trails indicates that a crucial aspect of the growth factor wound-healing strategy is the effective delivery of these polypeptides to the wound site. A molecular approach in which genetically modified cells synthesize and deliver the desired growth factor in regulated fashion has been used to overcome the limitations associated with the (topical) application of recombinant growth factor proteins. We have summarized the molecular and cellular basis of repair mechanisms and their failure, and we give an overview of techniques and studies applied to gene transfer in tissue repair. PMID:17276205

  9. Current Advances in Retroviral Gene Therapy

    PubMed Central

    Yi, Youngsuk; Jong Noh, Moon; Hee Lee, Kwan

    2011-01-01

    There have been major changes since the incidents of leukemia development in X-SCID patients after the treatments using retroviral gene therapy. Due to the risk of oncogenesis caused by retroviral insertional activation of host genes, most of the efforts focused on the lentiviral therapies. However, a relative clonal dominance was detected in a patient with ?-thalassemia Major, two years after the subject received genetically modified hematopoietic stem cells using lentiviral vectors. This disappointing result of the recent clinical trial using lentiviral vector tells us that the current and most advanced vector systems does not have enough safety. In this review, various safety features that have been tried for the retroviral gene therapy are introduced and the possible new ways of improvements are discussed. Additional feature of chromatin insulators, co-transduction of a suicidal gene under the control of an inducible promoter, conditional expression of the transgene only in appropriate target cells, targeted transduction, cell type-specific expression, targeted local administration, splitting of the viral genome, and site specific insertion of retroviral vector are discussed here. PMID:21453283

  10. Suicide Gene Therapy for Cancer – Current Strategies

    PubMed Central

    Zarogoulidis, Paul; Darwiche, Kaid; Sakkas, Antonios; Yarmus, Lonny; Huang, Haidong; Li, Qiang; Freitag, Lutz; Zarogoulidis, Konstantinos; Malecki, Marek

    2013-01-01

    Current cancer treatments may create profound iatrogenic outcomes. The adverse effects of these treatments still remain, as the serious problems that practicing physicians have to cope with in clinical practice. Although, non-specific cytotoxic agents constitute an effective treatment modality against cancer cells, they also tend to kill normal, quickly dividing cells. On the other hand, therapies targeting the genome of the tumors are both under investigation, and some others are already streamlined to clinical practice. Several approaches have been investigated in order to find a treatment targeting the cancer cells, while not affecting the normal cells. Suicide gene therapy is a therapeutic strategy, in which cell suicide inducing transgenes are introduced into cancer cells. The two major suicide gene therapeutic strategies currently pursued are: cytosine deaminase/5-fluorocytosine and the herpes simplex virus/ganciclovir. The novel strategies include silencing gene expression, expression of intracellular antibodies blocking cells’ vital pathways, and transgenic expression of caspases and DNases. We analyze various elements of cancer cells’ suicide inducing strategies including: targets, vectors, and mechanisms. These strategies have been extensively investigated in various types of cancers, while exploring multiple delivery routes including viruses, non-viral vectors, liposomes, nanoparticles, and stem cells. We discuss various stages of streamlining of the suicide gene therapy into clinical oncology as applied to different types of cancer. Moreover, suicide gene therapy is in the center of attention as a strategy preventing cancer from developing in patients participating in the clinical trials of regenerative medicine. In oncology, these clinical trials are aimed at regenerating, with the aid of stem cells, of the patients’ organs damaged by pathologic and/or iatrogenic factors. However, the stem cells carry the risk of neoplasmic transformation. We discuss cell suicide inducing strategies aimed at preventing stem cell-originated cancerogenesis. PMID:24294541

  11. Engineering HSV-1 vectors for gene therapy.

    PubMed

    Goins, William F; Huang, Shaohua; Cohen, Justus B; Glorioso, Joseph C

    2014-01-01

    Virus vectors have been employed as gene transfer vehicles for various preclinical and clinical gene therapy applications, and with the approval of Glybera (alipogene tiparvovec) as the first gene therapy product as a standard medical treatment (Yla-Herttuala, Mol Ther 20: 1831-1832, 2013), gene therapy has reached the status of being a part of standard patient care. Replication-competent herpes simplex virus (HSV) vectors that replicate specifically in actively dividing tumor cells have been used in Phase I-III human trials in patients with glioblastoma multiforme, a fatal form of brain cancer, and in malignant melanoma. In fact, T-VEC (talimogene laherparepvec, formerly known as OncoVex GM-CSF) displayed efficacy in a recent Phase III trial when compared to standard GM-CSF treatment alone (Andtbacka et al. J Clin Oncol 31: sLBA9008, 2013) and may soon become the second FDA-approved gene therapy product used in standard patient care. In addition to the replication-competent oncolytic HSV vectors like T-VEC, replication-defective HSV vectors have been employed in Phase I-II human trials and have been explored as delivery vehicles for disorders such as pain, neuropathy, and other neurodegenerative conditions. Research during the last decade on the development of HSV vectors has resulted in the engineering of recombinant vectors that are totally replication defective, nontoxic, and capable of long-term transgene expression in neurons. This chapter describes methods for the construction of recombinant genomic HSV vectors based on the HSV-1 replication-defective vector backbones, steps in their purification, and their small-scale production for use in cell culture experiments as well as preclinical animal studies. PMID:24671677

  12. Advanced Imaging Applications to Cardiac Resynchronization Therapy

    E-print Network

    Zanibbi, Richard

    Advanced Imaging Applications to Cardiac Resynchronization Therapy Justin D. Pearlman Professor pacemaker leads can be placed to improve cardiac output, avoiding areas of dead tissue, and achieving of Medicine and Radiology Director of Advanced CV Imaging Dartmouth 4pm, Wed, Jan. 31, 2007 Auditorium

  13. Newer gene editing technologies toward HIV gene therapy.

    PubMed

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

    2013-11-01

    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

  14. 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

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

    E-print Network

    Sawyer, Sara

    original article© The American Society of Gene & Cell Therapy Molecular Therapy 1 Restriction treatment strategies to disrupt the host- virus interaction, including cell-based gene therapy approaches alone or a combination of ablative therapy and transplantation with HIV resistant cells that led

  16. New gene therapy strategies for hepatic fibrosis

    PubMed Central

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

    2015-01-01

    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

  17. Vectors of Gene Therapy KATHERINE PARKER PONDER, M.D.

    E-print Network

    Ponder, Katherine P.

    therapy refers to the transfer of a gene that encodes a functional protein into a cell or the transferCHAPTER 4 Vectors of Gene Therapy KATHERINE PARKER PONDER, M.D. INTRODUCTION Currently, gene of an entity that will alter the expression of an endogenous gene in a cell. The efficient transfer

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

    E-print Network

    West, Anne

    in the functioning of adult neurons.13 It will thus be necessary for gene therapy approaches in RTT both to achieveoriginal article© The American Society of Gene & Cell Therapy Molecular Therapy 1 Typical Rett protein 2 (MECP2) gene. The demonstrated reversibility of RTT-like phenotypes in mice suggests that MECP2

  19. Creating a Cardiac Pacemaker by Gene Therapy

    Microsoft Academic Search

    Traian M. Anghel; Steven M. Pogwizd

    While electronic cardiac pacing in its various modalities represents standard of care for treatment of symptomatic bradyarrhythmias\\u000a and heart failure, it has limitations ranging from absent or rudimentary autonomic modulation to severe complications. This\\u000a has prompted experimental studies to design and validate a biological pacemaker that could supplement or replace electronic\\u000a pacemakers. Advances in cardiac gene therapy have resulted in

  20. Creating a cardiac pacemaker by gene therapy

    Microsoft Academic Search

    Traian M. Anghel; Steven M. Pogwizd

    2007-01-01

    While electronic cardiac pacing in its various modalities represents standard of care for treatment of symptomatic bradyarrhythmias\\u000a and heart failure, it has limitations ranging from absent or rudimentary autonomic modulation to severe complications. This\\u000a has prompted experimental studies to design and validate a biological pacemaker that could supplement or replace electronic\\u000a pacemakers. Advances in cardiac gene therapy have resulted in

  1. Gene therapy for type 1 diabetes

    Microsoft Academic Search

    Antonella D'Anneo; Pleunie Rood; Rita Bottino; A. N. Balamurugan; Jing He; Nick Giannoukakis

    2006-01-01

    This review, in addition to updating the growing list of type 1 diabetes-relevant gene therapies, offers an outline of short-term\\u000a objectives that can readily be met to move, at least, adenoviral and adeno-associated viral-based protocols into the clinic,\\u000a first as a means of facilitating islet allografts as well as platforms with which to introduce immunoregulatory transgenes.\\u000a A wide array of

  2. Gene therapy to create biological pacemakers

    Microsoft Academic Search

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

    2007-01-01

    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 ?2-adrenergic receptor overexpression, down regulation

  3. 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

  4. Gene Therapy in Thalassemia and Hemoglobinopathies

    PubMed Central

    Breda, Laura; Gambari, Roberto; Rivella, Stefano

    2009-01-01

    Sickle cell disease (SCD) and ß-thalassemia represent the most common hemoglobinopathies caused, respectively, by the alteration of structural features or deficient production of the ß-chain of the Hb molecule. Other hemoglobinopathies are characterized by different mutations in the ?- or ß-globin genes and are associated with anemia and might require periodic or chronic blood transfusions. Therefore, ß-thalassemia, SCD and other hemoglobinopathies are excellent candidates for genetic approaches since they are monogenic disorders and, potentially, could be cured by introducing or correcting a single gene into the hematopoietic compartment or a single stem cell. Initial attempts at gene transfer of these hemoglobinopathies have proved unsuccessful due to limitations of available gene transfer vectors. With the advent of lentiviral vectors many of the initial limitations have been overcame. New approaches have also focused on targeting the specific mutation in the ß-globin genes, correcting the DNA sequence or manipulating the fate of RNA translation and splicing to restore ß-globin chain synthesis. These techniques have the potential to correct the defect into hematopoietic stem cells or be utilized to modify stem cells generated from patients affected by these disorders. This review discusses gene therapy strategies for the hemoglobinopathies, including the use of lentiviral vectors, generation of induced pluripotent stem cells (iPS) cells, gene targeting, splice-switching and stop codon readthrough. PMID:21415990

  5. Liver-directed gene therapy for dyslipidemia and diabetes

    Microsoft Academic Search

    Kazuhiro Oka; Lawrence Chan

    2004-01-01

    This article provides an update of liver-directed gene therapy for dyslipidemia, reviewing papers published since 2002 and\\u000a summarizing progress in gene transfer vectors. Despite the availability of polypharmacy and other therapeutic interventions,\\u000a the treatment of severe dyslipidemia remains a challenge and continues to be an important target for experimental gene therapy.\\u000a Gene therapy strategies that focus on long-term therapeutic efficacy

  6. 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

  7. 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

  8. Creating a cardiac pacemaker by gene therapy.

    PubMed

    Anghel, Traian M; Pogwizd, Steven M

    2007-02-01

    While electronic cardiac pacing in its various modalities represents standard of care for treatment of symptomatic bradyarrhythmias and heart failure, it has limitations ranging from absent or rudimentary autonomic modulation to severe complications. This has prompted experimental studies to design and validate a biological pacemaker that could supplement or replace electronic pacemakers. Advances in cardiac gene therapy have resulted in a number of strategies focused on beta-adrenergic receptors as well as specific ion currents that contribute to pacemaker function. This article reviews basic pacemaker physiology, as well as studies in which gene transfer approaches to develop a biological pacemaker have been designed and validated in vivo. Additional requirements and refinements necessary for successful biopacemaker function by gene transfer are discussed. PMID:17139515

  9. Curing genetic disease with gene therapy.

    PubMed

    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

  10. Gene therapies for hepatitis C virus.

    PubMed

    Verstegen, Monique M A; Pan, Qiuwei; van der Laan, Luc J W

    2015-01-01

    Hepatitis C virus (HCV) is a leading cause of chronic hepatitis and infects approximately three to four million people per year, about 170 million infected people in total, making it one of the major global health problems. In a minority of cases HCV is cleared spontaneously, but in most of the infected individuals infection progresses to a chronic state associated with high risk to develop liver cirrhosis, hepatocellular cancer, or liver failure. The treatment of HCV infection has evolved over the years. Interferon (IFN)-? in combination with ribavirin has been used for decades as standard therapy. More recently, a new standard-of-care treatment has been approved based on a triple combination with either HCV protease inhibitor telaprevir or boceprevir. In addition, various options for all-oral, IFN-free regimens are currently being evaluated. Despite substantial improvement of sustained virological response rates, some intrinsic limitations of these new direct-acting antivirals, including serious side effects, the risk of resistance development and high cost, urge the development of alternative or additional therapeutic strategies. Gene therapy represents a feasible alternative treatment. Small RNA technology, including RNA interference (RNAi) techniques and antisense approaches, is one of the potentially promising ways to investigate viral and host cell factors that are involved in HCV infection and replication. With this, newly developed gene therapy regimens will be provided to treat HCV. In this chapter, a comprehensive overview guides you through the current developments and applications of RNAi and microRNA-based gene therapy strategies in HCV treatment. PMID:25757613

  11. Imaging techniques in cardiac resynchronization therapy

    PubMed Central

    Sá, Maria Isabel; de Roos, Albert; Westenberg, Jos J. M.

    2007-01-01

    Cardiac resynchronization therapy is a high cost therapeutic option with proven efficacy on improving symptoms of ventricular failure and for reducing both hospitalization and mortality. However, a significant number of patients do not respond to cardiac resynchronization therapy that is due to various reasons. Identification of the optimal pacing site is crucial to obtain the best therapeutic result that necessitates careful patient selection. Currently, using echocardiography for mechanical dyssynchrony assessment performs patient selection. Multi-Detector-Row Computed Tomography (MDCT) and Magnetic Resonance Imaging (MRI) are new imaging techniques that may assist the cardiologist in patient selection. These new imaging techniques have the potential to improve the success rate of cardiac resynchronization therapy, due to pre-interventional evaluation of the venous coronary anatomy, to evaluation of the presence of scar tissue, and to improved evaluation of mechanical dyssynchrony. In conclusion, clinical issues associated with heart failure in potential candidates for cardiac resynchronization therapy, and the information regarding this therapy that can be provided by the imaging techniques echocardiography, MDCT, and MRI, are reviewed. PMID:17503216

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

    E-print Network

    Ford, James

    original article© The American Society of Gene & Cell Therapy Molecular Therapy 1 (IDUA) gene resulting in inactivation of the IDUA enzyme. The loss of IDUA protein results pathology. Gene replacement strategies have relied on the use of viral or nonviral gene delivery systems

  13. WU Image-guided Therapy Center (ITC)

    Cancer.gov

    Image-guided Therapy Center Washington University Saint Louis, Missouri Walter R. Bosch, D.Sc. Associate Director, Operations WRB 9-26-2002 IMAGE-GUIDED THERAPY CENTER Acknowledgements 4511 F o rest Park , Sui t e 200 St. Louis, MO 63108 J. A. Purdy, Ph.D. D irector Walter Bosch, D.Sc. Assoc. Director, Operations Jeff Michalski, M.D. Assoc. Director, Clinical Bill Straube, M.S. Medical Physicist John Matthews, D.Sc. C omputer Scientist Sean O ’Leary, M.S. Programmer Analyst WRB 9-26-2002 ITC HISTORY April 1992 3DQA Center established at WU-St.

  14. MINI REVIEW MODIFIED ADENOVIRUSES FOR CANCER GENE THERAPY

    E-print Network

    Hemminki, Akseli

    ,2 * 1 Cancer Gene Therapy Group, Rational Drug Design, Biomedicum Helsinki, University of HelsinkiMINI REVIEW MODIFIED ADENOVIRUSES FOR CANCER GENE THERAPY Anna KANERVA 1­3 and Akseli HEMMINKI 1 is an exciting novel approach for treating cancers resistant to currently available therapies. However, currently

  15. Gene therapy for primary adaptive immune deficiencies.

    PubMed

    Fischer, Alain; Hacein-Bey-Abina, Salima; Cavazzana-Calvo, Marina

    2011-06-01

    Gene therapy has become an option for the treatment of 2 forms of severe combined immunodeficiency (SCID): X-linked SCID and adenosine deaminase deficiency. The results of clinical trials initiated more than 10 years ago testify to sustained and reproducible correction of the underlying T-cell immunodeficiency. Successful treatment is based on the selective advantage conferred on T-cell precursors through their expression of the therapeutic transgene. However, "first-generation" retroviral vectors also caused leukemia in some patients with X-linked SCID because of the constructs' tendency to insert into active genes (eg, proto-oncogenes) in progenitor cells and transactivate an oncogene through a viral element in the long terminal repeat. These elements have been deleted from the vectors now in use. Together with the use of lentiviral vectors (which are more potent for transducing stem cells), these advances should provide a basis for the safe and effective extension of gene therapy's indications in the field of primary immunodeficiencies. Nevertheless, this extension will have to be proved by examining the results of the ongoing clinical trials. PMID:21624615

  16. Gene therapy in Duchenne muscular dystrophy.

    PubMed

    Inui, K; Okada, S; Dickson, G

    1996-01-01

    Experiments in dystrophin gene transgenic mice have supported the concept of treating Duchenne muscular dystrophy (DMD) by demonstrating that regional expression of recombinant dystrophin in dystrophic muscle leads to regional restoration of normal muscle morphology and that dystrophin mini-genes driven by muscle specific regulatory elements are probably more effective than the full-length dystrophin gene. As a gene therapy trial for DMD, dystrophin cDNAs were introduced into skeletal muscle fibers of dystrophin-deficient mice (mdx) through direct DNA injection into plasmid expression vectors, and by replication-defective recombinant retrovirus or adenovirus vectors. With direct injection of dystrophin cDNA into a plasmid expression vector or retrovirus vectors, less than 10% of adult mdx fibers of the injected muscle expressed dystrophin. On the other hand, greater efficiency has been reported for recombinant adenovirus injection into young mdx muscle. However, it is necessary to develop vectors, viral or plasmid DNA, which can be injected intravenously and directed to muscle tissues. This will involve designing vectors possessing appropriate cell-type specific tropism and/or gene transcriptional activity for DMD treatment. This is anticipated to be a vital component in the second stage of experiments aimed at DMD treatment. PMID:8891229

  17. 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

  18. Gene therapy to create biological pacemakers.

    PubMed

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

    2007-02-01

    Old age and a variety of cardiovascular disorders may disrupt normal sinus node function. Currently, this is successfully treated with electronic pacemakers, which, however, leave room for improvement. During the past decade, different strategies to initiate pacemaker function by gene therapy were developed. In the search for a biological pacemaker, various approaches were explored, including beta(2)-adrenergic receptor overexpression, down regulation of the inward rectifier current, and overexpression of the pacemaker current. The most recent advances include overexpression of bioengineered ion channels and genetically modified stem cells. This review considers the strengths and the weaknesses of the different approaches and discusses some of the different viral vectors currently used. PMID:17048028

  19. The American Society of Gene Therapy original article

    E-print Network

    Kay, Mark A.

    © The American Society of Gene Therapy original article Molecular Therapy vol. 16 no. 5, 931 profiling of cultured cells is informative, but cannot capture the complex cross talk between cells in vivo

  20. Perspectives on best practices for gene therapy programs.

    PubMed

    Cheever, Thomas R; Berkley, Dale; Braun, Serge; Brown, Robert H; Byrne, Barry J; Chamberlain, Jeffrey S; Cwik, Valerie; Duan, Dongsheng; Federoff, Howard J; High, Katherine A; Kaspar, Brian K; Klinger, Katherine W; Larkindale, Jane; Lincecum, John; Mavilio, Fulvio; McDonald, Cheryl L; McLaughlin, James; Weiss McLeod, Bonnie; Mendell, Jerry R; Nuckolls, Glen; Stedman, Hansell H; Tagle, Danilo A; Vandenberghe, Luk H; Wang, Hao; Wernett, Pamela J; Wilson, James M; Porter, John D; Gubitz, Amelie K

    2015-03-01

    With recent successes in gene therapy trials for hemophilia and retinal diseases, the promise and prospects for gene therapy are once again garnering significant attention. To build on this momentum, the National Institute of Neurological Disorders and Stroke and the Muscular Dystrophy Association jointly hosted a workshop in April 2014 on "Best Practices for Gene Therapy Programs," with a focus on neuromuscular disorders. Workshop participants included researchers from academia and industry as well as representatives from the regulatory, legal, and patient advocacy sectors to cover the gamut from preclinical optimization to intellectual property concerns and regulatory approval. The workshop focused on three key issues in the field: (1) establishing adequate scientific premise for clinical trials in gene therapy, (2) addressing regulatory process issues, and (3) intellectual property and commercialization issues as they relate to gene therapy. The outcomes from the discussions at this workshop are intended to provide guidance for researchers and funders in the gene therapy field. PMID:25654329

  1. Gene therapy of primary T cell immunodeficiencies.

    PubMed

    Fischer, Alain; Hacein-Bey-Abina, Salima; Cavazzana-Calvo, Marina

    2013-08-10

    Gene therapy of severe combined immunodeficiencies has been proven to be effective to provide sustained correction of the T cell immunodeficiencies. This has been achieved for 2 forms of SCID, i.e SCID-X1 (?c deficiency) and adenosine deaminase deficiency. Occurrence of gene toxicity generated by integration of first generation retroviral vectors, as observed in the SCID-X1 trials has led to replace these vectors by self inactivated (SIN) retro(or lenti) viruses that may provide equivalent efficacy with a better safety profile. Results of ongoing clinical studies in SCID as well as in other primary immunodeficiencies, such as the Wiskott Aldrich syndrome, will be thus very informative. PMID:23583799

  2. Gene therapy: progress in childhood disease.

    PubMed

    Ginn, Samantha L; Alexander, Ian E

    2012-06-01

    The recent sequencing of the human genome combined with the development of massively high throughput genetic analysis technologies is driving unprecedented growth in our knowledge of the molecular basis of disease. While this has already had a major impact on our diagnostic power, the therapeutic benefits remain largely unrealised. This review examines progress in the exciting and challenging field of gene therapy. In particular we focus on the treatment of genetic disease in infants and children where the most significant successes have been observed to date, despite the majority of trial participants being adults. Notably, gene transfer to the haematopoietic compartment has provided the clearest examples of therapeutic benefit, particularly in the context of primary immunodeficiencies. The triumphs and tribulations of these successes are explored, and the key challenges confronting researchers as they seek to further advance the field are defined and discussed. PMID:22017270

  3. Synthesis and Evaluation of a 18F-Labeled 4-Ipomeanol as an Imaging Agent for CYP4B1 Gene Prodrug Activation Therapy

    PubMed Central

    Moon, Byung Seok; Jang, Su Jin; Kim, Sung Joo; Lee, Tae Sup; Chi, Dae Yoon; Kim, Sang Eun

    2013-01-01

    Abstract We report the development of a 18F-labeled 4-ipomeanol (4-IM), which is metabolized by the CYP4B1 enzyme, to image tumors and monitor enzyme-activating anticancer prodrugs. The fluorine-substituted derivative, 1-(3-furyl)-4-hydroxy-5-fluoro-1-pentanone (F-4-IM, 1), was synthesized from 3-furaldehyde. [18F]F-4-IM ([18F]1) was prepared in 20%–35% radiochemical yield by a fluorine-18 displacement reaction, followed by reduction and deprotection of the ketal group, and was shown to be stable (>96% at 2 hours) in human serum at 37°C. The biodistribution of [18F]F-4-IM in normal rats was high in the lung, where CYP4B1 gene is preferentially expressed. We transduced C6-glioma cells with a retrovirus-expressing CYP4B1 (C6-CYP4B1). Evaluation of CYP4B1 expression was confirmed by reverse transcription polymerase chain reaction and MTT assay. Cell assays were carried out using C6 and C6-CYP4B, and the uptake of [18F]F-4-IM in these cells was compared with that in parental controls. The uptake ratio of [18F]F-4-IM was 2.8-fold higher in C6-CYP4B1 compared with that in parental cells at 1 hour, whereas [3H]4-IM was taken up at similar rates in both cell lines after 6 hours. These results suggest that [18F]F-4-IM could be a promising PET imaging agent with potential to be used for imaging of CYP4B1-transfected tumor cells, as well as for monitoring CYP4B1 enzyme/prodrug interactions. PMID:23682585

  4. 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

  5. Overview of image-guided radiation therapy

    SciTech Connect

    Xing Lei [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States)]. E-mail: lei@reyes.stanford.edu; Thorndyke, Brian [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Schreibmann, Eduard [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Yang Yong [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Li, T.-F. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Kim, Gwe-Ya [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Luxton, Gary [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Koong, Albert [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States)

    2006-07-01

    Radiation therapy has gone through a series of revolutions in the last few decades and it is now possible to produce highly conformal radiation dose distribution by using techniques such as intensity-modulated radiation therapy (IMRT). The improved dose conformity and steep dose gradients have necessitated enhanced patient localization and beam targeting techniques for radiotherapy treatments. Components affecting the reproducibility of target position during and between subsequent fractions of radiation therapy include the displacement of internal organs between fractions and internal organ motion within a fraction. Image-guided radiation therapy (IGRT) uses advanced imaging technology to better define the tumor target and is the key to reducing and ultimately eliminating the uncertainties. The purpose of this article is to summarize recent advancements in IGRT and discussed various practical issues related to the implementation of the new imaging techniques available to radiation oncology community. We introduce various new IGRT concepts and approaches, and hope to provide the reader with a comprehensive understanding of the emerging clinical IGRT technologies. Some important research topics will also be addressed.

  6. Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients

    PubMed Central

    Adair, Jennifer E.; Johnston, Sandra K.; Mrugala, Maciej M.; Beard, Brian C.; Guyman, Laura A.; Baldock, Anne L.; Bridge, Carly A.; Hawkins-Daarud, Andrea; Gori, Jennifer L.; Born, Donald E.; Gonzalez-Cuyar, Luis F.; Silbergeld, Daniel L.; Rockne, Russell C.; Storer, Barry E.; Rockhill, Jason K.; Swanson, Kristin R.; Kiem, Hans-Peter

    2014-01-01

    BACKGROUND. Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMThi). Coadministration of O6-benzylguanine (O6BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O6BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome. METHODS. We enrolled 7 newly diagnosed glioblastoma patients with MGMThi tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O6BG/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patient-specific biomathematical modeling of tumor growth was performed. Progression-free survival (PFS) and overall survival (OS) were also evaluated. RESULTS. Gene therapy permitted a significant increase in the mean number of tolerated O6BG/TMZ cycles (4.4 cycles per patient, P < 0.05) compared with historical controls without gene therapy (n = 7 patients, 1.7 cycles per patient). One patient tolerated an unprecedented 9 cycles and demonstrated long-term PFS without additional therapy. Overall, we observed a median PFS of 9 (range 3.5–57+) months and OS of 20 (range 13–57+) months. Furthermore, biomathematical modeling revealed markedly delayed tumor growth at lower cumulative TMZ doses in study patients compared with patients that received standard TMZ regimens without O6BG. CONCLUSION. These data support further development of chemoprotective gene therapy in combination with O6BG and TMZ for the treatment of glioblastoma and potentially other tumors with overexpression of MGMT. TRIAL REGISTRATION. Clinicaltrials.gov NCT00669669. FUNDING. R01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970. PMID:25105369

  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. Gene Replacement Therapy for Genetic Hepatocellular Jaundice.

    PubMed

    van Dijk, Remco; Beuers, Ulrich; Bosma, Piter J

    2014-10-16

    Jaundice results from the systemic accumulation of bilirubin, the final product of the catabolism of haem. Inherited liver disorders of bilirubin metabolism and transport can result in reduced hepatic uptake, conjugation or biliary secretion of bilirubin. In patients with Rotor syndrome, bilirubin (re)uptake is impaired due to the deficiency of two basolateral/sinusoidal hepatocellular membrane proteins, organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3. Dubin-Johnson syndrome is caused by a defect in the ATP-dependent canalicular transporter, multidrug resistance-associated protein 2 (MRP2), which mediates the export of conjugated bilirubin into bile. Both disorders are benign and not progressive and are characterised by elevated serum levels of mainly conjugated bilirubin. Uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) is responsible for the glucuronidation of bilirubin; deficiency of this enzyme results in unconjugated hyperbilirubinaemia. Gilbert syndrome is the mild and benign form of inherited unconjugated hyperbilirubinaemia and is mostly caused by reduced promoter activity of the UGT1A1 gene. Crigler-Najjar syndrome is the severe inherited form of unconjugated hyperbilirubinaemia due to mutations in the UGT1A1 gene, which can cause kernicterus early in life and can be even lethal when left untreated. Due to major disadvantages of the current standard treatments for Crigler-Najjar syndrome, phototherapy and liver transplantation, new effective therapeutic strategies are under development. Here, we review the clinical features, pathophysiology and genetic background of these inherited disorders of bilirubin metabolism and transport. We also discuss the upcoming treatment option of viral gene therapy for genetic disorders such as Crigler-Najjar syndrome and the possible immunological consequences of this therapy. PMID:25315738

  9. [Gene therapy with vector-producing multipotent mesenchymal stromal cells].

    PubMed

    Okada, Takashi

    2010-11-01

    Suicide gene therapy with retroviral vector-producing cells was feasible as an adjuvant to the surgical resection of recurrent glioblastoma, although any benefit appeared to be marginal. Further evaluation of the therapeutic strategy with the vector-producing cells must incorporate improved delivery of vectors and transgenes to the target cells. We have previously demonstrated the ability of vector-producing tumor cells engineered by the adenovirus-retrovirus hybrid vector to destroy satellite tumor cells, although therapeutic efficacy for aggressive tumor has to be further evaluated by the systemic delivery of the vector-producing cells. Mesenchymal stem cells (MSCs) should be an effective delivery vehicle to seek out tumor cells in vivo and transport cancer-killing gene or immune products with minimal rejection reaction by the host. We developed vector-producing tumor-tracking cells to improve suicide cancer gene therapy. Nucleofection was attempted to deliver retrovirus vector components into rodent MSCs. Athymic nude mice with subcutaneous 9L glioma were received vector-producing MSCs through the left ventricular cavity. Optical bioluminescence imaging in vivo revealed accumulation of the MSCs into the subcutaneous 9L tumors but not Rat-1 transplants. Consequently, the vector-producing MSCs significantly enhanced pro-drug killing of glioma cells compared to MSCs without ability to generate progeny virus. Our study demonstrated the effective MSCs-mediated tumor transduction with progeny vector production to improve suicide gene therapy. Although therapeutic benefit in the various orthotopic or metastatic tumor models has to be further validated, this transduction strategy would eradicate evasive tumors in situ. PMID:21048411

  10. The companions: regulatory T cells and gene therapy

    PubMed Central

    Eghtesad, Saman; Morel, Penelope A; Clemens, Paula R

    2009-01-01

    Undesired immunological responses to products of therapeutic gene replacement have been obstacles to successful gene therapy. Understanding such responses of the host immune system to achieve immunological tolerance to a transferred gene product is therefore crucial. In this article, we review relevant studies of immunological responses to gene replacement therapy, the role of immunological tolerance mediated by regulatory T cells in down-regulating the unwanted immune responses, and the interrelationship of the two topics. PMID:19368560

  11. Gene therapy progress and prospects cancer: oncolytic viruses

    E-print Network

    Cai, Long

    REVIEW Gene therapy progress and prospects cancer: oncolytic viruses T-C Liu1 and D Kirn1,2 1 key findings in this field over the past 2 years, and provides directions for future success. Gene, RNA viruses, poxviruses); (2) viral gene-deleted mutants--critical viral gene expendable for growth

  12. Nanomaterials for Cancer Therapy and Imaging

    PubMed Central

    Bae, Ki Hyun; Chung, Hyun Jung; Park, Tae Gwan

    2011-01-01

    A variety of organic and inorganic nanomaterials with dimensions below several hundred nanometers are recently emerging as promising tools for cancer therapeutic and diagnostic applications due to their unique characteristics of passive tumor targeting. A wide range of nanomedicine platforms such as polymeric micelles, liposomes, dendrimers, and polymeric nanoparticles have been extensively explored for targeted delivery of anti-cancer agents, because they can accumulate in the solid tumor site via leaky tumor vascular structures, thereby selectively delivering therapeutic payloads into the desired tumor tissue. In recent years, nanoscale delivery vehicles for small interfering RNA (siRNA) have been also developed as effective therapeutic approaches to treat cancer. Furthermore, rationally designed multi-functional surface modification of these nanomaterials with cancer targeting moieties, protective polymers, and imaging agents can lead to fabrication versatile theragnostic nanosystems that allow simultaneous cancer therapy and diagnosis. This review highlights the current state and future prospects of diverse biomedical nanomaterials for cancer therapy and imaging. PMID:21360197

  13. Imaging Cell Therapy for Myocardial Regeneration.

    PubMed

    Zhang, Hualei; Qiao, Hui; Ferrari, Victor A; Zhou, Rong

    2012-02-01

    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

  14. Repetitive, non-invasive imaging of the dopamine D2 receptor as a reporter gene in living animals

    Microsoft Academic Search

    D C MacLaren; S S Gambhir; N Satyamurthy; J R Barrio; S Sharfstein; T Toyokuni; L Wu; A J Berk; S R Cherry; M E Phelps; H R Herschman

    1999-01-01

    Reporter genes (eg ?-galactosidase, chloramphenicol-acetyltransferase, green fluorescent protein, luciferase) play critical roles in investigating mechanisms of gene expression in transgenic animals and in developing gene delivery systems for gene therapy. However, measuring expression of these reporter genes requires biopsy or death. We now report a procedure to image reporter gene expression repetitively and non-invasively in living animals with positron emission

  15. Ocular gene therapy: experimental studies and clinical possibilities.

    PubMed

    Murata, T; Kimura, H; Sakamoto, T; Osusky, R; Spee, C; Stout, T J; Hinton, D R; Ryan, S J

    1997-01-01

    The Human Genome Project will identify, map and sequence all 50,000-100,000 human genes and will provide the tools to determine the genetic basis of both common and rare diseases. Understanding the genetic basis of human disease will allow for the development of highly specific drugs and for replacement of the altered gene through gene therapy. Gene therapy may also be used to introduce a new function into cells with resulting therapeutic benefit. Genes may be delivered into cells in vitro or in vivo utilizing viral or nonviral vectors. Viral vectors which have been used include retroviruses, adenoviruses, adeno-associated viruses and herpes viruses. Ocular disorders with the greatest potential for benefit of gene therapy at the current time include hereditary ocular diseases, including retinitis pigmentosa, tumors such as retinoblastoma or melanoma, and acquired proliferative and neovascular retinal disorders. We have demonstrated the feasibility of ocular gene therapy in a rabbit model of proliferative vitreoretinopathy, using retroviral vectors containing the herpes simplex virus thymidine kinase 'suicide' gene. Although in vivo transduction efficiency is low, the strong bystander effect results in prominent killing of proliferating cells in this model leading to inhibition of disease. In the future, gene therapy has the potential for the replacement of defective gene products or introduction of new gene products into ocular cells. The selection of appropriate target genes and cells will be critical, as will the development of a methodology for safe, targeted gene transfer. PMID:9323715

  16. Gene Therapy Ameliorates Cardiovascular Disease in Dogs With Mucopolysaccharidosis VII

    E-print Network

    Ponder, Katherine P.

    Gene Therapy Ameliorates Cardiovascular Disease in Dogs With Mucopolysaccharidosis VII M.M. Sleeper;110:815-820.) Key Words: cardiovascular diseases gene therapy lysosomes mucopolysaccharidosis--Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by deficient -glucuronidase (GUSB) activity

  17. Prospects for Gene Therapy in the Fragile X Syndrome

    ERIC Educational Resources Information Center

    Rattazzi, Mario C.; LaFauci, Giuseppe; Brown, W. Ted

    2004-01-01

    Gene therapy is unarguably the definitive way to treat, and possibly cure, genetic diseases. A straightforward concept in theory, in practice it has proven difficult to realize, even when directed to easily accessed somatic cell systems. Gene therapy for diseases in which the central nervous system (CNS) is the target organ presents even greater…

  18. Large Animal Models of Neurological Disorders for Gene Therapy

    Microsoft Academic Search

    Christine Gagliardi; Bruce A. Bunnell

    The development of therapeutic interventions for genetic disorders and diseases that affect the central nervous system (CNS) has proven challenging. There has been signifi cant progress in the development of gene therapy strategies in murine models of human disease, but gene therapy outcomes in these models do not always translate to the human setting. Therefore, large animal models are crucial

  19. Perspectives on gene therapy in the treatment of ocular inflammation

    Microsoft Academic Search

    Robert B Nussenblatt; Karl Csaky

    1997-01-01

    Gene therapy may become a powerful therapeutic strategy. However, the application of this method in the treatment of ocular disease presents us with interesting and unique questions. Gene therapy for ocular inflammatory disease has the potential for both therapeutic interventions and a method for studying mechanisms of disease. An evolving philosophy on this subject would support the use of somatic

  20. MOLECULAR THERAPY Vol. 4, No. 6, December 2001 Copyright The American Society of Gene Therapy

    E-print Network

    Ford, James

    transfer approaches for hemophilia B, we explored the risk of germline transmission of vector sequences transmission, AAV vectors, gene therapy, hemophilia INTRODUCTION Reproductive toxicology in the setting of gene

  1. [Gene replacement therapy in achromatopsia type 2].

    PubMed

    Mühlfriedel, R; Tanimoto, N; Seeliger, M W

    2014-03-01

    Achromatopsia is an autosomal recessive inherited retinal disease caused by a complete loss of cone photoreceptor function. About 80?% of achromatopsia patients show mutations in the alpha or beta subunit (A3 and B3) of the cGMP controlled cation channel CNG (cyclic nucleotide-gated channel) of cone photoreceptors. Homologous to the human disease, CNGA3 deficient mice reveal a loss of cone specific functionality leading to degeneration of affected cone photoreceptors. The Institute for Ophthalmic Research in Tübingen has now succeeded in curing achromatopsia ACHM2 in an animal model. In this article, we explain the recombinant adeno-associated virus-based approach in detail. Furthermore, applied non-invasive diagnostic techniques for quality and success control, ERG, SLO and OCT, are described. The success of the therapy is indicated by a restored cone photoreceptor function as well as the neuronal processing of retinal signals resulting in a specific, cone-mediated behaviour. The outstanding results derived from the animal model are the starting point for the first human translation of a gene therapy for achromatopsia in Germany. PMID:24658860

  2. 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

    ...guidance are cellular therapy, gene therapy, therapeutic vaccination, and xenotransplantation. The guidance is intended to clarify...guidance are cellular therapy, gene therapy, therapeutic vaccination, and xenotransplantation. The guidance is intended to...

  3. 78 FR 70307 - Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-25

    ...guidance are cellular therapy, gene therapy, therapeutic vaccination, xenotransplantation, and certain biologic-device combination...guidance include cellular therapy, gene therapy, therapeutic vaccination, xenotransplantation, and certain biologic-device...

  4. 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.

  5. Gene therapy in The Netherlands: highlights from the Low Countries.

    PubMed

    Schenk-Braat, Ellen A M; Kaptein, Leonie C M; Hallemeesch, Marcella M; Bangma, Chris H; Hoeben, Rob C

    2007-10-01

    Gene therapy is an active research area in The Netherlands and Dutch scientists involved in fundamental and clinical gene therapy research significantly contribute to the progresses made in this field. This ranges from the establishment of the 293, 911 and PER.C6 cell lines, which are used worldwide for the production of replication-defective adenoviral vectors, to the development of targeted viral vectors and T lymphocytes as well as of non-viral vectors. Several milestones have been achieved in Dutch clinical gene therapy trials, including the first treatment worldwide of patients with adenosine deaminase deficiency with genetically corrected hematopoietic stem cells in collaboration with French and British scientists. Until now, about 230 patients with various diseases have been treated with viral and non-viral gene therapy in this country. Ongoing and upcoming Dutch clinical trials focus on the translation of new developments in gene therapy research, including the restoration of genetic defects other than SCID, and the use of oncolytic adenoviruses and targeted T cells for the treatment of cancer. The growing commercial interest in Dutch clinical gene therapy is reflected by the involvement of two Dutch companies in ongoing trials as well as the participation of Dutch clinical centres in large phase III international multicenter immuno-gene therapy trials on prostate cancer sponsored by an American company. Translational gene therapy research in The Netherlands is boosted at a governmental level by the Dutch Ministry of Health via a dedicated funding programme. This paper presents an overview on milestones in Dutch basic gene therapy research as well as on past, present and future clinical gene therapy trials in The Netherlands. PMID:17721875

  6. Gene replacement therapy for retinal CNG channelopathies.

    PubMed

    Schön, Christian; Biel, Martin; Michalakis, Stylianos

    2013-10-01

    Visual phototransduction relies on the function of cyclic nucleotide-gated channels in the rod and cone photoreceptor outer segment plasma membranes. The role of these ion channels is to translate light-triggered changes in the second messenger cyclic guanosine 3'-5'-monophosphate levels into an electrical signal that is further processed within the retinal network and then sent to higher visual centers. Rod and cone photoreceptors express distinct CNG channels. The rod photoreceptor CNG channel is composed of one CNGB1 and three CNGA1 subunits, whereas the cone channel is formed by one CNGB3 and three CNGA3 subunits. Mutations in any of these channel subunits result in severe and currently untreatable retinal degenerative diseases like retinitis pigmentosa or achromatopsia. In this review, we provide an overview of the human diseases and relevant animal models of CNG channelopathies. Furthermore, we summarize recent results from preclinical gene therapy studies using adeno-associated viral vectors and discuss the efficacy and translational potential of these gene therapeutic approaches. PMID:23861024

  7. 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

  8. 78 FR 44133 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-23

    ...Cellular, Tissue and Gene Therapies Advisory Committee. General...Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation...trials of cellular and gene therapy products. CBER is planning...to accommodate persons with physical disabilities or special...

  9. 77 FR 63840 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-17

    ...Cellular, Tissue and Gene Therapies Advisory Committee; Notice...Cellular, Tissue and Gene Therapies Advisory Committee. General...Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation...to accommodate persons with physical disabilities or special...

  10. 76 FR 81513 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-28

    ...Cellular, Tissue, and Gene Therapies Advisory Committee; Notice...Cellular, Tissue, and Gene Therapies Advisory Committee. General...Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation...to accommodate persons with physical disabilities or special...

  11. 75 FR 65640 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-26

    ...Cellular, Tissue and Gene Therapies Advisory Committee; Notice...Cellular, Tissue and Gene Therapies Advisory Committee. General...Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation...to accommodate persons with physical disabilities or special...

  12. 78 FR 79699 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-31

    ...Cellular, Tissue, and Gene Therapies Advisory Committee. General...Cellular, Tissue, and Gene Therapies, Center for Biologics Evaluation...trials of cellular and gene therapy products. CBER published...to accommodate persons with physical disabilities or special...

  13. Gene therapy for eye as regenerative medicine? Lessons from RPE65 gene therapy for Leber's Congenital Amaurosis.

    PubMed

    Rakoczy, Elizabeth P; Narfström, Kristina

    2014-11-01

    Recombinant virus mediated gene therapy of Leber's Congenital Amaurosis has provided a wide range of data on the utility of gene replacement therapy for recessive diseases. Studies to date demonstrate that gene therapy in the eye is safe and can result in long-term recovery of visual function, but they also highlight that further research is required to identify optimum intervention time-points, target populations and the compatibility of associate therapies. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation. PMID:25286304

  14. Imaging for Planning of Cardiac Resynchronization Therapy

    PubMed Central

    Heydari, Bobak; Jerosch-Herold, Michael; Kwong, Raymond Y.

    2014-01-01

    Cardiac resynchronization therapy (CRT) is a novel therapy for patients with refractory heart failure (HF). Large clinical trials evaluating CRT have demonstrated significant improvements in cardiac survival, decreases in recurrent HF hospitalization, and improvements in indexes of quality of life. Although numerous mechanisms are involved in CRT’s therapeutic effects, correction of both interventricular and intraventricular mechanical dyssynchrony has been postulated as the key mechanism. To date, most large randomized controlled trials evaluating CRT have identified dyssynchronous patients on the basis of prolongation of the QRS complex from the baseline electrocardiogram. Concerns have been raised regarding the use of this measure for patient selection, stemming from a significant 30% to 40% nonresponse rate to CRT. Because of the cost and invasive nature of CRT, optimal patient selection for this therapy has become a priority for HF specialists and electrophysiologists. Cardiac imaging modalities have attempted to fulfill this need to improve patient selection by identifying mechanical dyssynchrony. Although early echocardiographic studies reported promising results, more recent larger scale studies have curtailed this enthusiasm, with a lack of established selection criteria for CRT in the current practice guidelines. This review summarizes the evidence to date and the potential role of imaging modalities in the selection and care of patients with HF referred for CRT. PMID:22239899

  15. 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

  16. Translational Approaches towards Cancer Gene Therapy: Hurdles and Hopes

    PubMed Central

    Barar, Jaleh; Omidi, Yadollah

    2012-01-01

    Introduction Of the cancer gene therapy approaches, gene silencing, suicide/apoptosis inducing gene therapy, immunogene therapy and targeted gene therapy are deemed to sub-stantially control the biological consequences of genomic changes in cancerous cells. Thus, a large number of clinical trials have been conducted against various malignancies. In this review, we will discuss recent translational progresses of gene and cell therapy of cancer. Methods Essential information on gene therapy of cancer were reviewed and discussed towards their clinical translations. Results Gene transfer has been rigorously studied in vitro and in vivo, in which some of these gene therapy endeavours have been carried on towards translational investigations and clinical applications. About 65% of gene therapy trials are related to cancer therapy. Some of these trials have been combined with cell therapy to produce personalized medicines such as Sipuleucel-T (Provenge®, marketed by Dendreon, USA) for the treatment of asymptomatic/minimally symptomatic metastatic hormone-refractory prostate cancer. Conclusion Translational approach links two diverse boundaries of basic and clinical researches. For successful translation of geno-medicines into clinical applications, it is essential 1) to have the guidelines and standard operating procedures for development and application of the genomedicines specific to clinically relevant biomarker(s); 2) to conduct necessary animal experimental studies to show the “proof of concept” for the proposed genomedicines; 3) to perform an initial clinical investigation; and 4) to initiate extensive clinical trials to address all necessary requirements. In short, translational researches need to be refined to accelerate the geno-medicine development and clinical applications. PMID:23678451

  17. PET imaging to monitor cancer therapy.

    PubMed

    Malviya, Gaurav; Nayak, Tapan K

    2013-01-01

    Improved knowledge and understanding of key aspects of cancer has led to the development of novel cancer therapeutics acting through complex pathways and mode of actions. The success of these novel cancer therapeutics is often difficult to predict using standard response criteria based on anatomic changes. Monitoring response to cancer therapy at molecular level using Positron Emission Tomography (PET) has gained popularity in recent years. PET allows longitudinal assessment of specific biological processes rather than just changes in anatomic changes in tumor size. In this review, we provide an overview on application for PET imaging to monitor cancer therapy with emphases on PET of tumor metabolism, cell proliferation, angiogenesis, hypoxia and receptor dynamics. PMID:24372238

  18. review The American Society of Gene & Cell Therapy Molecular Therapy vol. 20 no. 4, 699708 apr. 2012 699

    E-print Network

    Schaffer, David V.

    review© The American Society of Gene & Cell Therapy Molecular Therapy vol. 20 no. 4, 699­708 apr clinical trials for gene therapy of inherited and acquired diseases using first generation AAV2 vectors-related macular degeneration.2 Perhaps the most striking example of successful gene therapy in a clinical setting

  19. Current status of gene delivery and gene therapy in lacrimal gland using viral vectors

    Microsoft Academic Search

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

    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

  20. 76 FR 18768 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-05

    ...Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of...Cellular, Tissue, and Gene Therapies Advisory Committee. General...Molecular Oncology, Division of Monoclonal Antibodies, Center for Drug...

  1. 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.

  2. 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

  3. Preclinical and clinical endpoint assays for cystic fibrosis gene therapy

    Microsoft Academic Search

    Uta Griesenbach; A. Christopher Boyd

    2005-01-01

    The credibility and hence value of pre-clinical and clinical cystic fibrosis gene therapy studies depend on the assays used to evaluate gene transfer. Awareness of assay suitability, sensitivity and variability is therefore crucial to the design of experimental programmes. Here, we review the assays that are in use to assess the efficacy of gene transfer in pre-clinical and clinical CF

  4. Publications by Gene Therapy Center Members January 2012 -December 2012

    E-print Network

    , Welsh MJ, McCray PB, Jr. and Uc A. Pancreatic damage in fetal and newborn cystic fibrosis pigs involvesPublications by Gene Therapy Center Members January 2012 - December 2012 Center Members are in BOLD polarity gene glypican 5 as a human spina bifida candidate gene. Hum Mol Genet. 2012. 9. Bazazzadegan N

  5. Monitoring Murine Skeletal Muscle Function for Muscle Gene Therapy

    PubMed Central

    Hakim, Chady H.; Li, Dejia; Duan, Dongsheng

    2011-01-01

    The primary function of skeletal muscle is to generate force. Muscle force production is compromised in various forms of acquired and/or inherited muscle diseases. An important goal of muscle gene therapy is to recover muscle strength. Genetically engineered mice and spontaneous mouse mutants are readily available for preclinical muscle gene therapy studies. In this chapter, we outlined the methods commonly used for measuring murine skeletal muscle function. These include ex vivo and in situ analysis of the contractile profile of a single intact limb muscle (the extensor digitorium longus for ex vivo assay and the tibialis anterior muscle for in situ assay), grip force analysis, and downhill treadmill exercise. Force measurement in a single muscle is extremely useful for pilot testing of new gene therapy protocols by local gene transfer. Grip force and treadmill assessments offer body-wide evaluation following systemic muscle gene therapy. PMID:21194022

  6. HUMAN GENE THERAPY 16:845858 (July 2005) Mary Ann Liebert, Inc.

    E-print Network

    Tian, Weidong

    HUMAN GENE THERAPY 16:845­858 (July 2005) © Mary Ann Liebert, Inc. Potent Antitumor Activity in a targeting gene-vi- rotherapy strategy, has potential for gene therapy of human cancers. INTRODUCTION GENE THERAPY is the newest therapeutic strategy for treat- ing human diseases and about 63% of gene therapy pro

  7. Despite the remarkable preclinical success of gene therapy, its clinical applications remain limited13

    E-print Network

    Cai, Long

    Despite the remarkable preclinical success of gene therapy, its clinical applications remain gene therapy, the appropriate genes must be delivered to and expressed in target cells, without harming in 70% of gene therapy clinical trials as of January 2007 (REF. 5). Non- viral gene therapy, although

  8. Communicating in context: a priority for gene therapy researchers.

    PubMed

    Robillard, Julie M

    2015-03-01

    History shows that public opinion of emerging biotechnologies has the potential to impact the research process through mechanisms such as funding and advocacy. It is critical, therefore, to consider public attitudes towards modern biotechnology such as gene therapy and more specifically towards the ethics of gene therapy, alongside advances in basic and clinical research. Research conducted through social media recently assessed how online users view the ethics of gene therapy and showed that while acceptability is high, significant ethical concerns remain. To address these concerns, the development of effective and evidence-based communication strategies that engage a wide range of stakeholders should be a priority for researchers. PMID:25556839

  9. Predicting gene function from images of cells

    E-print Network

    Jones, Thouis Raymond, 1971-

    2007-01-01

    This dissertation shows that biologically meaningful predictions can be made by analyzing images of cells. In particular, groups of related genes and their biological functions can be predicted using images from large ...

  10. Identification of Hematopoietic Stem Cell Engraftment Genes in Gene Therapy Studies

    PubMed Central

    Powers, John M; Trobridge, Grant D

    2013-01-01

    Hematopoietic stem cell (HSC) therapy using replication-incompetent retroviral vectors is a promising approach to provide life-long correction for genetic defects. HSC gene therapy clinical studies have resulted in functional cures for several diseases, but in some studies clonal expansion or leukemia has occurred. This is due to the dyregulation of endogenous host gene expression from vector provirus insertional mutagenesis. Insertional mutagenesis screens using replicating retroviruses have been used extensively to identify genes that influence oncogenesis. However, retroviral mutagenesis screens can also be used to determine the role of genes in biological processes such as stem cell engraftment. The aim of this review is to describe the potential for vector insertion site data from gene therapy studies to provide novel insights into mechanisms of HSC engraftment. In HSC gene therapy studies dysregulation of host genes by replication-incompetent vector proviruses may lead to enrichment of repopulating clones with vector integrants near genes that influence engraftment. Thus, data from HSC gene therapy studies can be used to identify novel candidate engraftment genes. As HSC gene therapy use continues to expand, the vector insertion site data collected will be of great interest to help identify novel engraftment genes and may ultimately lead to new therapies to improve engraftment. PMID:24383045

  11. Development and Assessment of Gene Therapies for

    E-print Network

    Kolstad, Kathleen Durgin

    2009-01-01

    in blind animals suggest that it is a promising therapy forin blind animals suggests that it is a promising therapy fortherapy as it is immune privileged, accessible for the introduction of therapeutic material, and many animal

  12. 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

  13. Imaging of enzyme replacement therapy using PET

    PubMed Central

    Phenix, Christopher P.; Rempel, Brian P.; Colobong, Karen; Doudet, Doris J.; Adam, Michael J.; Clarke, Lorne A.; Withers, Stephen G.

    2010-01-01

    Direct enzyme replacement therapy (ERT) has been introduced as a means to treat a number of rare, complex genetic conditions associated with lysosomal dysfunction. Gaucher disease was the first for which this therapy was applied and remains the prototypical example. Although ERT using recombinant lysosomal enzymes has been shown to be effective in altering the clinical course of Gaucher disease, Fabry disease, Hurler syndrome, Hunter syndrome, Maroteaux-Lamy syndrome, and Pompe disease, the recalcitrance of certain disease manifestations underscores important unanswered questions related to dosing regimes, tissue half-life of the recombinant enzyme and the ability of intravenously administered enzyme to reach critical sites of known disease pathology. We have developed an innovative method for tagging acid ?-glucocerebrosidase (GCase), the recombinant enzyme formulated in Cerezyme® used to treat Gaucher disease, using an 18F-labeled substrate analogue that becomes trapped within the active site of the enzyme. Using micro-PET we show that the tissue distribution of injected enzyme can be imaged in a murine model and that the PET data correlate with tissue 18F counts. Further we show that PET imaging readily monitors pharmacokinetic changes effected by receptor blocking. The ability to 18F-label GCase to monitor the enzyme distribution and tissue half-life in vivo by PET provides a powerful research tool with an immediate clinical application to Gaucher disease and a clear path for application to other ERTs. PMID:20534487

  14. Image-guided therapy: evolution and breakthrough.

    PubMed

    Haigron, Pascal; Dillenseger, Jean-Louis; Luo, Limin; Coatrieux, Jean-Louis

    2010-01-01

    Beyond the advances made in computer-assisted interventions and robotic systems, the demand for more efficient and safer therapies remains challenging. Thus, if it is possible to improve the instrument tracking, steering, and target localization, to miniaturize the sensors and actuators, and to conduct preoperatively planned minimally invasive therapies, we still need new resources to achieve permanent destruction of abnormal tissues or suppression of pathological processes. Most of the physics-based (or energy-based) therapeutic principles at our disposal have been established a long time ago, but their actions on basic cellular and molecular mechanisms are not yet fully understood. They all have a wide spectrum of clinical targets in terms of organs and pathologies, modes of application (external, interstitial, intraluminal, etc.) with advantages and side-effect drawbacks, proven indications, and contraindications. Some of them may still face controversies regarding their outcomes. This short article, mainly focused on tumor destruction, briefly reviews in its first part some of these techniques and sketches the next generation under investigation. The former include radio frequency (RF), high-intensity focused ultrasound (HiFU), microwaves, and cryotherapy, of which all are temperature based. Laser-based approaches [e.g., photodynamic therapy (PDT) at large] are also discussed. Radiotherapy and its variants (hadrontherapy, brachytherapy, Gamma Knife, and CyberKnife) remain, of course, as the reference technique in cancer treatment. The next breakthroughs are examined in the second part of the article. They are based on the close association between imaging agents, drugs, and some stimulation techniques. The ongoing research efforts in that direction show that, if they are still far from clinical applications, strong expectations are made. From the point of view of interventional planning and image guidance, all of them share a lot of concerns. PMID:20176527

  15. [Polymeric nanoparticles with therapeutic gene for gene therapy: I. Preparation and in vivo gene transfer study].

    PubMed

    Yang, Jing; Song, Cunxian; Sun, Hongfan; Wu, Li; Tang, Lina; Leng, Xigang; Wang, Pengyan; Xu, Yiyao; Li, Yongjun; Guan, Heng

    2005-06-01

    VEGF nanoparticle (VEGF-NP) was prepared by a multi-emulsification technique using a biodegradable poly-dl-lactic-co-glycolic (PLGA) as matrix material. The nanoparticles were characterized for size, VEGF loading capacity, and in vitro release. VEGF-NP and naked VEGF plasmid were intramuscularly injected into the ischemia site of the rabbit chronic hindlimb ischemia model and the efficiency of VEGF-NP as gene delivery carrier for gene therapy in animal model was evaluated. Gene therapuetic effect was assessed evaluated by RT-PCR, immunohistochemistry and angiography assay. The average size of VEGF-NP was around 300 nm. The encapsulation efficiency of VEGF was above 96%. Loading amount of VEGF in the nanoparticles was about 4%. In vitro, nanoparticles maintained sustained-release of VEGF for two weeks. Two weeks post gene injection the capillary density in VEGF-NP group (81.22 per mm2) was significantly higher than that in control group (29.54 mm2). RT-PCR results showed greatly higher VEGF expression in VEGF-NP group (31.79au * mm) than that in naked VEGF group (9.15 au * mm). As a carrier system for gene therapy in animal model, VEGF-NP is much better than naked DNA plasmid. The results demonstrate great possibility of using NP carrier in human gene therapy. PMID:16013231

  16. 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

  17. Bacteriophage-Derived Vectors for Targeted Cancer Gene Therapy

    PubMed Central

    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

  18. Gene therapy for adenosine-deaminase-deficient severe combined immunodeficiency

    Microsoft Academic Search

    Alessandro Aiuti

    2004-01-01

    Adenosine-deaminase-deficient SCID was the first inherited disease to be treated with gene therapy. This life-threatening disorder is characterized by a purine defect that leads to impaired immune functions, recurrent infections and systemic metabolic abnormalities. The early gene therapy trials showed the safety and feasibility of engineering haematopoietic stem cells and peripheral blood lymphocytes using retroviral vectors. However, all patients were

  19. Gene therapy in immune-mediated diseases of the eye

    Microsoft Academic Search

    Uwe Pleyer; Thomas Ritter

    2003-01-01

    Therapy of ocular immune-mediated diseases has changed dramatically over the past two decades. Although a variety of non-specific immunosuppressive agents are introduced, with advances in cell biology a number of more specific therapeutic options will become available. Gene therapy has the potential to interfere with the immune response at different steps modulating the microenvironment of the eye. In this chapter

  20. Gene therapy in dentistry: tool of genetic engineering. Revisited.

    PubMed

    Gupta, Khushboo; Singh, Saurabh; Garg, Kavita Nitish

    2015-03-01

    Advances in biotechnology have brought gene therapy to the forefront of medical research. The concept of transferring genes to tissues for clinical applications has been discussed nearly half a century, but the ability to manipulate genetic material via recombinant DNA technology has brought this goal to reality. The feasibility of gene transfer was first demonstrated using tumour viruses. This led to development of viral and nonviral methods for the genetic modification of somatic cells. Applications of gene therapy to dental and oral problems illustrate the potential impact of this technology on dentistry. Preclinical trial results regarding the same have been very promising. In this review we will discuss methods, vectors involved, clinical implication in dentistry and scientific issues associated with gene therapy. PMID:25540850

  1. 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

  2. Cancer gene therapy with oncolytic adenoviruses K. Guse,A. Hemminki

    E-print Network

    Hemminki, Akseli

    Cancer gene therapy with oncolytic adenoviruses K. Guse,A. Hemminki Cancer Gene Therapy Group therapy hold promise for the treatment of various tu- mor types. Among the most promising cancer gene with oncolytic adenoviruses is given. Key words: cancer gene therapy, clinical trials, oncolytic adenovirus

  3. Gene delivery to human sweat glands: a model for cystic fibrosis gene therapy

    Microsoft Academic Search

    H Lee; D R Koehler; C Y Pang; R H Levine; P Ng; D J Palmer; P M Quinton; J Hu

    2005-01-01

    Gene therapy vectors are mostly studied in cultured cells, rodents, and sometimes in non-human primates, but it is useful to test them in human tissue prior to clinical trials. In this study, we investigated the possibility of using human sweat glands as a model for testing cystic fibrosis (CF) gene therapy vectors. Human sweat glands are relatively easy to obtain

  4. 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

  5. Stem-Cell-Based Gene Therapy for HIV Infection

    PubMed Central

    Zhen, Anjie; Kitchen, Scott

    2013-01-01

    Despite the enormous success of combined anti-retroviral therapy, HIV infection is still a lifelong disease and continues to spread rapidly worldwide. There is a pressing need to develop a treatment that will cure HIV infection. Recent progress in stem cell manipulation and advancements in humanized mouse models have allowed rapid developments of gene therapy for HIV treatment. In this review, we will discuss two aspects of HIV gene therapy using human hematopoietic stem cells. The first is to generate immune systems resistant to HIV infection while the second strategy involves enhancing anti-HIV immunity to eliminate HIV infected cells. PMID:24368413

  6. original article The American Society of Gene & Cell Therapy Molecular Therapy vol. 18 no. 12, 20572063 dec. 2010 2057

    E-print Network

    Gollisch, Tim

    original article© The American Society of Gene & Cell Therapy Molecular Therapy vol. 18 no. 12 gene replacement therapy as a poten- tial treatment for this disease in the CNGA3-/- mouse model. We show that such therapy can restore cone- specific visual processing in the central nervous system even

  7. 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

  8. Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency

    Microsoft Academic Search

    Alessandro Aiuti; Federica Cattaneo; Stefania Galimberti; Ulrike Benninghoff; Barbara Cassani; Luciano Callegaro; Samantha Scaramuzza; Grazia Andolfi; Massimiliano Mirolo; Immacolata Brigida; Antonella Tabucchi; Filippo Carlucci; Martha Eibl; Memet Aker; Shimon Slavin; Hamoud Al-Mousa; Abdulaziz Al Ghonaium; Alina Ferster; Andrea Duppenthaler; Luigi Notarangelo; Uwe Wintergerst; Rebecca H. Buckley; Marco Bregni; Sarah Marktel; Maria Grazia Valsecchi; Paolo Rossi; Fabio Ciceri; Roberto Miniero; Claudio Bordignon; Maria-Grazia Roncarolo

    2009-01-01

    Background We investigated the long-term outcome of gene therapy for severe combined immu- nodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. Methods We infused autologous CD34+ bone marrow cells transduced with a retroviral vec- tor containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked

  9. Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy

    E-print Network

    Collins, James J.

    Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy Timothy K. Lua, we engineered bacteriophage to overexpress proteins and attack gene networks that are not directly bacteriophage en- hances killing by quinolones by several orders of magnitude in vitro and significantly

  10. Gene therapy in nonhuman primate models of human autoimmune disease

    Microsoft Academic Search

    B A t'Hart; M. J. B. M. Vervoordeldonk; J. L. Heeney; P. P. Tak

    2003-01-01

    Before autoimmune diseases in humans can be treated with gene therapy, the safety and efficacy of the used vectors must be tested in valid experimental models. Monkeys, such as the rhesus macaque or the common marmoset, provide such models. This publication reviews the state of the art in monkey models for rheumatoid arthritis and multiple sclerosis and the (few) gene

  11. Ocular gene therapy: current progress and future prospects

    Microsoft Academic Search

    Pasqualina Colella; Gabriella Cotugno; Alberto Auricchio

    2008-01-01

    As gene therapy begins to produce its first clinical successes, interest in ocular gene transfer has grown owing to the favorable safety and efficacy characteristics of the eye as a target organ for drug delivery. Important advances also include the availability of viral and non- viral vectors that are able to efficiently transduce various ocular cell types, the use of

  12. Gene Therapy for Genetic and Acquired Retinal Diseases

    Microsoft Academic Search

    Edward Chaum; Mark P Hatton

    2002-01-01

    We present an overview of the current status of basic science and translational research being applied to gene therapy for eye disease, focusing on diseases of the retina. We discuss the viral and nonviral methods being used to transfer genes to the retina and retinal pigment epithelium, and the advantages and disadvantages of each approach. We review the various genetic

  13. Polyethylenimine shows properties of interest for cystic fibrosis gene therapy

    Microsoft Academic Search

    Stefano Ferrari; Andrea Pettenazzo; Nicoletta Garbati; Franco Zacchello; Jean-Paul Behr; Maurizio Scarpa

    1999-01-01

    Before being considered for a cystic fibrosis (CF) gene therapy trial, any gene delivery agent must be able to show that it produces low levels of toxicity as well as being able to protect the DNA from nuclease degradation. Here we show that complexes of linear polyethylenimine (L-PEI) and DNA can repeatedly be administered to animals (up to 21 consecutive

  14. 350. PreClinical Assays for Cystic Fibrosis Gene Therapy

    Microsoft Academic Search

    Uta Griesenbach

    2005-01-01

    Cystic fibrosis (CF) has long been a model disease to study lung gene therapy and we and others have carried out a number of phase I\\/II clinical trials using viral or non-viral vectors carrying the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In addition to safety, measurements of potential difference (PD) across the airway epithelium, which is altered in CF

  15. Gene expression of osteogenic factors following gene therapy in mandibular lengthening.

    PubMed

    Wu, Guoping; Zhou, Bin; Hu, Chunbing; Li, Shaolan

    2015-03-01

    This study investigated the effect of gene therapy on the expression of osteogenic mediators in mandibular distraction osteogenesis rabbits. Bilateral mandibular osteotomies were performed in 45 New-Zealand rabbits. After a latency of 3 days, the mandibles were elongated using distractors with a rate of 0.8 mm/d for 7 days. After the completion of distraction, the rabbits were randomly divided into 5 groups: 2 ?g (0.1 ?g/?L) of recombinant plasmid pIRES-hVEGF165-hBMP-2, recombinant plasmid pIRES-hBMP2, recombinant plasmid pIRES-hVEGF165, pIRES, and the same volume of normal saline were injected into the distraction gap of groups A, B, C, D, and E, respectively, followed by electroporation. Three animals were killed at the 7th, 14th, and 28th day after gene transfected in different groups, respectively. The lengthened mandibles were harvested and processed for immunohistochemical examinations; the mean optic densities (MODs) and integral optical density of bone morphogenetic protein (BMP-2) and transforming growth factor ?1 (TGF-?1)-positive cells were measured by CMIAS-2001A computerized image analyzer. The data were analyzed with SPSS (SPSS Inc, Chicago, IL). Bone morphogenetic protein 2 and TGF-?1 staining was mainly located in inflammatory cells, monocytes, fibroblasts, osteoblasts, osteocytes, and chondrocytes in the distraction zones. Their strongest expression reached to the peak at the seventh day and decreased at the 14th day of consolidation stage; at the 28th day, they expressed weakly. Image analysis results show that, at the seventh day, the expression of BMP-2 in group B (0.26 ± 0.03, 0.36 ± 0.02) was the strongest; there was significant difference among them (P < 0.01), whereas the expression of TGF-?1 in group C (0.38 ± 0.06, 1.05 ± 0.19) is strongest followed by group A (0.34 ± 0.05, 0.95 ± 0.16) and B (0.33 ± 0.07, 0.90 ± 0.19). At every time point, the level of expression of BMP-2 and TGF-?1 in gene therapy groups (groups A, B, and C) was remarkably higher than those in non-gene therapy groups(groups D and E). There were significant differences between gene therapy groups and non-gene therapy groups (P < 0.05 or P < 0.001). These results indicated that local gene transfection can up-regulate the expression of osteogenic mediators (BMP-2 and TGF-?1), which may promote cell differentiation and proliferation and stimulate extracellular matrix synthesis and new bone formation in distraction gap. PMID:25723654

  16. Genetic Therapy for Duchenne Muscular Dystrophy: Viral Vectors and Micro-Gene Therapy

    E-print Network

    Royal Holloway, University of London

    Genetic Therapy for Duchenne Muscular Dystrophy: Viral Vectors and Micro-Gene Therapy Taeyoung Koo, Royal Holloway-University of London, Egham, TW20 0EX What is Duchenne Muscular Dystrophy (DMD)? DMD is Duchenne Muscular Dystrophy (DMD)? DMD is a Neuromuscular disease caused by mutations in the dystrophin

  17. Development of Viral Vectors for Use in Cardiovascular Gene Therapy

    PubMed Central

    Williams, Paul D.; Ranjzad, Parisa; Kakar, Salik J.; Kingston, Paul A.

    2010-01-01

    Cardiovascular disease represents the most common cause of mortality in the developed world but, despite two decades of promising pre-clinical research and numerous clinical trials, cardiovascular gene transfer has so far failed to demonstrate convincing benefits in the clinical setting. In this review we discuss the various targets which may be suitable for cardiovascular gene therapy and the viral vectors which have to date shown the most potential for clinical use. We conclude with a summary of the current state of clinical cardiovascular gene therapy and the key trials which are ongoing. PMID:21994642

  18. Salmonella-mediated gene therapy in experimental colitis in mice.

    PubMed

    Palffy, Roland; Gardlik, Roman; Behuliak, Michal; Jani, Peter; Balakova, Denisa; Kadasi, Ludevit; Turna, Jan; Celec, Peter

    2011-02-01

    Bacterial gene therapy - bactofection is a simple and effective method to deliver plasmid DNA into target tissue. We hypothesize that oral in vivo bactofection can be an interesting approach to influence the course of inflammatory bowel diseases. The aim of this study was to prove the effects of antioxidative and anti-inflammatory bactofection in dextran sulfate sodium (DSS)-treated mice. Attenuated bacteria Salmonella Typhimurium SL7207 carrying plasmids with genes encoding Cu-Zn superoxide dismutase and an N-terminal deletion mutant of monocyte chemoattractant protein-1 were prepared. Male Balb/c mice had ad libitum access to 1% DSS solution in drinking water during 10 days (mild model of colitis). The animals were daily fed with 200 Mio bacteria via gastric gavage during the experiment. Fecal consistency, clinical status, food and water intake were monitored. After 10 days samples were taken and markers of oxidative stress and inflammatory cytokine levels were measured. Colonic tissue was scored histologically by a blinded investigator. DSS treatment significantly increased the levels of inflammatory cytokines and malondialdehyde as a marker of lipoperoxidation in the colon. Anti-inflammatory gene therapy improved the total antioxidative capacity. In comparison with the untreated group, bacterial gene therapy lowered the histological colitis score. Salmonella-mediated antioxidative and anti-inflammatory gene therapy alleviated colitis in mice. The effect seems to be mediated by increased antioxidative status. Further studies will show whether recombinant probiotics expressing therapeutic gene might be used for the therapy of inflammatory bowel diseases. PMID:21321314

  19. Large Animal Models of Hematopoietic Stem Cell Gene Therapy

    PubMed Central

    Trobridge, Grant D.; Kiem, Hans-Peter

    2010-01-01

    Large animal models have been instrumental in advancing hematopoietic stem cell (HSC) gene therapy. Here we review the advantages of large animal models, their contributions to the field of HSC gene therapy, and recent progress in this field. Several properties of human HSCs including their purification, their cell-cycle characteristics, their response to cytokines, and the proliferative demands put on them after transplantation are more similar in large animal models than in mice. Progress in the development and use of retroviral vectors and ex vivo transduction protocols over the last decade has led to efficient gene transfer in both dogs and in nonhuman primates. Importantly, the approaches developed in these models have translated well to the clinic. Large animals continue to be useful to evaluate the efficacy and safety of gene therapy, and dogs with hematopoietic diseases have now been cured by HSC gene therapy. Nonhuman primates allow evaluation of aspects of transplantation as well as disease-specific approaches such as AIDS gene therapy that can not be modeled well in the dog. Finally, large animal models have been used to evaluate the genotoxicity of viral vectors by comparing integration sites in hematopoietic repopulating cells and monitoring clonality after transplantation. PMID:20428209

  20. Imaging techniques for prostate cancer: implications for focal therapy

    PubMed Central

    Turkbey, Baris; Pinto, Peter A.; Choyke, Peter L.

    2012-01-01

    The multifocal nature of prostate cancer has necessitated whole-gland therapy in the past; however, since the widespread use of PSA screening, patients frequently present with less-advanced disease. Many men with localized disease wish to avoid the adverse effects of whole-gland therapy; therefore, focal therapy for prostate cancer is being considered as a treatment option. For focal treatment to be viable, accurate imaging is required for diagnosis, staging, and monitoring of treatment. Developments in MRI and PET have brought more attention to prostate imaging and the possibility of improving the accuracy of focal therapy. In this Review, we discuss the advantages and disadvantages of conventional methods for imaging the prostate, new developments for targeted imaging, and the possible role of image-guided biopsy and therapy for localized prostate cancer. PMID:19352394

  1. Advances in gene therapy technologies to treat retinitis pigmentosa

    PubMed Central

    Petrs-Silva, Hilda; Linden, Rafael

    2014-01-01

    Retinitis pigmentosa (RP) is a class of diseases that leads to progressive degeneration of the retina. Experimental approaches to gene therapy for the treatment of inherited retinal dystrophies have advanced in recent years, inclusive of the safe delivery of genes to the human retina. This review is focused on the development of gene therapy for RP using recombinant adenoassociated viral vectors, which show a positive safety record and have so far been successful in several clinical trials for congenital retinal disease. Gene therapy for RP is under development in a variety of animal models, and the results raise expectations of future clinical application. Nonetheless, the translation of such strategies to the bedside requires further understanding of the mutations and mechanisms that cause visual defects, as well as thorough examination of potential adverse effects. PMID:24391438

  2. Targeting Transgene Expression for Cystic Fibrosis Gene Therapy

    Microsoft Academic Search

    David R. Koehler; Vicky Hannam; Rosetta Belcastro; Brent Steer; Yanxia Wen; Martin Post; Gregory Downey; A. Keith Tanswell; Jim Hu

    2001-01-01

    We have developed an expression cassette for cystic fibrosis (CF) gene therapy using control elements from the human cytokeratin 18 gene (KRT18, also known as K18). KRT18 is naturally expressed in a spatial pattern similar to that of CFTR, the gene mutated in CF. We delivered a KRT18-driven lacZ plasmid complexed with cationic liposomes intravenously to mice and examined expression

  3. Gene therapy (germ line), 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 Cell therapy (germline) Mario Capecchi discusses the idea that someday therapies may be created to correct defective genes in egg and sperm cells.

  4. Recent trends in the gene therapy of ?-thalassemia.

    PubMed

    Finotti, Alessia; Breda, Laura; Lederer, Carsten W; Bianchi, Nicoletta; Zuccato, Cristina; Kleanthous, Marina; Rivella, Stefano; Gambari, Roberto

    2015-01-01

    The ?-thalassemias are a group of hereditary hematological diseases caused by over 300 mutations of the adult ?-globin gene. Together with sickle cell anemia, thalassemia syndromes are among the most impactful diseases in developing countries, in which the lack of genetic counseling and prenatal diagnosis have contributed to the maintenance of a very high frequency of these genetic diseases in the population. Gene therapy for ?-thalassemia has recently seen steadily accelerating progress and has reached a crossroads in its development. Presently, data from past and ongoing clinical trials guide the design of further clinical and preclinical studies based on gene augmentation, while fundamental insights into globin switching and new technology developments have inspired the investigation of novel gene-therapy approaches. Moreover, human erythropoietic stem cells from ?-thalassemia patients have been the cellular targets of choice to date whereas future gene-therapy studies might increasingly draw on induced pluripotent stem cells. Herein, we summarize the most significant developments in ?-thalassemia gene therapy over the last decade, with a strong emphasis on the most recent findings, for ?-thalassemia model systems; for ?-, ?-, and anti-sickling ?-globin gene addition and combinatorial approaches including the latest results of clinical trials; and for novel approaches, such as transgene-mediated activation of ?-globin and genome editing using designer nucleases. PMID:25737641

  5. Potential of gene therapy for the treatment of pituitary tumors.

    PubMed

    Goya, R G; Sarkar, D K; Brown, O A; Hereñú, C B

    2004-03-01

    Pituitary adenomas constitute the most frequent neuroendocrine pathology, comprising up to 15% of primary intracranial tumors. Current therapies for pituitary tumors include surgery and radiotherapy, as well as pharmacological approaches for some types. Although all of these approaches have shown a significant degree of success, they are not devoid of unwanted side effects, and in most cases do not offer a permanent cure. Gene therapy-the transfer of genetic material for therapeutic purposes-has undergone an explosive development in the last few years. Within this context, the development of gene therapy approaches for the treatment of pituitary tumors emerges as a promising area of research. We begin by presenting a brief account of the genesis of prolactinomas, with particular emphasis on how estradiol induces prolactinomas in animals. In so doing, we discuss the role of each of the recently discovered growth inhibitory and growth stimulatory substances and their interactions in estrogen action. We also evaluate the cell-cell communication that may govern these growth factor interactions and subsequently promote the growth and survival of prolactinomas. Current research efforts to implement gene therapy in pituitary tumors include the treatment of experimental prolactinomas or somatomammotropic tumors with adenoviral vector-mediated transfer of the suicide gene for the herpes simplex type 1 (HSV1) thymidine kinase, which converts the prodrug ganciclovir into a toxic metabolite. In some cases, the suicide transgene has been placed under the control of pituitary cell-type specific promoters, like the human prolactin or human growth hormone promoters. Also, regulatable adenoviral vector systems are being assessed in gene therapy approaches for experimental pituitary tumors. In a different type of approach, an adenoviral vector, encoding the human retinoblastoma suppressor oncogene, has been successfully used to rescue the phenotype of spontaneous pituitary tumors of the pars intermedia in mice. We close the article by discussing the future of molecular therapies. We point out that although, gene therapy represents a key step in the development of molecular medicine, it has inherent limitations. As a consequence, it is our view that at some point, genetic therapies will have to move from exogenous gene transfer (i.e. gene therapy) to endogenous gene repair. This approach will call for radically new technologies, such as nanotechnology, whose present state of development is outlined. PMID:15032616

  6. Prospects for gene therapy in corneal disease

    Microsoft Academic Search

    A S Jun; D F P Larkin; DFP Larkin

    2003-01-01

    Transfer of cDNA to corneal cells has been accomplished using viral and nonviral vectors. Studies examining the feasibility and optimal methods for vector-mediated gene transfer to the cornea have, as in other tissues, been performed using histochemical or fluorescent marker genes. These have used corneal cells or cell lines in vitro, and whole corneas maintained in ex vivo culture. Gene-based

  7. Gene therapy for dyslipidemia: a review of gene replacement and gene inhibition strategies

    PubMed Central

    Kassim, Sadik H; Wilson, James M; Rader, Daniel J

    2012-01-01

    Despite numerous technological and pharmacological advances and more detailed knowledge of molecular etiologies, cardiovascular diseases remain the leading cause of morbidity and mortality worldwide claiming over 17 million lives a year. Abnormalities in the synthesis, processing and catabolism of lipoprotein particles can result in severe hypercholesterolemia, hypertriglyceridemia or low HDL-C. Although a plethora of antidyslipidemic pharmacological agents are available, these drugs are relatively ineffective in many patients with Mendelian lipid disorders, indicating the need for new and more effective interventions. In vivo somatic gene therapy is one such intervention. This article summarizes current strategies being pursued for the development of clinical gene therapy for dyslipidemias that cannot effectively be treated with existing drugs. PMID:22505953

  8. original article The American Society of Gene & Cell Therapy Molecular Therapy vol. 19 no. 4, 667675 apr. 2011 667

    E-print Network

    Schaffer, David V.

    original article© The American Society of Gene & Cell Therapy Molecular Therapy vol. 19 no. 4, 667­675 apr. 2011 667 Gene delivery to, and gene targeting in, stem cells would be a highly enabling- neering AAV delivery systems to enhance gene delivery to stem cells may have an impact in stem cell

  9. original article The American Society of Gene & Cell Therapy Molecular Therapy vol. 20 no. 2, 329338 feb. 2012 329

    E-print Network

    Schaffer, David V.

    original article© The American Society of Gene & Cell Therapy Molecular Therapy vol. 20 no. 2, 329 are of particular interest for their capacity to mediate efficient gene delivery to and gene targeting in various have applied this approach to create a novel AAV variant with high gene delivery efficiencies (~50

  10. Gene transfer vector biodistribution: pivotal safety studies in clinical gene therapy development

    Microsoft Academic Search

    P Gonin; C Gaillard

    2004-01-01

    Techniques allowing for gene transfer vectors biodistribution investigation, in the frame of preclinical gene therapy development, are exposed. Emphasis is given on validation and test performance assessment. In the second part, specific gene vector distribution properties are reviewed (adenovirus, AAV, plasmid, retroviruses, herpes-derived vectors, germline transmission risks). The rationale for biodistribution by quantitative PCR, animal study and result interpretation is

  11. Ocular gene therapy: current progress and future prospects.

    PubMed

    Colella, Pasqualina; Cotugno, Gabriella; Auricchio, Alberto

    2009-01-01

    As gene therapy begins to produce its first clinical successes, interest in ocular gene transfer has grown owing to the favorable safety and efficacy characteristics of the eye as a target organ for drug delivery. Important advances also include the availability of viral and non-viral vectors that are able to efficiently transduce various ocular cell types, the use of intraocular delivery routes and the development of transcriptional regulatory elements that allow sustained levels of gene transfer in small and large animal models after a single administration. Here, we review recent progress in the field of ocular gene therapy. The first experiments in humans with severe inherited forms of blindness seem to confirm the good safety and efficacy profiles observed in animal models and suggest that gene transfer has the potential to become a valuable therapeutic strategy for otherwise untreatable blinding diseases. PMID:19097940

  12. An early history of gene transfer and therapy.

    PubMed

    Wolff, J A; Lederberg, J

    1994-04-01

    The term "gene therapy" was coined to distinguish it from the Orwellian connotations of "human genetic engineering," which, in turn, was derived from the term "genetic engineering." Genetic engineering was first used at the Sixth International Congress of Genetics held in 1932 and was taken to mean "the application of genetic principles to animal and plant breeding." Once the basics of molecular genetics and gene transfer in bacteria were established in the 1960s, gene transfer into animals and humans using either viral vectors and/or genetically modified cultured cells became inevitable. Despite the early exposition of the concept of gene therapy, progress awaited the advent of recombinant DNA technology. The lack of trustworthy techniques did not stop many researchers from attempting to transfer genes into cells in culture, animals, and humans. Viral genomes were used for the development of the first relatively efficient methods for gene transfer into mammalian cells in culture. In the late 1970s, early transfection techniques were combined with selection systems for cultured cells and recombinant DNA technology. With the development of retroviral vectors in the early 1980s, the possibility of efficient gene transfer into mammalian cells for the purpose of gene therapy became widely accepted. PMID:8049304

  13. Retinal Structure and Function in Achromatopsia: Implications for Gene Therapy

    PubMed Central

    Sundaram, Venki; Wilde, Caroline; Aboshiha, Jonathan; Cowing, Jill; Han, Colin; Langlo, Christopher S.; Chana, Ravinder; Davidson, Alice E.; Sergouniotis, Panagiotis I.; Bainbridge, James W.; Ali, Robin R.; Dubra, Alfredo; Rubin, Gary; Webster, Andrew R.; Moore, Anthony T.; Nardini, Marko; Carroll, Joseph; Michaelides, Michel

    2013-01-01

    Purpose To characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical trials of gene therapy. Design Cross-sectional study. Participants Forty subjects with ACHM. Methods All subjects underwent spectral domain optical coherence tomography (SD-OCT), microperimetry, and molecular genetic testing. Foveal structure on SD-OCT was graded into 5 distinct categories: (i) continuous inner segment ellipsoid (ISe), (ii) ISe disruption, (iii) ISe absence, (iv) presence of a hyporeflective zone (HRZ), and (v) outer retinal atrophy including retinal pigment epithelial (RPE) loss. Foveal and outer nuclear layer (ONL) thickness was measured, and presence of hypoplasia determined. Main Outcome Measures Photoreceptor appearance on SD-OCT imaging; foveal and ONL thickness; presence of foveal hypoplasia; retinal sensitivity and fixation stability; and association of these parameters with age and genotype. Results Forty subjects with mean age of 24.9 years (range 6 to 52) were included. Disease-causing variants were found in CNGA3 (n=18), CNGB3 (n=15), GNAT2 (n=4), and PDE6C (n=1). No variants were found in 2 individuals. 22.5% of subjects had a continuous ISe layer at the fovea; 27.5% had ISe disruption; 20% had an absent ISe layer; 22.5% had a HRZ; and 7.5% had outer retinal atrophy. No significant differences in age (p=0.77), mean retinal sensitivity (p=0.21) or fixation stability (p=0.34) across the 5 SD-OCT categories were evident. No significant correlation was found between age and foveal thickness (p=0.84), or between age and foveal ONL thickness (p=0.12). Conclusions The lack of clear association of disruption of retinal structure or function in ACHM with age suggests that the window of opportunity for intervention by gene therapy is wider in some individuals than previously indicated. Therefore the potential benefit for a given subject is likely to be better predicted by specific measurement of photoreceptor structure rather than simply by age. The ability to directly assess cone photoreceptor preservation with SD-OCT and/or adaptive optics imaging is likely to prove invaluable in selecting subjects for future trials and measuring their impact. PMID:24148654

  14. Gene Therapy and Children (For Parents)

    MedlinePLUS

    ... or set of genes causes each disease. The Human Genome Project and other international efforts have completed the initial work of sequencing and mapping virtually all of the 25,000 genes in the human cell. This research will provide new strategies to ...

  15. Vascular applications of human gene therapy

    Microsoft Academic Search

    J. Geoffrey Pickering; Satoshi Takeshita; Laurent Feldman; Douglas W. Losordo; Jeffrey M. Isner

    1995-01-01

    Summary Complexing recombinant DNA with cationic liposomes is a convenient means of introducing foreign genes into cells (lipofection) and could potentially form the basis for genetically modifying diseased blood vessels in patients. The mechanism of lipofection is incompletely understood, but it is recognized that the degree of successful gene transfer is highly dependent on cell type. We have transfected primary

  16. Intravascular Photoacoustic and Ultrasound Imaging: From Tissue Characterization to Molecular Imaging to Image-Guided Therapy

    Microsoft Academic Search

    Bo Wang; Jimmy Su; Andrei Karpiouk; Doug Yeager; Stanislav Emelianov

    \\u000a Successful diagnosis and treatment of atherosclerosis demands imaging modalities that can characterize the composition of\\u000a atherosclerotic plaques, stage the disease, and guide interventional therapy. In this chapter, combined intravascular photoacoustic\\u000a (IVPA) and intravascular ultrasound (IVUS) imaging is used to address these issues. Based on the difference in optical absorption\\u000a spectra, lipid-rich tissues can be differentiated using spectroscopic IVPA imaging. Using

  17. 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.

  18. Large Animal Models of Neurological Disorders for Gene Therapy

    PubMed Central

    Gagliardi, Christine; Bunnell, Bruce A.

    2009-01-01

    The development of therapeutic interventions for genetic disorders and diseases that affect the central nervous system (CNS) has proven challenging. There has been significant progress in the development of gene therapy strategies in murine models of human disease, but gene therapy outcomes in these models do not always translate to the human setting. Therefore, large animal models are crucial to the development of diagnostics, treatments, and eventual cures for debilitating neurological disorders. This review focuses on the description of large animal models of neurological diseases such as lysosomal storage diseases, Parkinson’s disease, Huntington’s disease, and neuroAIDS. The review also describes the contributions of these models to progress in gene therapy research. PMID:19293458

  19. 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

  20. GENE AND CELL THERAPY FOR LIFE-THREATENING CARDIAC ARRHYTHMIAS

    PubMed Central

    Rosen, Michael R.; Danilo, Peter; Robinson, Richard B.

    2009-01-01

    Gene and cell therapies of cardiac arrhythmias are nascent fields whose raison d’etre derives from (1) the problematic state of arrhythmia treatment today (especially atrial and ventricular tachyarrhythmias for which drugs, devices and ablation remain more stopgaps then optimal interventions), and (2) the opportunity to learn and potentially treat and cure by exploring new technologies. The state of antiarrhythmic therapy and new directions being taken are reviewed. PMID:20191107

  1. Immunotherapy of Uveitis: is Gene Therapy in our Future?

    Microsoft Academic Search

    Rachel R. Caspi

    Gene therapy is a very attractive therapeutic option, as it carries the promise of more or less permanently curing a clinical\\u000a condition. As our understanding of the critical checkpoints in the pathogenesis of autoimmune ocular disease improves, more\\u000a and more potential intervention points and candidate therapeutic targets are identified. New technologies emerge, promising\\u000a more specific and more easily applied therapies.

  2. Translational Applications of Molecular Imaging and Radionuclide Therapy

    SciTech Connect

    Welch, Michael J.; Eckelman, William C.; Vera, David

    2005-06-17

    Molecular imaging is becoming a larger part of imaging research and practice. The Office of Biological and Environmental Research of the Department of Energy funds a significant number of researchers in this area. The proposal is to partially fund a workshop to inform scientists working in nuclear medicine and nuclear medicine practitioners of the recent advances of molecular imaging in nuclear medicine as well as other imaging modalities. A limited number of topics related to radionuclide therapy will also be discussed. The proposal is to request partial funds for the workshop entitled “Translational Applications of Molecular Imaging and Radionuclide Therapy” to be held prior to the Society of Nuclear Medicine Annual Meeting in Toronto, Canada in June 2005. The meeting will be held on June 17-18. This will allow scientists interested in all aspects of nuclear medicine imaging to attend. The chair of the organizing group is Dr. Michael J. Welch. The organizing committee consists of Dr. Welch, Dr. William C. Eckelman and Dr. David Vera. The goal is to invite speakers to discuss the most recent advances of modern molecular imaging and therapy. Speakers will present advances made in in vivo tagging imaging assays, technical aspects of small animal imaging, in vivo imaging and bench to bedside translational study – the role of a diagnostic scan on therapy selection. This latter topic will include discussions on ? therapy and new approaches to dosimetry. Several of these topics are those funded by the Department of Energy Office of Biological and Environmental Research.

  3. 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

  4. Ernährungsmanagement versus Body-Image-Therapie bei Anorexia nervosa

    Microsoft Academic Search

    Reimund Böse

    2007-01-01

    Body image disturbances are highly predictive of the course of eating disorders, and addressing these problems effectively, has been an ongoing challenge to clinicians. This study examines whether a specific group therapy program geared to body image reduces different components of the body image disturbance more effectively than an unspecific nutritional management program. Patients and Methods: All 57 carefully diagnosed

  5. Single stem cell gene therapy for genetic skin disease

    PubMed Central

    Larsimont, Jean-Christophe; Blanpain, Cédric

    2015-01-01

    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. Developing adenoviral-mediated in vivo gene therapy for ornithine transcarbamylase deficiency

    Microsoft Academic Search

    S. E. Raper; J. M. Wilson; M. Yudkoff; M. B. Robinson; X. Ye; M. L. Batshaw

    1998-01-01

    There are a number of reasons for choosing ornithine transcarbamylase (OTC) deficiency as a candidate for gene therapy: the gene has been cloned; the disorder is relatively common; the current clinical outcome is poor; and there are authentic animal models. In considering the development of gene therapy for OTC deficiency, we focused on the use of in vivo gene therapy

  7. Capsid-Modified Adenoviral Vectors for Improved Muscle-Directed Gene Therapy

    E-print Network

    Hemminki, Akseli

    Capsid-Modified Adenoviral Vectors for Improved Muscle-Directed Gene Therapy Kilian Guse,1 Masataka represents an attractive target tissue for adenoviral gene therapy to treat muscle disorders-directed gene therapy. Introduction Skeletal muscle-directed gene transfer holds promise for the treatment

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

    E-print Network

    Fischer, Itzhak

    on and Gene Therapy Volume 7, Number 1, 2001THE NEUROSCIENTIST n REVIEW Transplantation and Gene genes to protect neurons and to stimulate regeneration. The ability to engineer cells by gene therapy Therapy: Combined Approaches for Repair of Spinal Cord Injury MARION MURRAY and ITZHAK FISCHER Department

  9. Microneedle Electrode Array for Electroporation of Skin for Gene Therapy Seong-O Choi1

    E-print Network

    Microneedle Electrode Array for Electroporation of Skin for Gene Therapy Seong-O Choi1 , Jung and was able to electroporate red blood cells as an in vitro model. INTRODUCTION One approach to gene therapy of gene therapy is limited in part by the need to improve DNA delivery into cells for increased gene

  10. Current status of gene therapy for brain tumors

    PubMed Central

    MURPHY, ANDREA M.; RABKIN, SAMUEL D.

    2013-01-01

    Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults, with current treatments having limited impact on disease progression. Therefore the development of alternative treatment options is greatly needed. Gene therapy is a treatment strategy that relies on the delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes, and has been applied to GBM with increasing promise. We have included selectively replication-competent oncolytic viruses within this strategy, although the virus acts directly as a complex biologic anti-tumor agent rather than as a classic gene delivery vehicle. GBM is a good candidate for gene therapy because tumors remain locally within the brain and only rarely metastasize to other tissues; the majority of cells in the brain are post-mitotic, which allows for specific targeting of dividing tumor cells; and tumors can often be accessed neurosurgically for administration of therapy. Delivery vehicles used for brain tumors include nonreplicating viral vectors, normal adult stem/progenitor cells, and oncolytic viruses. The therapeutic transgenes or viruses are typically cytotoxic or express prodrug activating suicide genes to kill glioma cells, immunostimulatory to induce or amplify anti-tumor immune responses, and/or modify the tumor microenvironment such as blocking angiogenesis. This review describes current preclinical and clinical gene therapy strategies for the treatment of glioma. PMID:23246627

  11. Imaging in targeted delivery of therapy to cancer.

    PubMed

    Dancey, Gairin; Begent, Richard H; Meyer, Tim

    2009-09-01

    We review the current status of imaging as applied to targeted therapy with particular focus on antibody-based therapeutics. Antibodies have high tumor specificity and can be engineered to optimize delivery to, and retention within, the tumor. Whole antibodies can activate natural immune effector mechanisms and can be conjugated to beta- and alpha-emitting radionuclides, toxins, enzymes, and nanoparticles for enhanced therapeutic effect. Imaging is central to the development of these agents and is used for patient selection, performing dosimetry and assessment of response. gamma- and positron-emitting radionuclides may be used to image the distribution of antibody-targeted therapeutics While some radionuclides such as iodine-131 emit both beta and gamma radiation and are therefore suitable for both imaging and therapy, others are more suited to imaging or therapy alone. Hence for radionuclide therapy of neuroendocrine tumors, patients can be selected for therapy on the basis of gamma-emitting indium-111-octreotide imaging and treated with beta-emitting yttrium-90-octreotate. Positron-emitting radionuclides can give greater sensitivity that gamma-emitters but only a single radionuclide can be imaged at one time and the range of radionuclides is more limited. The multiple options for antibody-based therapeutic molecules, imaging technologies and therapeutic scenarios mean that very large amounts of diverse data are being acquired. This can be most effectively shared and progress accelerated by use of common data standards for imaging, biological, and clinical data. PMID:19838639

  12. Development of gene therapy for blood disorders: an update

    PubMed Central

    2013-01-01

    This review addresses the current status of gene therapy for immunodeficiencies, chronic granulomatous disease, suicide gene therapy for graft-versus-host disease, viral infections, malignant hematologic disorders, hemophilia, and the hemoglobin disorders. New developments in vector design have fostered improved expression as well as enhanced safety, particularly of integrating retroviral vectors. Several immunodeficiencies have been treated successfully by stem cell–targeted, retroviral-mediated gene transfer with reconstitution of the immune system following infusion of the transduced cells. In a trial for hemophilia B, long-term expression of human FIX has been observed following adeno-associated viral vector–mediated gene transfer into the liver. This approach should be successful in treating any disorder in which liver production of a specific protein is therapeutic. PMID:23843498

  13. review The American Society of Gene & Cell Therapy Molecular Therapy vol. 19 no. 8, 14071415 aug. 2011 1407

    E-print Network

    Schaffer, David V.

    drugs (e.g., siroli- mus) and proteins (e.g., growth hormone),13,14 and these systems may alsoreview© The American Society of Gene & Cell Therapy Molecular Therapy vol. 19 no. 8, 1407­1415 aug. 2011 1407 IntroductIon Gene therapy has shown increasing promise in clinical trials for disorders

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

    E-print Network

    Cai, Long

    original article© The American Society of Gene Therapy Molecular Therapy vol. 16 no. 9, 1637­colony-stimulating factor (GM-CSF) trans- gene expression. We have previously shown, in animal models of hepatocellular prior regimens) and had failed all prior therapies. Their Childs-Pugh status was A. The patients

  15. Gene therapy to protect haematopoietic cells from cytotoxic cancer drugs

    Microsoft Academic Search

    Brian P. Sorrentino

    2002-01-01

    One of the most important complications of cancer chemotherapy is the toxic effect that the drugs have on normal tissues — particularly the bone marrow. Several gene-therapy vectors have been developed with the aim of expressing drug-resistance genes specifically in bone-marrow stem cells, so protecting them from chemotherapeutics. The feasibility of this approach has been established in animal model systems,

  16. Adenoviral Gene Therapy With Catalase Suppresses Experimental Optic Neuritis

    Microsoft Academic Search

    John Guy; Xiaoping Qi; Hui Wang; William W. Hauswirth

    1999-01-01

    Objective: To determine if adenoviral-mediated trans- fer of the gene for catalase (CAT), the reactive oxygen spe- cies scavenger, suppresses experimental optic neuritis. Clinical Relevance: Gene therapy with CAT deliv- ered by an adeno-associated viral vector was previously shown to suppress experimental optic neuritis. Because the transduction of protein expression with recombi- nant adeno-associated viral vector is relatively slow, tak-

  17. A Perspective of Gene Therapy in the Glaucomas

    Microsoft Academic Search

    Paul L Kaufman; William W-G Jia; Jiren Tan; Zheng Chen; B’Ann T Gabelt; Virginia Booth; Frank Tufaro; Max Cynader

    1999-01-01

    Gene therapy in the anterior and posterior segment tissues may have the potential to favorably influence aqueous hydrodynamics and retinal ganglion cell biology, thereby preventing, delaying, or minimizing glaucomatous damage to the optic nerve. We demonstrated the feasibility of using a herpes viral vector (ribonucleotide reductase defective HSV-1, hrR3) to deliver the lacZ reporter gene to living cat and rat

  18. Angiogenic Gene Therapy for the Treatment of Retinopathies

    Microsoft Academic Search

    Jacob M. Jones; Trevor McFarland; J. Timothy Stout

    \\u000a In the past decade, advances in vector design and delivery have helped guide gene therapy technologies from the laboratory\\u000a to clinical trials. These technologies are poised to tackle a key problem in opthalmology: pathologic angiogenesis. Gene transfer\\u000a techonologies offer the potential for highly regulated and sustained delivery of a therapeutic agent, and may have the potential\\u000a to arrest a pathological

  19. Gene Therapy of X-Linked Severe Combined Immunodeficiency

    Microsoft Academic Search

    Salima Hacein-Bey-Abina; Alain Fischer; Marina Cavazzana-Calvoa

    2002-01-01

    Severe combined immunodeficiency (SCID) conditions appear to be the best possible candidates for a gene therapy approach.\\u000a Transgene expression by lymphocyte precursors should confer to these cells a selective growth advantage that gives rise to\\u000a long-lived T-lymphocytes. This rationale was used as a basis for a clinical trial of the SCID-X1 disorder caused by common\\u000a ? (?c) gene mutations. This

  20. Gene therapy for primary immunodeficiencies: current status and future prospects.

    PubMed

    Qasim, Waseem; Gennery, Andrew R

    2014-06-01

    Gene therapy using autologous haematopoietic stem cells offers a valuable treatment option for patients with primary immunodeficiencies who do not have access to an HLA-matched donor, although such treatments have not been without their problems. This review details gene therapy trials for X-linked and adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). X-linked SCID was chosen for gene therapy because of previous 'natural' genetic correction through a reversion event in a single lymphoid precursor, demonstrating limited thymopoiesis and restricted T-lymphocyte receptor repertoire, showing selective advantage of progenitors possessing the wild-type gene. In early studies, patients were treated with long terminal repeats-intact gamma-retroviral vectors, without additional chemotherapy. Early results demonstrated gene-transduced cells, sustained thymopoiesis, and a diverse T-lymphocyte repertoire with normal function. Serious adverse effects were subsequently reported in 5 of 20 patients, with T-lymphocyte leukaemia developing, secondary to the viral vector integrating adjacent to a known oncogene. New trials using self-inactivating gamma-retroviral vectors are progressing. Trials for ADA-SCID using gamma-retroviral vectors have been successful, with no similar serious adverse effects reported; trials using lentiviral vectors are in progress. Patients with WAS and CGD treated with early gamma-retroviral vectors have developed similar lymphoproliferative adverse effects to those seen in X-SCID--current trials are using new-generation vectors. Targeted gene insertion using homologous recombination of corrected gene sequences by cellular DNA repair pathways following targeted DNA breakage will improve efficacy and safety of gene therapy. A number of new techniques are discussed. PMID:24848753

  1. Glaucoma: genes, phenotypes, and new directions for therapy

    PubMed Central

    Fan, Bao Jian; Wiggs, Janey L.

    2010-01-01

    Glaucoma, a leading cause of blindness worldwide, is characterized by progressive optic nerve damage, usually associated with intraocular pressure. Although the clinical progression of the disease is well defined, the molecular events responsible for glaucoma are currently poorly understood and current therapeutic strategies are not curative. This review summarizes the human genetics and genomic approaches that have shed light on the complex inheritance of glaucoma genes and the potential for gene-based and cellular therapies that this research makes possible. PMID:20811162

  2. Antisense gene silencing: therapy for neurodegenerative disorders?

    PubMed

    Nielsen, Troels T; Nielsen, Jørgen E

    2013-01-01

    Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi) has been intensively exploited as an experimental tool to study gene function. With the subsequent discovery that RNAi could also be applied to mammalian cells, the technology of RNAi expanded from being a valuable experimental tool to being an applicable method for gene-specific therapeutic regulation, and much effort has been put into further refinement of the technique. This review will focus on how RNAi has developed over the years and how the technique is exploited in a pre-clinical and clinical perspective in relation to neurodegenerative disorders. PMID:24705213

  3. Cognitive)ehavioral body image therapy for body dysmorphic disorder

    Microsoft Academic Search

    James C. Rosen; Jeff Reiter; Pam Orosan

    1995-01-01

    Body dysmorphic disorder (BDD) is a distressing body image disorder that involves excessive pre- occupation with physical appearance in a normal appearing person. Prior case reports of behavior therapy were encouraging, but no controlled evaluation of behavior therapy or any other type of treatment had been conducted. In the present study, 54 BDD subjects were randomly assigned to cognitive behavior

  4. 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

  5. Ligand-inducible transgene regulation for gene therapy.

    PubMed

    Ye, Xiangcang; Schillinger, Kurt; Burcin, Mark M; Tsai, Sophia Y; O'Malley, Bert W

    2002-01-01

    A synthetic ligand regulable system for gene transfer and expression has been developed in our laboratory based on mechanistic studies of steriod hormone receptor and transcriptional regulation. This gene switch system possesses most of the important features that are required for application of the system in biological research and clinical gene therapy in the future. As the primary ligand tested in this system, mifepristone can effectively turn on the regulatory circuit at doses much lower than those used in the clinic. By modification of the chimeric regulator and its feedback regulatory mode, this system has been optimized to produce very low basal activity with high inducibility in the presence of mifepristone. Also, improvements in regulator composition have been made to minimize immunogenicity and make the system more amenable to human gene therapy. Moreover, incorporation of this gene switch system into the HC-Ad vector system has further enhanced the efficiency of gene transfer and the long-term inducible expression of transgenes. However, for each application within a different biological system, the gene switch needs to be optimized to achieve appropriate inductions. In particular, the method used to deliver the transgenes and adjustment of ligand dosage are critical for in vivo gene expression. PMID:11883090

  6. Large animal models and gene therapy

    Microsoft Academic Search

    Margret Casal; Mark Haskins

    2006-01-01

    Over the last two decades, gene transfer experiments for the treatment of inherited or acquired diseases have mainly been performed in mice. While mice provide proof of principle and allow testing of a variety of therapeutic modalities, mouse models have some limitations, as only short-term experiments can be performed, their homogenous genetic background is unlike humans, and the knockout models

  7. I. GENE THERAPY FOR SICKLE CELL DISEASE

    E-print Network

    Mark C. Walters; Arthur W. Nienhuis; Elliott Vichinsky; Arthur W. Nienhuis

    The ability to efficiently insert a gene into repopulating hematopoietic cells and to achieve regulated expression in specific hematopoietic lineages would create many therapeutic opportunities.1 Indeed, sickle cell anemia has long been recognized as a potential candidate for the development of

  8. Ribozyme uses in retinal gene therapy

    Microsoft Academic Search

    William W Hauswirth; Alfred S Lewin

    2000-01-01

    In this chapter we discuss the design, delivery and preclinical testing of mutation-specific ribozymes for the treatment of dominantly inherited retinal disease. We focus particular attention on the initial screening of ribozymes in vitro, because the activity of RNA enzymes in cell-free systems can be used to predict their suitability for animal experiments. Current techniques for delivering genes of interest

  9. HSV Recombinant Vectors for Gene Therapy

    PubMed Central

    Manservigi, Roberto; Argnani, Rafaela; Marconi, Peggy

    2010-01-01

    The very deep knowledge acquired on the genetics and molecular biology of herpes simplex virus (HSV), has allowed the development of potential replication-competent and replication-defective vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous systems, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases, and targeted infection to specific tissues or organs. Replication-defective recombinant vectors are non-toxic gene transfer tools that preserve most of the neurotropic features of wild type HSV-1, particularly the ability to express genes after having established latent infections, and are thus proficient candidates for therapeutic gene transfer settings in neurons. A replication-defective HSV vector for the treatment of pain has recently entered in phase 1 clinical trial. Replication-competent (oncolytic) vectors are becoming a suitable and powerful tool to eradicate brain tumours due to their ability to replicate and spread only within the tumour mass, and have reached phase II/III clinical trials in some cases. The progress in understanding the host immune response induced by the vector is also improving the use of HSV as a vaccine vector against both HSV infection and other pathogens. This review briefly summarizes the obstacle encountered in the delivery of HSV vectors and examines the various strategies developed or proposed to overcome such challenges. PMID:20835362

  10. Lentiviral Vectors and Cystic Fibrosis Gene Therapy

    Microsoft Academic Search

    Stefano Castellani; Massimo Conese

    2010-01-01

    Cystic fibrosis (CF) is a chronic autosomic recessive syndrome, caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, a chloride channel expressed on the apical side of the airway epithelial cells. The lack of CFTR activity brings a dysregulated exchange of ions and water through the airway epithelium, one of the main aspects of CF lung disease pathophysiology.

  11. Progress and Prospects: Gene Therapy Clinical Trials (Part 2)

    Microsoft Academic Search

    U Griesenbach

    2007-01-01

    This is the second part of a review summarizing progress and prospects in gene therapy clinical research. Twenty key diseases\\/strategies are succinctly described and commented on by leaders in the field. This part includes clinical trials for skin diseases, neurological disorders, HIV\\/AIDS, ornithine transcarbamylase deficiency, ?1-antitrypsin deficiency, haemophilia and cancer.

  12. Human erythropoietin gene therapy for patients with chronic renal failure

    Microsoft Academic Search

    Yitzhak Lippin; Michal Dranitzki-Elhalel; Einat Brill-Almon; Chava Mei; Sarah Mizrachi; Yael Liberman; Adrian Iaina; Eli Kaplan; Eduardo Podjarny; Evelyne Zeira; Menahem Harati; Nicole Casadevall; Noam Shani; Eithan Galun

    2005-01-01

    Gene therapy holds a major promise. However, until now, this promise was fulfilled only in few cases, in rare genetic diseases. One very common clinical con- dition is anemia. Patients with anemia of chronic renal failure are treated with eryth- ropoietin. The objective of this study was to develop a therapeutic platform for se- rum-secreted proteins like erythropoi- etin. We

  13. Advances in Preclinical Investigation of Prostate Cancer Gene Therapy

    E-print Network

    Cai, Long

    Advances in Preclinical Investigation of Prostate Cancer Gene Therapy Marxa L Figueiredo1, Indianapolis, Indiana, USA Treating recurrent prostate cancer poses a great challenge to clinicians. Research to translate many preclinical discoveries into clinical practices. At this juncture, it is important

  14. 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

  15. Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs

    E-print Network

    Ponder, Katherine P.

    Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs Katherine Parker Ponder South Euclid Avenue, St. Louis, MO 63110; Departments of Pathobiology and Clinical Studies, School, Washington University School of Medicine, St. Louis, MO, and approved July 17, 2002 (received for review June

  16. Gene therapy and transplantation in CNS repair: The visual system

    Microsoft Academic Search

    Alan R. Harvey; Ying Hu; Simone G. Leaver; Carla B. Mellough; Kevin Park; Joost Verhaagen; Giles W. Plant; Qi Cui

    2006-01-01

    Normal visual function in humans is compromised by a range of inherited and acquired degenerative conditions, many of which affect photoreceptors and\\/or retinal pigment epithelium. As a consequence the majority of experimental gene- and cell-based therapies are aimed at rescuing or replacing these cells. We provide a brief overview of these studies, but the major focus of this review is

  17. Gene therapy and transplantation in the retinofugal pathway

    Microsoft Academic Search

    Alan R. Harvey; Mats Hellström; Jenny Rodger

    2009-01-01

    The mature CNS has limited intrinsic capacity for repair after injury; therefore, strategies are needed to enhance the viability and regrowth of damaged neurons. Here we review gene therapy studies in the eye, aimed at improving the survival and regeneration of injured retinal ganglion cells (RGCs). To target RGCs most current methods use recombinant adeno-associated viral vectors (AAV), usually serotype-2

  18. Lentiviral hematopoietic stem cell gene therapy in inherited metabolic disorders.

    PubMed

    Wagemaker, Gerard

    2014-10-01

    After more than 20 years of development, lentiviral hematopoietic stem cell gene therapy has entered the stage of initial clinical implementation for immune deficiencies and storage disorders. This brief review summarizes the development and applications, focusing on the lysosomal enzyme deficiencies, especially Pompe disease. PMID:25184354

  19. Gutless adenoviral vectors — Promising tools for gene therapy

    Microsoft Academic Search

    Alicja Jozkowicz; J. Dulak; J. Nanobashvili; P. Polterauer; M. Prager; I. Huk

    2002-01-01

    Summary  \\u000a Background: Progress in gene therapy depends on establishing the appropriate gene transfer methods. The most efficient vehicles for\\u000a the delivery of foreign genes to the target tissues are modified adenoviruses.\\u000a \\u000a \\u000a Methods: Adenoviral vectors of the first generation despite the high infection efficiency, have an essential drawback: They induce\\u000a a strong immune response, which excludes them from clinical trials.\\u000a \\u000a \\u000a \\u000a \\u000a Results:

  20. bcl-2 Gene Therapy Exacerbates Excitotoxicity

    Microsoft Academic Search

    Perikles D. Simon; Christian K. Vorwerk; Sharad S. Mansukani; Shu-Jen Chen; James M. Wilson; David Zurakowski; Jean Bennett; Evan B. Dreyer

    1999-01-01

    The protooncogene bcl-2 can block neuronal death from both naturally occurring apoptosis and exogenous insults. bcl-2 is therefore a promising candidate for the prevention of excitotoxic neuronal death. Using an adeno-associated viral vector, we delivered the bcl-2 gene to the ganglion cell layer of the rat eye. We hy- pothesized that infection with bcl-2 would protect ganglion cells against excitotoxic

  1. Gene therapy (somatic cell), 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 Cell therapy (somatic) Mario Capecchi talks about the possibility of correcting genetic defects.

  2. An inventory of shedding data from clinical gene therapy trials.

    PubMed

    Schenk-Braat, Ellen A M; van Mierlo, Marjolein M K B; Wagemaker, Gerard; Bangma, Chris H; Kaptein, Leonie C M

    2007-10-01

    Viruses are the most commonly used vectors for clinical gene therapy. The risk of dissemination of a viral vector into the environment via excreta from the treated patient, a phenomenon called shedding, is a major safety concern for the environment. Despite the significant number of clinical gene therapy trials that have been conducted worldwide, there is currently no overview of actual shedding data available. In this article, an inventory of shedding data obtained from a total of 100 publications on clinical gene therapy trials using retroviral, adenoviral, adeno-associated viral and pox viral vectors is presented. In addition, the experimental set-up for shedding analysis including the assays used and biological materials tested is summarized. The collected data based on the analysis of 1619 patients in total demonstrate that shedding of these vectors occurs in practice, mainly determined by the type of vector and the route of vector administration. Due to the use of non-quantitative assays, the lack of information on assay sensitivity in most publications, and the fact that assay sensitivity is expressed in various ways, general conclusions cannot be made as to the level of vector shedding. The evaluation of the potential impact and consequences of the observations is complicated by the high degree of variety in the experimental design of shedding analysis between trials. This inventory can be supportive to clinical gene therapy investigators for the establishment of an evidence-based risk assessment to be included in a clinical protocol application, as well as to national regulatory authorities for the ongoing development of regulatory guidelines regarding gene therapy. PMID:17880045

  3. Vector platforms for gene therapy of inherited retinopathies.

    PubMed

    Trapani, Ivana; Puppo, Agostina; Auricchio, Alberto

    2014-11-01

    Inherited retinopathies (IR) are common untreatable blinding conditions. Most of them are inherited as monogenic disorders, due to mutations in genes expressed in retinal photoreceptors (PR) and in retinal pigment epithelium (RPE). The retina's compatibility with gene transfer has made transduction of different retinal cell layers in small and large animal models via viral and non-viral vectors possible. The ongoing identification of novel viruses as well as modifications of existing ones based either on rational design or directed evolution have generated vector variants with improved transduction properties. Dozens of promising proofs of concept have been obtained in IR animal models with both viral and non-viral vectors, and some of them have been relayed to clinical trials. To date, recombinant vectors based on the adeno-associated virus (AAV) represent the most promising tool for retinal gene therapy, given their ability to efficiently deliver therapeutic genes to both PR and RPE and their excellent safety and efficacy profiles in humans. However, AAVs' limited cargo capacity has prevented application of the viral vector to treatments requiring transfer of genes with a coding sequence larger than 5 kb. Vectors with larger capacity, i.e. nanoparticles, adenoviral and lentiviral vectors are being exploited for gene transfer to the retina in animal models and, more recently, in humans. This review focuses on the available platforms for retinal gene therapy to fight inherited blindness, highlights their main strengths and examines the efforts to overcome some of their limitations. PMID:25124745

  4. 77 FR 73472 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-10

    ...FDA-2012-N-0001] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting...Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General Function...every effort to accommodate persons with physical disabilities or special needs. If...

  5. 76 FR 64951 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-19

    ...FDA-2011-N-0002] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting...Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General Function...every effort to accommodate persons with physical disabilities or special needs. If...

  6. 76 FR 22405 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-21

    ...Committee: Cellular, Tissue and Gene Therapies Advisory Committee. General Function...committee will discuss cellular and gene therapy products for the treatment of retinal...repeat administration or second eye administration, and (3)...

  7. Multimodality Molecular Imaging of Stem Cells Therapy for Stroke

    PubMed Central

    Zhang, Hong; Tian, Mei

    2013-01-01

    Stem cells have been proposed as a promising therapy for treating stroke. While several studies have demonstrated the therapeutic benefits of stem cells, the exact mechanism remains elusive. Molecular imaging provides the possibility of the visual representation of biological processes at the cellular and molecular level. In order to facilitate research efforts to understand the stem cells therapeutic mechanisms, we need to further develop means of monitoring these cells noninvasively, longitudinally and repeatedly. Because of tissue depth and the blood-brain barrier (BBB), in vivo imaging of stem cells therapy for stroke has unique challenges. In this review, we describe existing methods of tracking transplanted stem cells in vivo, including magnetic resonance imaging (MRI), nuclear medicine imaging, and optical imaging (OI). Each of the imaging techniques has advantages and drawbacks. Finally, we describe multimodality imaging strategies as a more comprehensive and potential method to monitor transplanted stem cells for stroke. PMID:24222920

  8. Imaging, Diagnosis, Prognosis Gene Expression Analysis Identifies Potential Biomarkers of

    E-print Network

    Hammerton, James

    Imaging, Diagnosis, Prognosis Gene Expression Analysis Identifies Potential Biomarkers microarray gene expression analysis to define 92 genes that encode putative secreted proteins in neurofibroma sera. Results: Of 13 candidate genes evaluated, only adrenomedullin (ADM) was confirmed

  9. Gene Therapy: The First Approved Gene-Based Medicines, Molecular Mechanisms and Clinical Indications

    Microsoft Academic Search

    J. K. Raty; J. T. Pikkarainen; T. Wirth; S. Yla-Herttuala

    2010-01-01

    As gene therapy has matured from clinical trials to the first commercial products, understanding of the mecha- nisms of gene delivery has increased tremendously. This has also been reflected in viral vector development, creating a number of new approaches to tackle issues in transduction efficiency, biodistribution and viral safety. This review will highlight the most important issues and advancements in

  10. Artificial mammalian gene regulation networks—novel approaches for gene therapy and bioengineering

    Microsoft Academic Search

    Wilfried Weber; Martin Fussenegger

    2002-01-01

    Recently developed strategies for targeted molecular interventions in mammalian cells have created novel opportunities in biotechnological and biomedical research with huge economic and therapeutic impact: the design of mammalian cells with desired phenotypes for biopharmaceutical manufacturing, tissue engineering and gene therapy. These advances have been enabled by constructing artificial gene regulation systems with control modalities similar to those evolved in

  11. Biology students' understanding of cystic fibrosis, gene therapy, and gene screening

    Microsoft Academic Search

    Ruaraidh Hill; Helen OSullivan; Martin Stanisstreet; Edward Boyes

    1998-01-01

    The ideas of 290 Year 1 biology undergraduate students about cystic fibrosis, gene therapy, and gene screening have been explored using a multiple-choice-type questionnaire. Students were reasonably informed about the nature of cystic fibrosis disease, although many underestimated its prevalence. Fewer of the students understood the mechanism of inheritance of cystic fibrosis. Only a third of the students appreciated the

  12. Progress and prospects: gene therapy for inherited immunodeficiencies.

    PubMed

    Qasim, W; Gaspar, H B; Thrasher, A J

    2009-11-01

    Haematopoietic stem cell transplantation (HSCT) is now widely used to treat primary immunodeficiencies (PID). For patients with specific disorders (severe combined immunodeficiency (SCID)-X1, adenosine deaminase deficiency (ADA)-SCID, X-chronic granulomatous disease (CGD) and Wiskott-Aldrich Syndrome (WAS)) who lack a suitable human leukocyte antigen (HLA)-matched donor, gene therapy has offered an important alternative treatment option. The success of gene therapy can be attributed, in part, to the selective advantage offered to gene-corrected cells, the avoidance of graft-versus-host disease and to the use of pre-conditioning in patients with chemotherapy to facilitate engraftment of corrected cells. Adverse events have been encountered and this has led to detailed characterization of retroviral vector integration profiles. A new generation of self-inactivating retroviral and lentiviral vectors have been designed to address these safety concerns, and are at an advanced stage of preparation for the next phase of clinical testing. PMID:19776764

  13. Clinicians’ Expectations for Gene-Driven Cancer Therapy

    PubMed Central

    Jekunen, Antti

    2014-01-01

    A new era of medicine is rapidly approaching, which will change not only pathological diagnosis but also medical decision-making. This paper raises the question of how well prepared doctors are to address the new issues that will soon confront them. The human genome has been completely sequenced and general understanding about cancer biology has increased enormously with understanding that unregulated gene function and complicated changes in signal pathways are related to uncontrolled cell growth. Thus, gene-driven therapy involving alterations to genes are recognized to present new therapy options. This advance will necessitate major changes to the decision-making aspect of physicians. This article focuses on defining the pertinent changes and addressing what they mean for practicing physicians. PMID:25574148

  14. Radiopeptide imaging and therapy in Europe.

    PubMed

    Ambrosini, Valentina; Fani, Melpomeni; Fanti, Stefano; Forrer, Flavio; Maecke, Helmut R

    2011-12-01

    Receptor targeting with radiolabeled peptides has become an important topic, particularly in nuclear oncology. Strong research efforts are under way in radiopharmaceutical science laboratories and in nuclear medicine departments in Europe. The target receptors belong to the large family of G-protein-coupled receptors. The prototypes of these radiopeptides are based on analogs of somatostatin targeting somatostatin receptor-positive tumors, particularly well-differentiated neuroendocrine tumors. These radiopeptides have an important impact not only on diagnosis but also on targeted radionuclide therapy of these tumors. Besides the registered radiopeptide (111)In-pentetreotide, efficient SPECT tracers labeled with (99m)Tc and PET agents based on generator-produced (68)Ga have been developed and used in the clinic. In parallel to the development of diagnostic agents, radiopeptides labeled with the ?(-) emitters (90)Y and (177)Lu are also widely used. Because the same chelators and therefore the same conjugates can be used in diagnosis and therapy, they constitute ideal theranostic pairs. This progress is driven not only by scientists and clinicians but also by patient interest groups. New radiopeptides targeting other G-protein-coupled receptors are entering the clinic, among them glucagon-like peptide 1 receptor-targeting molecules. This receptor is overexpressed on literally all benign insulinomas. (111)In-labeled derivatives of the insulinotropic 39-mer peptide exendin-4 were beneficial in the pre- and perioperative localization of these benign lesions. In contrast, lack of localization may indicate malignant insulinoma. The bombesin- and gastrin-releasing peptide receptor family is potentially important because these receptors are overexpressed on major human tumors such as prostate tumors, breast tumors, gastrointestinal stromal tumors, and vessels of ovarian cancer. (99m)Tc-labeled peptides for SPECT and (68)Ga-, as well as (64)Cu-labeled agonists or antagonists, have been studied in breast tumors, prostate tumors, gastrointestinal stromal tumors, and gliomas with considerable success. A phase I therapeutic study with a (177)Lu-labeled agonist has been completed. There are not enough clinical data available to reveal the significance of these new modalities in patient care, but several phase I studies are under way in larger patient cohorts using PET agents. Another G-protein-coupled receptor with high overexpression on human tumors is the gastrin/cholecystokinin-2 receptor. It is overexpressed in more than 90% of cases of medullary thyroid cancer, in small cell lung cancer, and in a subgroup of neuroendocrine tumors. Correlating with in vitro receptor localization using autoradiography of 27 patients with metastasized medullary thyroid cancer, SPECT or planar imaging of these patients resulted in a 95% sensitivity of tumor localization. Finally, another G-protein-coupled receptor is found in brain tumors and peritumoral vessels. Literally all cases of glioblastoma multiforme overexpress the neurokinin type 1 receptor; the natural ligand is substance P, which was metabolically stabilized, labeled with (90)Y and (213)Bi, and injected into resection cavities or directly into tumors, which were critically located via a catheter system. The major advantage of this approach appeared to be the facilitated resectability of tumors, particularly in those patients who had been treated up front with the locoregional approach. It appears that neoadjuvant treatment before resection is a valid concept. Finally, another peptide family, the arginine-glycine-aspartate-based radiotracers, has made it to the clinic labeled with a variety of radioisotopes for monitoring the integrins ?(v)?(3) overexpressed during tumor angiogenesis. PMID:22144555

  15. Laser-Based Gene Transfection and Gene Therapy

    Microsoft Academic Search

    Cui-Ping Yao; Zhen-Xi Zhang; Ramtin Rahmanzadeh; Gereon Huettmann

    2008-01-01

    The plasma membrane of mammalian cells can be transiently permeablized by optical means and exogenous materials or genes can be introduced into the cytoplasm of living cells. Until now, few mechanisms were exploited for the manipulation: laser is directly and tightly focused on the cells for optoinjection, laser-induced stress waves, photochemical internalization, and irradiation of selective cell targeting with light-absorbing

  16. 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) ­ Bachelor of Radiologic and Imaging Sciences Technology [RE-BRIT-RIS-RTAA] Regional College Catalog Year Hours] Note: Students must have earned an AAS degree in Radiologic Technology (36 semester credits from

  17. Recombinant Adenovirus Deleted of All Viral Genes for Gene Therapy of Cystic Fibrosis

    Microsoft Academic Search

    KRISHNA J. FISHER; HESTER CHOI; JOHN BURDA; SHU-JEN CHEN; JAMES M. WILSON

    1996-01-01

    Recombinant adenoviruses are being developed for gene therapy of inherited disorders such as cystic fibrosis because they efficiently transduce recombinant genes into nondividing cellsin 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

  18. 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

  19. 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

  20. Role of imaging in neoadjuvant therapy for breast cancer.

    PubMed

    Dialani, Vandana; Chadashvili, Tamuna; Slanetz, Priscilla J

    2015-05-01

    Neoadjuvant chemotherapy (NAC) involves administration of chemotherapeutic agents to patients with newly diagnosed breast cancer prior to definitive surgical treatment. Assessment of disease response to chemotherapeutic agents in vivo prior to any surgical intervention is necessary as medical oncologists are commonly tailoring or changing therapy during NAC based on response. It can also maximize the pathologic complete response (pCR) rate, resulting in more women undergoing breast conservation rather than mastectomy. Although some studies show a pCR to NAC in only 13-26 % of women, recent studies have shown higher pCR rates, especially for HER2-positive disease treated with targeted anti-HER2 therapy. Thus, accurate imaging tools for quantifying disease response are critical in the evaluation and management of patients undergoing NAC. There is currently no standard imaging method for monitoring response to therapy. Response to therapy tends to vary by tumor subtype and can be accurately assessed on imaging. We review the role of imaging before and after neoadjuvant therapy and discuss the advantages and limitations of currently available modalities, including mammography, ultrasonography, magnetic resonance imaging, and nuclear imaging. PMID:25727555

  1. 75 FR 54351 - Cell and Gene Therapy Clinical Trials in Pediatric Populations; Public Workshop

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-07

    ...Administration [Docket No. FDA-2010-N-0001] Cell and Gene Therapy Clinical Trials in Pediatric...announcing a public workshop entitled ``Cell and Gene Therapy Clinical Trials in Pediatric...stakeholders regarding best practices related to cell and gene therapy clinical trials in...

  2. Progress in developing cationic systems for non-viral vector systemic gene therapy against cancer

    E-print Network

    Paris-Sud XI, Université de

    1 Progress in developing cationic systems for non-viral vector systemic gene therapy against cancer;29(24-25):3477-96" DOI : 10.1016/j.biomaterials.2008.04.036 #12;2 Abstract: Initially, gene therapy was viewed with these carriers, the aim of this review is to describe the "perfect vector" for systemic gene therapy against

  3. HUMAN GENE THERAPY 18:367378 (April 2007) Mary Ann Liebert, Inc.

    E-print Network

    Schaffer, David V.

    HUMAN GENE THERAPY 18:367­378 (April 2007) © Mary Ann Liebert, Inc. DOI: 10.1089/hum.2006-associated virus (AAV) is a promising vehicle for gene therapy, which will rely on the generation of high SUMMARY Adeno-associated virus (AAV) is promising a vehicle for gene therapy. However, numerous

  4. HUMAN GENE THERAPY 14:12551264 (September 1, 2003) Mary Ann Liebert, Inc.

    E-print Network

    Kay, Mark A.

    HUMAN GENE THERAPY 14:1255­1264 (September 1, 2003) © Mary Ann Liebert, Inc. System, PETER D. PENG, and MARK A. KAY ABSTRACT Gene therapy has been proposed as an alternative strategy, thereby considerably enhancing the therapeutic win- dow of gene therapy. 1255 OVERVIEW SUMMARY We have

  5. HUMAN GENE THERAPY 18:8187 (January 2007) Mary Ann Liebert, Inc.

    E-print Network

    Engelhardt, John F.

    HUMAN GENE THERAPY 18:81­87 (January 2007) © Mary Ann Liebert, Inc. DOI: 10.1089/hum.2006.128 Brief., 2003). These studies have paved the way for the use of dual-vector trans-splicing in human gene therapy). 1Department of Anatomy and Cell Biology, 2Center for Gene Therapy, and 3Department of Internal

  6. HUMAN GENE THERAPY 18:871880 (October 2007) Mary Ann Liebert, Inc.

    E-print Network

    Kay, Mark A.

    HUMAN GENE THERAPY 18:871­880 (October 2007) © Mary Ann Liebert, Inc. DOI: 10.1089/hum.2007 therapy of dominantly active mutant alleles, and to the investigation of normal gene function in animal delivery of RNAi constructs offers a powerful and versatile approach for both gene therapy and the analysis

  7. ABCA4 disease progression and a proposed strategy for gene therapy

    E-print Network

    Palczewski, Krzysztof

    ABCA4 disease progression and a proposed strategy for gene therapy Artur V. Cideciyan1,Ã?- retinal gene therapy will aim to arrest disease progression in the extramacular retina. In 66 individuals in ABCA4 disease. INTRODUCTION Human ocular gene therapy success in a rare autosomal reces- sive blindness

  8. The American Society of Gene & Cell Therapy letter to the editor

    E-print Network

    Barbas III, Carlos F.

    proof of concept for a gene therapy approach in cell and animal models, they gener- ally lack© The American Society of Gene & Cell Therapy letter to the editor large budgets by various contrasts sharply with the relatively limited budgets that have been available for gene therapy research

  9. Unique risk factors for insertional mutagenesis in a mouse model of XSCID gene therapy

    Microsoft Academic Search

    Yan Shou; Zhijun Ma; Taihe Lu; Brian P. Sorrentino

    2006-01-01

    Although gene therapy can cure patients with severe combined immunodeficiency (SCID) syndromes, the clinical occurrence of T cell malignancies due to insertional mutagenesis has raised concerns about the safety of gene therapy. Several key questions have remained unanswered: (i) are there unique risk factors for X-linked SCID (XSCID) gene therapy that increase the risk of insertional mutagenesis; (ii) what other

  10. Qualitative study of cystic fibrosis(CF) patients' expectations of gene therapy 

    E-print Network

    Jannetta, Evelyn Elena

    2009-11-27

    Introduction: Gene therapy is currently being developed for people with cystic fibrosis (CF), a life-threatening condition for which there is no cure. The UK CF Gene Therapy Consortium are preparing for a multi-dose gene therapy trial of sufficient...

  11. 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

  12. [CANCER RESEARCH 64, 53905397, August 1, 2004] Effective Gene-Viral Therapy for Telomerase-Positive Cancers by Selective

    E-print Network

    Tian, Weidong

    , can exploit the virtues of gene therapy and virotherapy and overcome the limitations of conventional to achieve synergistic effect by combining virotherapy with gene therapy, chemotherapy, or radiotherapy

  13. 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

  14. Gene therapy for PIDs: progress, pitfalls and prospects.

    PubMed

    Mukherjee, Sayandip; Thrasher, Adrian J

    2013-08-10

    Substantial progress has been made in the past decade in treating several primary immunodeficiency disorders (PIDs) with gene therapy. Current approaches are based on ex-vivo transfer of therapeutic transgene via viral vectors to patient-derived autologous hematopoietic stem cells (HSCs) followed by transplantation back to the patient with or without conditioning. The overall outcome from all the clinical trials targeting different PIDs has been extremely encouraging but not without caveats. Malignant outcomes from insertional mutagenesis have featured prominently in the adverse events associated with these trials and have warranted intense pre-clinical investigation into defining the tendencies of different viral vectors for genomic integration. Coupled with issues pertaining to transgene expression, the therapeutic landscape has undergone a paradigm shift in determining safety, stability and efficacy of gene therapy approaches. In this review, we aim to summarize the progress made in the gene therapy trials targeting ADA-SCID, SCID-X1, CGD and WAS, review the pitfalls, and outline the recent advancements which are expected to further enhance favourable risk benefit ratios for gene therapeutic approaches in the future. PMID:23566838

  15. Gene therapy for PIDs: Progress, pitfalls and prospects

    PubMed Central

    Mukherjee, Sayandip; Thrasher, Adrian J.

    2013-01-01

    Substantial progress has been made in the past decade in treating several primary immunodeficiency disorders (PIDs) with gene therapy. Current approaches are based on ex-vivo transfer of therapeutic transgene via viral vectors to patient-derived autologous hematopoietic stem cells (HSCs) followed by transplantation back to the patient with or without conditioning. The overall outcome from all the clinical trials targeting different PIDs has been extremely encouraging but not without caveats. Malignant outcomes from insertional mutagenesis have featured prominently in the adverse events associated with these trials and have warranted intense pre-clinical investigation into defining the tendencies of different viral vectors for genomic integration. Coupled with issues pertaining to transgene expression, the therapeutic landscape has undergone a paradigm shift in determining safety, stability and efficacy of gene therapy approaches. In this review, we aim to summarize the progress made in the gene therapy trials targeting ADA-SCID, SCID-X1, CGD and WAS, review the pitfalls, and outline the recent advancements which are expected to further enhance favourable risk benefit ratios for gene therapeutic approaches in the future. PMID:23566838

  16. 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

  17. Pancreatic Cancer Gene Therapy: From Molecular Targets to Delivery Systems

    PubMed Central

    Fillat, Cristina; Jose, Anabel; Ros, Xavier Bofill-De; Mato-Berciano, Ana; Maliandi, Maria Victoria; Sobrevals, Luciano

    2011-01-01

    The continuous identification of molecular changes deregulating critical pathways in pancreatic tumor cells provides us with a large number of novel candidates to engineer gene-targeted approaches for pancreatic cancer treatment. Targets—both protein coding and non-coding—are being exploited in gene therapy to influence the deregulated pathways to facilitate cytotoxicity, enhance the immune response or sensitize to current treatments. Delivery vehicles based on viral or non-viral systems as well as cellular vectors with tumor homing characteristics are a critical part of the design of gene therapy strategies. The different behavior of tumoral versus non-tumoral cells inspires vector engineering with the generation of tumor selective products that can prevent potential toxic-associated effects. In the current review, a detailed analysis of the different targets, the delivery vectors, the preclinical approaches and a descriptive update on the conducted clinical trials are presented. Moreover, future possibilities in pancreatic cancer treatment by gene therapy strategies are discussed. PMID:24212620

  18. 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

  19. 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

  20. Gene therapy for trigeminal pain in mice

    PubMed Central

    Tzabazis, Alexander Z.; Klukinov, Michael; Feliciano, David P.; Wilson, Steven P.; Yeomans, David C.

    2014-01-01

    The aim of this study was to test the efficacy of a single direct injection of viral vector encoding for encephalin to induce a widespread expression of the transgene and potential analgesic effect in trigeminal behavioral pain models in mice. After direct injection of HSV-1 based vectors encoding for human preproenkephalin (SHPE) or the lacZ reporter gene (SHZ.1, control virus) into the trigeminal ganglia in mice, we performed an orofacial formalin test and assessed the cumulative nociceptive behavior at different time points after injection of the viral vectors. We observed an analgesic effect on nociceptive behavior that lasted up to 8 weeks after a single injection of SHPE into the trigeminal ganglia. Control virus injected animals showed nociceptive behavior similar to naïve mice. The analgesic effect of SHPE injection was reversed/attenuated by subcutaneous naloxone injections, a ?-opioid receptor antagonist. SHPE injected mice also showed normalization in withdrawal latencies upon thermal noxious stimulation of inflamed ears after subdermal complete Freund’s adjuvans injection indicating widespread expression of the transgene. Quantitative immunohistochemistry of trigeminal ganglia showed expression of human preproenkephalin after SHPE injection. Direct injection of viral vectors proved to be useful for exploring the distinct pathophysiology of the trigeminal system and could also be an interesting addition to the pain therapists’ armamentarium. PMID:24572785

  1. Imaging gene expression in single living cells

    Microsoft Academic Search

    Yaron Shav-Tal; Xavier Darzacq; Robert H. Singer

    2004-01-01

    Technical advances in the field of live-cell imaging have introduced the cell biologist to a new, dynamic, subcellular world. The static world of molecules in fixed cells has now been extended to the time dimension. This allows the visualization and quantification of gene expression and intracellular trafficking events of the studied molecules and the associated enzymatic processes in individual cells,

  2. Arthritis Gene Therapy and its Tortuous Path into the Clinic

    PubMed Central

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

    2013-01-01

    Arthritis is a disease of joints. The biology of joints makes them very difficult targets for drug delivery in a manner that is specific and selective. This is especially true for proteinaceous drugs (“biologics”). Gene transfer is the only technology that can solve the delivery problem in a clinically reasonable fashion. There is an abundance of pre-clinical data confirming that genes can be efficiently transferred to tissues within joints by intra-articular injection using a variety of different vectors in conjunction with ex vivo and in vivo strategies. Using the appropriate gene transfer technologies, long-term, intra-articular expression of anti-arthritic transgenes at therapeutic concentrations can be achieved. Numerous studies confirm that gene therapy is effective in treating experimental models of rheumatoid arthritis (RA) and osteoarthritis (OA) in the laboratory. A limited number of clinical trials have been completed, which confirm safety and feasibility but only three protocols have reached Phase II; as yet, there is no unambiguous evidence of efficacy in human disease. Only two clinical trials are presently underway, both Phase II studies using allogeneic chondrocytes expressing TGF-?1 for the treatment of OA. Phase I studies using adeno-associated virus to deliver IL-1Ra in OA and IFN-? in RA are going through the regulatory process. It is to be hoped that the recent successes in treating rare, Mendelian diseases by gene therapy will lead to accelerated development of genetic treatments for common, non-Medelian diseases, such as arthritis. PMID:23369825

  3. 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

  4. 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

  5. Gene and cell-mediated therapies for muscular dystrophy.

    PubMed

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

    2013-05-01

    Duchenne muscular dystrophy (DMD) is a devastating muscle disorder that affects 1 in 3,500 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, more 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 nonviral 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

  6. Prevention of peritoneal adhesions: A promising role for gene therapy

    PubMed Central

    Atta, Hussein M

    2011-01-01

    Adhesions are the most frequent complication of abdominopelvic surgery, yet the extent of the problem, and its serious consequences, has not been adequately recognized. Adhesions evolved as a life-saving mechanism to limit the spread of intraperitoneal inflammatory conditions. Three different pathophysiological mechanisms can independently trigger adhesion formation. Mesothelial cell injury and loss during operations, tissue hypoxia and inflammation each promotes adhesion formation separately, and potentiate the effect of each other. Studies have repeatedly demonstrated that interruption of a single pathway does not completely prevent adhesion formation. This review summarizes the pathogenesis of adhesion formation and the results of single gene therapy interventions. It explores the promising role of combinatorial gene therapy and vector modifications for the prevention of adhesion formation in order to stimulate new ideas and encourage rapid advancements in this field. PMID:22171139

  7. 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

  8. Baculovirus vectors for antiangiogenesis-based cancer gene therapy

    Microsoft Academic Search

    W-Y Luo; Y-S Shih; W-H Lo; H-R Chen; S-C Wang; C-H Wang; C-H Chien; C-S Chiang; Y-J Chuang; Y-C Hu

    2011-01-01

    Baculovirus is an insect virus that is non-pathogenic to humans and has emerged as a promising gene therapy vector. Since solid tumor growth\\/metastasis critically relies on angiogenesis and hEA, a fusion protein comprising human endostatin and angiostatin, exhibits potent antiangiogenic and antitumor efficacy in mouse models; this study aimed to evaluate the feasibility of baculovirus for hEA expression and antiangiogenesis-based

  9. New strategy for monitoring targeted therapy: molecular imaging

    PubMed Central

    Teng, Fei-Fei; Meng, Xue; Sun, Xin-Dong; Yu, Jin-Ming

    2013-01-01

    Targeted therapy is becoming an increasingly important component in the treatment of cancer. How to accurately monitor targeted therapy has been crucial in clinical practice. The traditional approach to monitor treatment through imaging has relied on assessing the change of tumor size by refined World Health Organization criteria, or more recently, by the Response Evaluation Criteria in Solid Tumors. However, these criteria, which are based on the change of tumor size, show some limitations for evaluating targeted therapy. Currently, genetic alterations are identified with prognostic as well as predictive potential concerning the use of molecularly targeted drugs. Conversely, considering the limitations of invasiveness and the issue of expression heterogeneity, molecular imaging is better able to assay in vivo biologic processes noninvasively and quantitatively, and has been a particularly attractive tool for monitoring treatment in clinical cancer practice. This review focuses on the applications of different kinds of molecular imaging including positron emission tomography-, magnetic resonance imaging-, ultrasonography-, and computed tomography-based imaging strategies on monitoring targeted therapy. In addition, the key challenges of molecular imaging are addressed to successfully translate these promising techniques in the future. PMID:24124361

  10. Cytokine and immuno-gene therapy for solid tumors.

    PubMed

    Li, Chuan-Yuan; Huang, Qian; Kung, Hsiang-Fu

    2005-04-01

    Despite recent progress in our understanding of cancer biology and in many areas of cancer treatment, the success rate for cancer therapy remains dismal. Immunotherapy for cancer has long been an exciting field for many cancer researchers due to the possibility to mobilize the body's own immune system to eradicate cancer not only locally but also systemically. Since its initial discovery, cytokine-based immunotherapy has been vigorously and extensively investigated for cancer treatment due to the perception of it as a relatively easily purifiable, injectable form of cancer treatment agent. However, so far most cytokine-based therapy trials have fallen short of expectations. One of main obstacles is the difficulty to achieve therapeutically relevant dosage in patients without generating excessive normal tissue toxicity. The emergence of novel gene therapy approach to deliver therapeutic cytokine to tumors locally generated great excitement since it has the potential of generating sustained high local concentration of immunostimulatory cytokine without raising the systemic levels of the cytokines, which is responsible for most of the observed toxicity. In this review, we will attempt to provide an overview of the field and discuss some of the problems associated with cytokine-based immuno-gene therapy and potential solutions. PMID:16191413

  11. The Fate of Mesenchymal Stem Cells Transplanted into Immunocompetent Neonatal Mice: Implications for Skeletal Gene Therapy via Stem Cells

    Microsoft Academic Search

    Christopher Niyibizi; Sujing Wang; Zhibao Mi; Paul D. Robbins

    2004-01-01

    To explore the feasibility of skeletal gene and cell therapies, we transduced murine bone marrow-derived mesenchymal stem cells (MSCs) with a retrovirus carrying the enhanced green fluorescent protein and zeocin-resistance genes prior to transplantation into 2-day-old immunocompetent neonatal mice. Whole-body imaging of the recipient mice at 7 days post-systemic cell injection demonstrated a wide distribution of the cells in vivo.

  12. Neurotrophic gene polymorphisms and response to psychological therapy

    PubMed Central

    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

  13. Imaging: Guiding the Clinical Translation of Cardiac Stem Cell Therapy

    PubMed Central

    Nguyen, Patricia K.; Lan, Feng; Wang, Yongming; Wu, Joseph C.

    2011-01-01

    Stem cells have been touted as the holy grail of medical therapy with promises to regenerate cardiac tissue, but it appears the jury is still out on this novel therapy. Using advanced imaging technology, scientists have discovered that these cells do not survive nor engraft long-term. In addition, only marginal benefit has been observed in large animal studies and human trials. However, all is not lost. Further application of advanced imaging technology will help scientists unravel the mysteries of stem cell therapy and address the clinical hurdles facing its routine implementation. In this review, we will discuss how advanced imaging technology will help investigators better define the optimal delivery method, improve survival and engraftment, and evaluate efficacy and safety. Insights gained from this review may direct the development of future preclinical investigations and clinical trials. PMID:21960727

  14. Multimodality Imaging of Gene Transfer with a Receptor-Based Reporter Gene

    PubMed Central

    Chen, Ron; Parry, Jesse J.; Akers, Walter J.; Berezin, Mikhail Y.; El Naqa, Issam M.; Achilefu, Samuel; Edwards, W. Barry; Rogers, Buck E.

    2010-01-01

    Gene therapy trials have traditionally used tumor and tissue biopsies for assessing the efficacy of gene transfer. Non-invasive imaging techniques offer a distinct advantage over tissue biopsies in that the magnitude and duration of gene transfer can be monitored repeatedly. Human somatostatin receptor subtype 2 (SSTR2) has been used for the nuclear imaging of gene transfer. To extend this concept, we have developed a somatostatin receptor–enhanced green fluorescent protein fusion construct (SSTR2-EGFP) for nuclear and fluorescent multimodality imaging. Methods An adenovirus containing SSTR2-EGFP (AdSSTR2-EGFP) was constructed and evaluated in vitro and in vivo. SCC-9 human squamous cell carcinoma cells were infected with AdEGFP, AdSSTR2, or AdSSTR2-EGFP for in vitro evaluation by saturation binding, internalization, and fluorescence spectroscopy assays. In vivo biodistribution and nano-SPECT imaging studies were conducted with mice bearing SCC-9 tumor xenografts directly injected with AdSSTR2-EGFP or AdSSTR2 to determine the tumor localization of 111In-diethylenetriaminepentaacetic acid (DTPA)-Tyr3-octreotate. Fluorescence imaging was conducted in vivo with mice receiving intratumoral injections of AdSSTR2, AdSSTR2-EGFP, or AdEGFP as well as ex vivo with tissues extracted from mice. Results The similarity between AdSSTR2-EGFP and wild-type AdSSTR2 was demonstrated in vitro by the saturation binding and internalization assays, and the fluorescence emission spectra of cells infected with AdSSTR2-EGFP was almost identical to the spectra of cells infected with wild-type AdEGFP. Biodistribution studies demonstrated that the tumor uptake of 111In-DTPA-Tyr3-octreotate was not significantly different (P > 0.05) when tumors (n = 5) were injected with AdSSTR2 or AdSSTR2-EGFP but was significantly greater than the uptake in control tumors. Fluorescence was observed in tumors injected with AdSSTR2-EGFP and AdEGFP in vivo and ex vivo but not in tumors injected with AdSSTR2. Although fluorescence was observed, there were discrepancies between in vivo imaging and ex vivo imaging as well as between nuclear imaging and fluorescent imaging. Conclusion These studies showed that the SSTR2-EGFP fusion construct can be used for in vivo nuclear and optical imaging of gene transfer. PMID:20720053

  15. Far-red fluorescence gene reporter tomography for determination of placement and viability of cell-based gene therapies

    PubMed Central

    Lu, Yujie; Darne, Chinmay D.; Tan, I-Chih; Zhu, Banghe; Hall, Mary A.; Lazard, ZaWaunyka W.; Davis, Alan R.; Simpson, LaShan; Sevick-Muraca, Eva M.; Olmsted-Davis, Elizabeth A.

    2013-01-01

    Non-invasive injectable cellular therapeutic strategies based on sustained delivery of physiological levels of BMP-2 for spinal fusion are emerging as promising alternatives, which could provide sufficient fusion without the associated surgical risks. However, these injectable therapies are dependent on bone formation occurring only at the specific target region. In this study, we developed and deployed fluorescence gene reporter tomography (FGRT) to provide information on in vivo cell localization and viability. This information is sought to confirm the ideal placement of the materials with respect to the area where early bone reaction is required, ultimately providing three dimensional data about the future fusion. However, because almost all conventional fluorescence gene reporters require visible excitation wavelengths, current in vivo imaging of fluorescent proteins is limited by high tissue absorption and confounding autofluorescence. We previously administered fibroblasts engineered to produce BMP-2, but is difficult to determine 3-D information of placement prior to bone formation. Herein we used the far-red fluorescence gene reporter, IFP1.4 to report the position and viability of fibroblasts and developed 3-D tomography to provide placement information. A custom small animal, far-red fluorescence tomography system integrated into a commercial CT scanner was used to assess IFP1.4 fluorescence and to demark 3-D placement of encapsulated fibroblasts with respect to the vertebrae and early bone formation as assessed from CT. The results from three experiments showed that the placement of the materials within the spine could be detected. This work shows that in vivo fluorescence gene reporter tomography of cell-based gene therapy is feasible and could help guide cell-based therapies in preclinical models. PMID:24104323

  16. Nuclear medicine imaging and therapy of neuroendocrine tumours

    PubMed Central

    Gotthardt, Martin; Dijkgraaf, Ingrid; Boerman, Otto C; Oyen, Wim J G

    2006-01-01

    Radiolabelled peptides are used for specific targeting of receptors (over-)expressed by tumour cells. Dependent on the kind of labelling and the radionuclide used, these compounds may be utilised for imaging or for therapy. A concise overview is provided on basic principles of designing and developing radiopeptides for these applications. Furthermore, clinical application of these compounds for imaging and therapy is described. Advantages of the method compared to other techniques (such as the use of radiolabelled antibodies or antibody fragments) are discussed as well as pitfalls and limitations. PMID:17114073

  17. Imaging Biomarkers for Intra-arterial Stroke Therapy

    PubMed Central

    Berkhemer, Olvert A.; Kamalian, Shervin; González, R. Gilberto; Majoie, Charles B. L. M.; Yoo, Albert J.

    2014-01-01

    Despite high rates of early revascularization with intra-arterial stroke therapy, the clinical efficacy of this approach has not been clearly demonstrated. Neuroimaging biomarkers will be useful in future trials for patient selection and for outcomes evaluation. To identify patients who are likely to benefit from intra-arterial therapy, the combination of vessel imaging, infarct size quantification and degree of neurologic deficit appears critical. Perfusion imaging may be useful in specific circumstances, but requires further validation. For measuring treatment outcomes, surrogate biomarkers that appear suitable are angiographic reperfusion as measured by the modified Thrombolysis in Cerebral Infarction scale and final infarct volume. PMID:24932316

  18. Image-guided, noninvasive, spatiotemporal control of gene expression

    PubMed Central

    Deckers, Roel; Quesson, Bruno; Arsaut, Josette; Eimer, Sandrine; Couillaud, Franck; Moonen, Chrit T. W.

    2009-01-01

    Spatiotemporal control of transgene expression is of paramount importance in gene therapy. Here, we demonstrate the use of magnetic resonance temperature imaging (MRI)-guided, high-intensity focused ultrasound (HIFU) in combination with a heat-inducible promoter [heat shock protein 70 (HSP70)] for the in vivo spatiotemporal control of transgene activation. Local gene activation induced by moderate hyperthermia in a transgenic mouse expressing luciferase under the control of the HSP70 promoter showed a high similarity between the local temperature distribution in vivo and the region emitting light. Modulation of gene expression is possible by changing temperature, duration, and location of regional heating. Mild heating protocols (2 min at 43°C) causing no tissue damage were sufficient for significant gene activation. The HSP70 promoter was shown to be induced by the local temperature increase and not by the mechanical effects of ultrasound. Therefore, the combination of MRI-guided HIFU heating and transgenes under control of heat-inducible HSP promoter provides a direct, noninvasive, spatial control of gene expression via local hyperthermia. PMID:19164593

  19. Bioelectrical strategies for image-guided therapies

    E-print Network

    Barley, Maya

    2007-01-01

    There is a pressing need in minimally-invasive surgery for novel imaging methods that can rapidly and accurately localize the surgical instrument and its target. We have developed two novel localization methods for the ...

  20. The Life Cycle of Images: Revisiting the Ethical Treatment of the Art Therapy Image

    ERIC Educational Resources Information Center

    Hinz, Lisa D.

    2013-01-01

    Using the metaphor of the human life cycle, the author of this viewpoint suggests that consideration of the birth, life, and death of images made in art therapy may promote a new perspective on their ethical treatment. A developmental view of images encourages art therapists to see art images as living entities that undergo a natural life cycle.…

  1. 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 of Radiologic Imaging Sciences Technology [RE-BRIT-RIS-RTFE] Regional College Catalog Year: 2012-2013 Page 1 Semester Seven (Summer): [2 Credit Hours] RIS 44000 Introduction to Radiologic Imaging Sciences 2 C

  2. Novel adeno-associated viral vectors for retinal gene therapy.

    PubMed

    Vandenberghe, L H; Auricchio, A

    2012-02-01

    Vectors derived from adeno-associated virus (AAV) are currently the most promising vehicles for therapeutic gene delivery to the retina. Recently, subretinal administration of AAV2 has been demonstrated to be safe and effective in patients with a rare form of inherited childhood blindness, suggesting that AAV-mediated retinal gene therapy may be successfully extended to other blinding conditions. This is further supported by the great versatility of AAV as a vector platform as there are a large number of AAV variants and many of these have unique transduction characteristics useful for targeting different cell types in the retina including glia, epithelium and many types of neurons. Naturally occurring, rationally designed or in vitro evolved AAV vectors are currently being utilized to transduce several different cell types in the retina and to treat a variety of animal models of retinal disease. The continuous and creative development of AAV vectors provides opportunities to overcome existing challenges in retinal gene therapy such as efficient transfer of genes exceeding AAV's cargo capacity, or the targeting of specific cells within the retina or transduction of photoreceptors following routinely used intravitreal injections. Such developments should ultimately advance the treatment of a wide range of blinding retinal conditions. PMID:21993172

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

    PubMed

    Ferrazzi, F; Bellazzi, R; Engel, F 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

  4. Immunological Monitoring to Rationally Guide AAV Gene Therapy.

    PubMed

    Britten, Cedrik Michael; Walter, Steffen; Janetzki, Sylvia

    2013-01-01

    Recent successes with adeno-associated virus (AAV)-based gene therapies fuel the hope for new treatments for hereditary diseases. Pre-existing as well as therapy-induced immune responses against both AAV and the encoded transgenes have been described and may impact on safety and efficacy of gene therapy approaches. Consequently, monitoring of vector- and transgene-specific immunity is mandated and may rationally guide clinical development. Next to the humoral immune response, the cellular response is central in our understanding of the host reaction in gene therapy. But in contrast to the monitoring of antibodies, which has matured over many decades, sensitive and robust monitoring of T cells is a relatively new development. To make cellular immune assessments fit for purpose, investigators need to know, control and report the critical assay variables that influence the results. In addition, the quality of immune assays needs to be continuously adjusted to allow for exploratory hypothesis generation in early stages and confirmatory hypothesis validation in later stages of clinical development. The concept of immune assay harmonization which includes use of field-wide benchmarks, harmonization guidelines, and external quality control can support the context-specific evolution of immune assays. Multi-center studies pose particular challenges to sample logistics and quality control of sample specimens. Cooperative groups need to define if immune assessments should be performed in one central facility, in peripheral labs or including a combination of both. Finally, engineered reference samples that contain a defined number of antigen-specific T cells may become broadly applicable tools to control assay performance over time or across institutions. PMID:24062741

  5. Magnetic resonance nanoparticles for cardiovascular molecular imaging and therapy.

    PubMed

    Cyrus, Tillmann; Winter, Patrick M; Caruthers, Shelton D; Wickline, Samuel A; Lanza, Gregory M

    2005-07-01

    Molecular vascular imaging represents a novel tool that promises to change the current medical paradigm of 'see and treat' to a 'detect and prevent' strategy. Nanoparticle agents, such as superparamagnetic nanoparticles and perfluorocarbon nanoparticle emulsions, have been developed for noninvasive imaging, particularly for magnetic resonance imaging. Designed to target specific epitopes in tissues, these agents are beginning to enter clinical trials for cardiovascular applications. The delivery of local therapy with these nanoparticles, using mechanisms such as contact-facilitated drug delivery, is in the advanced stages of preclinical research. Ultimately, combined diagnostic and therapeutic nanoparticle formulations may allow patients to be characterized noninvasively and segmented to receive custom-tailored therapy. This review focuses on recent developments of nanoparticle technologies with an emphasis on cardiovascular applications of magnetic resonance imaging. PMID:16076280

  6. A novel PET tracer for evaluation of gene therapy

    SciTech Connect

    Goldman, S.; Monclus, M.; Cool, V. [Cliniques Universitaires de Bruxelles-Hopital Erasme, Brussels (Belgium)] [and others

    1996-05-01

    A promising approach of gene therapy for cancer consist in the transduction of neoplastic cells with the herpes virus thymidine-kinase gene (HSV-tk) which renders transduced cells sensitive to the lethal effect of anti-viral agent such as ganciclovir (GCV). Pet with adapted radiotracers represents an adequate tool to determine in vivo the level of HSV-tk expression and to establish the optimal protocol of gene and GCV administrations in human. We have developed a new potential PET tracer, 9-((1-[F-18]fluoro-3-hydroxy-2-propoxy)methyl)guanine [F-18]FHPG should theoretically accumulate in cells expressing HSV-tk. [F-18]FHPG was obtained by nucleophilic substitution on a ditosylate precursor followed by hydrolysis. To determine the biological behavior of this compound, we synthetized the corresponding non radioactive fluorinated analog (FHPG) and tested its inhibitory activity on HSV-tk transduced 9L gliosarcoma cells maintained in culture. FHPG at 100 {mu}M suppress cell growth by 50% while GCV and acyclovir induced 100% suppression at 10 and 100 {mu}M, respectively. We then tested the in vitro uptake of n.c.a. [F-18]FHPG in cultured cells transduced with HSV-tk or a control gene (neomycin). Ratio of [F-18]FHPG uptake in HSV-tk versus control cells was 240 after 6 hours of incubation. In vivo uptake of [F-18]FHPG was tested in experimental tumors obtained by stereotactical implantion of transduced 9L cells in the brain of male Fischer 344 rats. Ratio of [F-18]FHPG uptake in HSV-tk versus control tumors was 2.5, 3 hours after intravenous tracer injection. Uptake in HSV-tk tumor was 19-fold higher than in the cortex. We concluded that [F-18]FHPG is a promising PET tracer for the evaluation of gene therapy involving viral thymidine kinase genes.

  7. Head and neck cancer: gene therapy approaches. Part II: genes delivered.

    PubMed

    Nemunaitis, John; O'Brien, John

    2002-03-01

    In Part I, the review summarised the safety of adenoviral vectors and provided insight into approaches being undertaken to improve the specificity, durability and potency of adenoviral delivery vehicles. In Part II, brief discussions are held regarding results of preclinical and clinical trials with a variety of different genes, which have demonstrated antitumour activity in squamous cell carcinoma of the head and neck region (HNSCC). Studies have been performed with a variety of immune modulatory genes. Preliminary results demonstrate activity with several cytokine genes, tumour antigen genes and co-stimulatory molecule genes. Despite only preliminary results, thus far, a theoretical attractive feature for the use of gene therapy for the enhancement of immune modulation is that local injection of the gene product appears to be well tolerated. It is also successful in inducing systemic immune response, potentially providing effect to metastatic sites distal from the injected site. Animal studies have confirmed efficacy in the use of specific targeting of molecules regulating cancer growth (EGF receptor [EGFR], super oxide dismutase [SOD], cyclin D1, E1A and Bcl-2). These approaches are discussed. However, the most significant clinical advances for the use of gene therapy in advanced HNSCC involves two agents: Adp53 and ONYX-015. Preliminary Phase I and II results suggest evidence of efficacy and justify accrual Phase III trials, which are currently ongoing. PMID:11890870

  8. Mucopolysaccharidosis I Cats Mount a Cytotoxic T Lymphocyte Response after Neonatal Gene Therapy

    E-print Network

    Ponder, Katherine P.

    with MPS include hematopoietic stem cell transplantation [3] and enzyme replacement therapy (ERT) [4]. GeneMucopolysaccharidosis I Cats Mount a Cytotoxic T Lymphocyte Response after Neonatal Gene Therapy therapy has reduced manifestations of genetic diseases, immune responses can abrogate the effect. One

  9. Treating hearing disorders with cell and gene therapy

    NASA Astrophysics Data System (ADS)

    Gillespie, Lisa N.; Richardson, Rachael T.; Nayagam, Bryony A.; Wise, Andrew K.

    2014-12-01

    Hearing loss is an increasing problem for a substantial number of people and, with an aging population, the incidence and severity of hearing loss will become more significant over time. There are very few therapies currently available to treat hearing loss, and so the development of new therapeutic strategies for hearing impaired individuals is of paramount importance to address this unmet clinical need. Most forms of hearing loss are progressive in nature and therefore an opportunity exists to develop novel therapeutic approaches to slow or halt hearing loss progression, or even repair or replace lost hearing function. Numerous emerging technologies have potential as therapeutic options. This paper details the potential of cell- and gene-based therapies to provide therapeutic agents to protect sensory and neural cells from various insults known to cause hearing loss; explores the potential of replacing lost sensory and nerve cells using gene and stem cell therapy; and describes the considerations for clinical translation and the challenges that need to be overcome.

  10. Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives

    Microsoft Academic Search

    F Rolling

    2004-01-01

    Retinal degenerative diseases such as retinal macular degeneration and retinitis pigmentosa constitute a broad group of diseases that all share one critical feature, the progressive apoptotic loss of cells in the retina. There is currently no effective treatment available by which the course of these disorders can be modified, and visual dysfunction often progresses to total blindness. Gene therapy represents

  11. Department of Medical Imaging and Radiation Sciences Short Course in Imaging for Advanced Radiation Therapy Practice

    E-print Network

    Albrecht, David

    your anatomical knowledge to clinical practice. You will also need to be self-directed to access Therapy Practice · Academic units must be studied concurrently or as a pre-requisite to studying clinical) Principles of Imaging for Advanced Radiation Therapy Practice 1 (Academic Unit) Duration 13 weeks Delivery

  12. Multiphoton Biomedical Imaging and Photodynamic Therapy: Agents & Applications

    E-print Network

    Van Stryland, Eric

    -reactive model Hydrophobic and hydrophilic dyes Two-Photon Photodynamic Therapy #12;"Two-photon laser scanning at the focus of the scanning pulsed-infrared laser beam, resulting in a much less harmful light dose during visible excitation. #12;Two-Photon Imaging can Afford 3D Localization Prepare cell Visualize and irradiate

  13. Angiogenesis and gene therapy in man: dream or reality?

    PubMed

    Amant, C; Berthou, L; Walsh, K

    1999-01-01

    Preclinical studies indicate that angiogenic growth factors can stimulate the development of collateral arteries in animal models of peripheral or myocardial ischaemia, a concept termed 'therapeutic angiogenesis'. The goal of this review is to provide a brief overview of the advantages and disadvantages of gene versus recombinant protein therapy for therapeutic angiogenesis. We also discuss different options for delivering genes to patients, including plasmids and modified viral vectors. Recently, the safety and potential utility of gene therapy for ischaemic disease were demonstrated in 3 clinical trials involving the delivery of plasmid DNA encoding the 165 amino acid isoform of human vascular endothelial growth factor (phVEGF165), a factor that specifically promotes the proliferation and migration of vascular endothelial cells. Two trials involved the administration of phVEGF165 for peripheral arterial disease. In one trial, the plasmid was administered to the arterial wall from a hydrogel-coated angioplasty balloon, while a second trial examined the direct injection of phVEGF165 into the skeletal muscle of the affected limb. More recently, phVEGF165 was directly injected into ischaemic myocardium. In all these trials, it appears that administration of phVEGF165 led to improvements in tissue perfusion. PMID:10526956

  14. Angiogenesis and gene therapy in man: dream or reality?

    PubMed

    Amant, C; Berthou, L; Walsh, K

    1999-01-01

    Preclinical studies indicate that angiogenic growth factors can stimulate the development of collateral arteries in animal models of peripheral or myocardial ischaemia, a concept termed 'therapeutic angiogenesis'. The goal of this review is to provide a brief overview of the advantages and disadvantages of gene versus recombinant protein therapy for therapeutic angiogenesis. We also discuss different options for delivering genes to patients, including plasmids and modified viral vectors. Recently, the safety and potential utility of gene therapy for ischaemic disease were demonstrated in 3 clinical trials involving the delivery of plasmid DNA encoding the 165 amino acid isoform of human vascular endothelial growth factor (phVEGF165), a factor that specifically promotes the proliferation and migration of vascular endothelial cells. Two trials involved the administration of phVEGF165 for peripheral arterial disease. In one trial, the plasmid was administered to the arterial wall from a hydrogel-coated angioplasty balloon, while a second trial examined the direct injection of phVEGF165 into the skeletal muscle of the affected limb. More recently, phVEGF165 was directly injected into ischaemic myocardium. In all these trials, it appears that administration of phVEGF165 led to improvements in tissue perfusion. PMID:10548390

  15. Gene Therapy to Enhance Allograft Incorporation After Host Tissue Irradiation

    PubMed Central

    Santoni, Brandon G.; Simon Turner, A.; Wheeler, Donna L.; Nicholas, Richard W.; Anchordoquy, Tom J.

    2008-01-01

    Structural bone allografts are used to reconstruct large skeletal defects after tumor surgery. Although allograft-related complications are declining, the use of perioperative radiation therapy is associated with a poorer outcome. Recently, BMP-2 levels in the host bed were reportedly diminished after exposure to radiation doses consistent with those used perioperatively to treat musculoskeletal sarcoma. Reintroduction of this osteogenic protein may circumvent the deleterious effects of preoperative radiation on allograft incorporation. We introduced a novel polymeric BMP-2 gene delivery system into the host-allograft junctions at the time of transplantation in an ovine tibial defect model with or without preoperative exposure to 50 Gy radiation. After 4 months, we noted no radiographic or histologic improvements in allograft incorporation after preoperative radiation and BMP-2 reintroduction; however, 50 Gy radiation was associated with increased porosity in the interface regions and poorer radiographic healing. We identified no BMP2-expressing cells or protein in the interface at the study end point, suggesting the polymeric gene delivery system was unable to promote extended expression of the protein or induce a healing response. Although gene therapy may hold promise as a novel technique to improve allograft incorporation, our data do not support that contention with the current approach. PMID:18506562

  16. 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

  17. Alipogene tiparvovec: gene therapy for lipoprotein lipase deficiency.

    PubMed

    Wierzbicki, Anthony S; Viljoen, Adie

    2013-01-01

    Homozygous lipoprotein lipase (LPL) deficiency is an ultra-orphan disease associated with increased rates of pancreatitis. Current treatments based on acute plasmapheresis allied with ultra-low fat diets are inadequate as responses to fibrates or other triglyceride-lowering therapies tend to be poor. Alipogene tiparvovec is an adeno-associated virus type I (AAV1) gene therapy using a hyper-functional LPL serine(447)-stop (S447X) insert administered intramuscularly under general anaesthetic with allied immunosuppression. Treatment results in histological muscle expression of LPL allied with a transient 40% reduction in triglycerides and improvements in postprandial chylomicron triglyceride content. Alipogene tiparvovec is the first possibly curative treatment for LPL deficiency. PMID:23126631

  18. Simian virus-40 as a gene therapy vector.

    PubMed

    Vera, Maria; Fortes, Puri

    2004-05-01

    Simian virus-40 (SV40), an icosahedral papovavirus, has recently been modified to serve as a gene delivery vector. Recombinant SV40 vectors (rSV40) are good candidates for gene transfer, as they display some unique features: SV40 is a well-known virus, nonreplicative vectors are easy-to-make, and can be produced in titers of 10(12) IU/ml. They also efficiently transduce both resting and dividing cells, deliver persistent transgene expression to a wide range of cell types, and are nonimmunogenic. Present disadvantages of rSV40 vectors for gene therapy are a small cloning capacity and the possible risks related to random integration of the viral genome into the host genome. Considerable efforts have been devoted to modifing this virus and setting up protocols for viral production. Preliminary therapeutic results obtained both in tissue culture cells and in animal models for heritable and acquired diseases indicate that rSV40 vectors are promising gene transfer vehicles. This article reviews the work performed with SV40 viruses as recombinant vectors for gene transfer. A summary of the structure, genomic organization, and life cycle of wild-type SV40 viruses is presented. Furthermore, the strategies utilized for the development, production, and titering of rSV40 vectors are discussed. Last, the therapeutic applications developed to date are highlighted. PMID:15169607

  19. The radionuclide molecular imaging and therapy of neuroendocrine tumors.

    PubMed

    Li, Shuren; Beheshti, Mohsen

    2005-03-01

    Neuroendocrine tumors (NETs) represent a large group of neoplasms deriving from pluripotent stem cells or from differentiated neuroendocrine cells that are characterized by the expression of different peptides and biogenic amines. These rare tumors tend to grow slowly and are notoriously difficult to localize, at least in the early stages. Diagnostics involve blood, urine and biochemical examination as well as imaging modalities. Imaging is achieved by a variety of techniques such as radiological morphological imaging methods, for example, sonography, computerized tomography (CT)/magnetic resonance imaging (MRI), angiography and finally, nuclear functional imaging methods such as metaiodobenzylguanidine (MIBG), somatostatin receptor scintigraphy (SRS), vasoactive intestinal peptide receptor scintigraphy (VIPRS) and positron emission tomography (PET) using (18)F labeled deoxyglucose (FDG) and fluorinated dihydroxyphenylalanine ((18)F-DOPA) as a radioisotopic marker. (131)I-labeled MIBG is a well-established radiopharmaceutical for localization and therapy of phechromocytoma and paraganglioma. The majority of neuroendocrine tumors possess a high density of somatostatin receptors. This observation provided the basis for the development of various radiolabeled somatostatin peptide analogs as imaging agents and therapeutics in nuclear medicine. FDG-PET is now performed in a wide variety of tumors and indications, including diagnosis, staging, re-staging and evaluation of the response to treatment. (18)F-DOPA-PET may be useful if (18)F-FDG-PET scan result is negative. (99m)Tc-pentavalent dimercaptosuccinic acid ((99m)Tc-DMSA-V) or (99m)Tc sestamibi ((99m)Tc-MIBI) or (99m)Tc-tetrofosmin is used only for diagnosis of certain NETs such as medullary thyroid cancer. The expiences with other nuclear medicinie imaging and therapy modalities such as cholecystokinin (CCK)-B/gastrin-receptors, bombesin/gastrin-releasing peptide receptor scintigraphy are still limited, and further clinical studies are needed. The studies using vascular endothelial growth factor (VEGF) for tumor angiogenesis imaging, annexin-V for imaging apoptosis and agents for hypoxia imaging are still in an early stage and the clinical role for these agents needs to be defined. In conclusion, no single imaging technique identifies all the metastatic sites of NETs. The best results may be obtained with a combination of functional imaging such as PET or/and SRS and morphologic imaging with CT and/or MR imaging. Many molecular imaging and therapy modalities fur NETs are recently under investigation or being developed, the usefulness of these modalities, however, has to be evaluated by well-designed and multicentre studies. PMID:15810878

  20. Gene Therapy (2000) 7, 12741283 2000 Macmillan Publishers Ltd All rights reserved 0969-7128/00 $15.00

    E-print Network

    Omiecinski, Curtis

    Gene Therapy (2000) 7, 1274­1283 © 2000 Macmillan Publishers Ltd All rights reserved 0969 vectors for study of cytochrome P450 gene regulation, as well as for liver-directed gene therapy in humans. Gene Therapy (2000) 7, 1274­1283. polyhedrosis virus) vectors can be used to shuttle foreign genes

  1. 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.

  2. 77 FR 65693 - Cellular, Tissue and Gene Therapies Advisory Committee; Amendment of Notice

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-30

    ...Cellular, Tissue and Gene Therapies Advisory Committee...On page 63841, in the first column, the Date and...research programs in the Gene Transfer and Immunogenicity...Cellular, Tissue and Gene Therapies, Center for...column, second paragraph, first sentence, the...

  3. Cellular Immunity to Viral Antigens Limits E1-Deleted Adenoviruses for Gene Therapy

    Microsoft Academic Search

    Yiping Yang; Frederick A. Nunes; Klara Berencsi; Emma E. Furth; Eva Gonczol; James M. Wilson

    1994-01-01

    An important limitation that has emerged in the use of adenoviruses for gene therapy has been loss of recombinant gene expression that occurs concurrent with the development of pathology in the organ expressing the transgene. We have used liver-directed approaches to gene therapy in mice to study mechanisms that underlie the problems with transient expression and pathology that have characterized

  4. HUMAN GENE THERAPY 15:793804 (August 2004) Mary Ann Liebert, Inc.

    E-print Network

    Paris-Sud XI, Université de

    HUMAN GENE THERAPY 15:793­804 (August 2004) © Mary Ann Liebert, Inc. Adenovirus-Mediated Fibroblast Hospital, AP-HP, 94010 Créteil, France. 2Cardiovascular Gene Therapy Department, Gencell, Vitry sur Seine. Recombinant adenovi- rus carrying the gene encoding human secreted FGF-1 (Ad.FGF1) increased the proliferation

  5. Pharmacological and rAAV Gene Therapy Rescue of Visual Functions in a Blind Mouse

    E-print Network

    Palczewski, Krzysztof

    Pharmacological and rAAV Gene Therapy Rescue of Visual Functions in a Blind Mouse Model of Leber) Pharmacological and rAAV gene therapy rescue of visual functions in a blind mouse model of Leber congenital of Washington, Seattle, Washington, United States of America, 6 Department of Ophthalmology, and Powell Gene

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

    Microsoft Academic Search

    Teresa Borrás

    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

  7. Molecular Evolution of Adeno-associated Virus for Improved Retinal Gene Therapies

    E-print Network

    Klimczak, Ryan Raymond

    2010-01-01

    The eye represents a strong candidate for gene therapyeye possesses unique properties that make it a great candidate for viral-mediated gene therapy.eye to serve as an internal control. However, current therapies based on AAV-mediated gene

  8. Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success

    Microsoft Academic Search

    Samuel G. Jacobson; Tomas S. Aleman; Artur V. Cideciyan; Alexander Sumaroka; Sharon B. Schwartz; Elizabeth A. M. Windsor; Elias I. Traboulsi; Elise Heon; Steven J. Pittler; Ann H. Milam; Albert M. Maguire; Krzysztof Palczewski; Edwin M. Stone; Jean Bennett

    2005-01-01

    Mutations in RPE65, a gene essential to normal operation of the visual (retinoid) cycle, cause the childhood blindness known as Leber congenital amaurosis (LCA). Retinal gene therapy restores vision to blind canine and murine models of LCA. Gene therapy in blind humans with LCA from RPE65 mutations may also have potential for success but only if the retinal photoreceptor layer

  9. 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.

  10. 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.

  11. Long-Term Follow-Up After Gene Therapy for Canavan Disease

    PubMed Central

    Leone, Paola; Shera, David; McPhee, Scott W.J.; Francis, Jeremy S.; Kolodny, Edwin H.; Bilaniuk, Larissa T.; Wang, Dah-Jyuu; Assadi, Mitra; Goldfarb, Olga; Goldman, H. Warren; Freese, Andrew; Young, Deborah; During, Matthew J.; Samulski, R. Jude; Janson, Christopher G.

    2013-01-01

    Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetylaspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 1011 vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status. PMID:23253610

  12. Quantitative analysis of non-viral gene therapy in primary liver culture systems

    E-print Network

    Tedford, Nathan C

    2007-01-01

    Gene therapy has the potential to cure thousands of diseases caused by genetic abnormalities, provide novel combination therapies for cancers and viral infections, and offer a new and effective platform for next generation ...

  13. 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.

  14. 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

  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. Molecular Imaging in Traditional Chinese Medicine Therapy for Neurological Diseases

    PubMed Central

    Wan, Haitong; Li, Jinhui; Zhang, Hong; Tian, Mei

    2013-01-01

    With the speeding tendency of aging society, human neurological disorders have posed an ever increasing threat to public health care. Human neurological diseases include ischemic brain injury, Alzheimer's disease, Parkinson's disease, and spinal cord injury, which are induced by impairment or specific degeneration of different types of neurons in central nervous system. Currently, there are no more effective treatments against these diseases. Traditional Chinese medicine (TCM) is focused on, which can provide new strategies for the therapy in neurological disorders. TCM, including Chinese herb medicine, acupuncture, and other nonmedication therapies, has its unique therapies in treating neurological diseases. In order to improve the treatment of these disorders by optimizing strategies using TCM and evaluate the therapeutic effects, we have summarized molecular imaging, a new promising technology, to assess noninvasively disease specific in cellular and molecular levels of living models in vivo, that was applied in TCM therapy for neurological diseases. In this review, we mainly focus on applying diverse molecular imaging methodologies in different TCM therapies and monitoring neurological disease, and unveiling the mysteries of TCM. PMID:24222911

  17. Plasmid-mediated gene therapy for cardiovascular disease.

    PubMed

    Williams, Paul D; Kingston, Paul A

    2011-09-01

    Gene transfer within the cardiovascular system was first demonstrated in 1989 yet, despite extensive basic-science and clinical research, unequivocal benefit in the clinical setting remains to be demonstrated. Potential reasons for this include the fact that recombinant viral vectors, used in the majority of clinical studies, have inherent problems with immunogenicity that are difficult to circumvent. Attention has turned therefore to plasmid vectors, which possess many advantages over viruses in terms of safety and ease of use, and many clinical studies have now been performed using non-viral technology. This review will provide an overview of clinical trials for cardiovascular disease using plasmid vectors, recent developments in plasmid delivery and design, and potential directions for this modality of gene therapy. PMID:21742674

  18. 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.

  19. Peptide nucleic acids: versatile tools for gene therapy strategies

    PubMed Central

    Dean, David A.

    2015-01-01

    Peptide nucleic acids, or PNAs, are oligonucleotide analogs in which the phosphodiester backbone is replaced with a polyamide structure. First synthesized less than 10 years ago, they have received great attention due to their several favorable properties, including resistance to nuclease and protease digestion, stability in serum and cell extracts, and their high affinity for RNA and single and double-stranded DNA targets. Although initially designed and demonstrated to function as antisense and antigene reagents that inhibit both transcription and translation by steric hindrance, more recent applications have included gene activation by synthetic promoter formation and mutagenesis of chromosomal targets. Most notably for gene delivery, they have been used to specifically label plasmids and act as adapters to link synthetic peptides or ligands to the DNA. Thus, their great potential lies in the ability to attach specific targeting peptides to plasmids to circumvent such barriers to gene transfer as cell-targeting or nuclear localization, thereby increasing the efficacy of gene therapy. PMID:11072107

  20. Neuroendocrine tumours: the role of imaging for diagnosis and therapy.

    PubMed

    van Essen, Martijn; Sundin, Anders; Krenning, Eric P; Kwekkeboom, Dik J

    2014-02-01

    In patients with neuroendocrine tumours (NETs), a combination of morphological imaging and nuclear medicine techniques is mandatory for primary tumour visualization, staging and evaluation of somatostatin receptor status. CT and MRI are well-suited for discerning small lesions that might escape detection by single photon emission tomography (SPECT) or PET, as well as for assessing the local invasiveness of the tumour or the response to therapy. Somatostatin receptor imaging, by (111)In-pentetreotide scintigraphy or PET with (68)Ga-labelled somatostatin analogues, frequently identifies additional lesions that are not visible on CT or MRI scans. Currently, somatostatin receptor scintigraphy with (111)In-pentetreotide is the more frequently available of the two techniques to determine somatostatin receptor expression and is needed to select patients for peptide receptor radionuclide therapy. In the future, because of its higher sensitivity, PET with (68)Ga-labelled somatostatin analogues is expected to replace somatostatin receptor scintigraphy. Whereas (18)F-FDG-PET is only used in high-grade neuroendocrine cancers, PET-CT with (18)F-dihydroxy-L-phenylalanine or (11)C-5-hydroxy-L-tryptophan is a useful problem-solving tool and could be considered for the evaluation of therapy response in the future. This article reviews the role of imaging for the diagnosis and management of intestinal and pancreatic NETs. Response evaluation and controversies in NET imaging will also be discussed. PMID:24322649

  1. Image-guided cancer therapy using PET/CT.

    PubMed

    Yap, Jeffrey T; Carney, Jonathan P J; Hall, Nathan C; Townsend, David W

    2004-01-01

    Functional imaging with positron emission tomography (PET) is playing an increasingly important role in the diagnosis and staging of malignant disease, image-guided therapy planning, and treatment monitoring. PET scanning with the radiolabeled glucose analogue (18)F-fluorodeoxyglucose ((18)FDG) is a relatively recent addition to the clinically available technology for imaging cancer, complementing the more conventional anatomical imaging modalities of computed tomography (CT) and magnetic resonance (MR). These modalities are complementary in the sense that CT provides accurate localization of organs and lesions while PET maps both normal and abnormal tissue function. When combined, the two modalities can identify and localize functional abnormalities. Attempts to align CT and PET data sets with fusion software are generally successful in the brain, whereas the remainder of the body is more challenging owing to the increased number of possible degrees of freedom between the two scans. Recently these challenges have been addressed by the introduction of the combined PET/CT scanner, a hardware-oriented approach to image fusion. With this device, accurately registered anatomical and functional images can be acquired for each patient in a single scanning session. Currently, over 400 combined PET/CT scanners are installed in medical institutions worldwide, almost all of them for the diagnosis and staging of malignant disease. However, the real impact of this technology undoubtedly will be for cancer therapy, where PET/CT images will be used to guide biopsies and assist in surgical intervention, to define target volumes for radiation therapy and optimize dose, and to monitor response to chemotherapy and establish individualized patient treatment strategies. PMID:15383203

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

    PubMed

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

    2014-07-16

    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 10(13) 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

  3. Preface Current Gene Therapy, 2013, Vol. 13, No. 1 1 It is not superstition that worries me, Herr Doctor, but genes and chromosomes

    E-print Network

    Boyer, Edmond

    Preface Current Gene Therapy, 2013, Vol. 13, No. 1 1 Preface « It is not superstition that worries. Current Gene Therapy is focused on genes; how to manipulate coding sequences, transferring them in the epigraph. This and preventing side effects are central to the field of gene therapy. During 2012, Current

  4. Image-guided plasma therapy of cutaneous wound

    NASA Astrophysics Data System (ADS)

    Zhang, Zhiwu; Ren, Wenqi; Yu, Zelin; Zhang, Shiwu; Yue, Ting; Xu, Ronald

    2014-02-01

    The wound healing process involves the reparative phases of inflammation, proliferation, and remodeling. Interrupting any of these phases may result in chronically unhealed wounds, amputation, or even patient death. Despite the clinical significance in chronic wound management, no effective methods have been developed for quantitative image-guided treatment. We integrated a multimodal imaging system with a cold atmospheric plasma probe for image-guided treatment of chronic wound. Multimodal imaging system offers a non-invasive, painless, simultaneous and quantitative assessment of cutaneous wound healing. Cold atmospheric plasma accelerates the wound healing process through many mechanisms including decontamination, coagulation and stimulation of the wound healing. The therapeutic effect of cold atmospheric plasma is studied in vivo under the guidance of a multimodal imaging system. Cutaneous wounds are created on the dorsal skin of the nude mice. During the healing process, the sample wound is treated by cold atmospheric plasma at different controlled dosage, while the control wound is healed naturally. The multimodal imaging system integrating a multispectral imaging module and a laser speckle imaging module is used to collect the information of cutaneous tissue oxygenation (i.e. oxygen saturation, StO2) and blood perfusion simultaneously to assess and guide the plasma therapy. Our preliminary tests show that cold atmospheric plasma in combination with multimodal imaging guidance has the potential to facilitate the healing of chronic wounds.

  5. 1042 www.moleculartherapy.org vol.15no.6,10421052june2007 The American Society of Gene Therapy

    E-print Network

    Cai, Long

    Therapy Prostate Cancer Gene Therapy Clinical Trials Svend O Freytag1 , Hans Stricker2 , Benjamin Movsas1 the possibility that gene therapy may have the potential to affect both localized and metastatic disease. Much work lies ahead. Nevertheless, for the time being, these studies provide hope that gene therapy may

  6. Photoacoustic imaging of lacZ gene expression

    E-print Network

    Wang, Lihong

    protein enables whole body imaging of small animals, although at low spatial resolution due to multiplePhotoacoustic imaging of lacZ gene expression in vivo Li Li,a, Roger J. Zemp,a, Gina Lungu,b George- aging as a promising candidate for imaging gene expression in vivo by exploiting a new contrast

  7. original article The American Society of Gene Therapy Molecular Therapy vol. 17 no. 4, 697706 apr. 2009 697

    E-print Network

    Cai, Long

    original article© The American Society of Gene Therapy Molecular Therapy vol. 17 no. 4, 697­706 apr in clearing the established footpad tumors and results in higher overall long-term animal survival has been reported to be an effective oncolytic agent in a variety of animal tumor models.2 It has been

  8. Nanoshell bioconjugates for integrated imaging and therapy of cancer

    NASA Astrophysics Data System (ADS)

    Loo, Christopher H.; Lee, Min-Ho; Hirsch, Leon R.; West, Jennifer L.; Halas, Naomi J.; Drezek, Rebekah A.

    2004-06-01

    Currently, separate diagnostic and therapeutic modalities are required for the diagnosis and treatment of cancer. In many cases, the present standard of care requires invasive surgical procedures and/or other treatments associated with significant side effect profiles, high cost, and poor clinical outcome. A single technology with dual diagnostic/therapeutic capabilities would potentially yield significant savings in the time and cost associated with diagnosing and treating many cancers. In this paper, we discuss gold nanoshell bioconjugates and their role in the development of an integrated cancer imaging and therapy application. Nanoshells are a novel class of nanomaterials that have unique properties including continuous and broad wavelength tunability, far greater scattering and absorption coefficients, increased chemical stability, and improved biocompatibility. Here, we describe the development of an integrated cancer imaging and therapy application using near-infrared (NIR) gold nanoshell bioconjugates.

  9. 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

  10. 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

  11. Strontium-89 therapy and imaging with bremsstrahlung in bone metastases.

    PubMed

    Uchiyama, M; Narita, H; Makino, M; Sekine, H; Mori, Y; Fukumitsu, N; Kawakami, K

    1997-09-01

    The bone-seeking radiopharmaceutical Sr-89 has been used as a palliative treatment for patients with bone pain caused by bone metastases. The authors report the results of nine patients (three with prostate cancer, four with breast cancer, one with thyroid cancer, and one with lung cancer) who underwent therapy with Sr-89 chloride for painful bone metastases, and evaluate Sr-89 imaging with bremsstrahlung. Two levels of dosage (1.5 and 2.2 MBq/kg) were used. Sr-89 imaging was performed in seven patients 1 week after injection. Abnormal uptake was seen in all and was consistent with the results of Tc-99m HMDP imaging. Six patients were assessed at 3 months and three patients toward the time they were terminal; 78% (seven of nine) derived some benefit. Two patients had a favorable clinical response and showed improvement on Tc-99m HMDP imaging. PMID:9298293

  12. Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy

    PubMed Central

    Peng, Xiang-Hong; Qian, Ximei; Mao, Hui; Wang, Andrew Y; Chen, Zhuo (Georgia); Nie, Shuming; Shin, Dong M

    2008-01-01

    Magnetic iron oxide (IO) nanoparticles with a long blood retention time, biodegradability and low toxicity have emerged as one of the primary nanomaterials for biomedical applications in vitro and in vivo. IO nanoparticles have a large surface area and can be engineered to provide a large number of functional groups for cross-linking to tumor-targeting ligands such as monoclonal antibodies, peptides, or small molecules for diagnostic imaging or delivery of therapeutic agents. IO nanoparticles possess unique paramagnetic properties, which and generate significant susceptibility effects resulting in strong T2 and T2* contrast, as well as T1 effects at very low concentrations for magnetic resonance imaging (MRI), which is widely used for clinical oncology imaging. We review recent advances in the development of targeted IO nanoparticles for tumor imaging and therapy. PMID:18990940

  13. Targeted Imaging and Therapy of Brain Cancer using Theranostic Nanoparticles

    PubMed Central

    Bhojani, Mahaveer Swaroop; Van Dort, Marcian; Rehemtulla, Alnawaz; Ross, Brian D.

    2012-01-01

    The past decade has seen momentous development in brain cancer research in terms of novel imaging-assisted surgeries, molecularly targeted drug-based treatment regimens or adjuvant therapies and in our understanding of molecular footprints of initiation and progression of malignancy. However, mortality due to brain cancer has essentially remained unchanged in the last three decades. Thus, paradigm-changing diagnostic and therapeutic reagents are urgently needed. Nanotheranostic platforms are powerful tools for imaging and treatment of cancer. Multifunctionality of these nanovehicles offers a number of advantages over conventional agents. These include targeting to a diseased site thereby minimizing systemic toxicity, the ability to solubilize hydrophobic or labile drugs leading to improved pharmacokinetics and their potential to image, treat and predict therapeutic response. In this article, we will discuss the application of newer theranostic nanoparticles in targeted brain cancer imaging and treatment. PMID:20964352

  14. MR imaging of therapy-induced changes of bone marrow

    PubMed Central

    Henning, Tobias; Link, Thomas M.

    2006-01-01

    MR imaging of bone marrow infiltration by hematologic malignancies provides non-invasive assays of bone marrow cellularity and vascularity to supplement the information provided by bone marrow biopsies. This article will review the MR imaging findings of bone marrow infiltration by hematologic malignancies with special focus on treatment effects. MR imaging findings of the bone marrow after radiation therapy and chemotherapy will be described. In addition, changes in bone marrow microcirculation and metabolism after anti-angiogenesis treatment will be reviewed. Finally, new specific imaging techniques for the depiction of regulatory events that control blood vessel growth and cell proliferation will be discussed. Future developments are directed to yield comprehensive information about bone marrow structure, function and microenvironment. PMID:17021706

  15. MR imaging of therapy-induced changes of bone marrow.

    PubMed

    Daldrup-Link, Heike E; Henning, Tobias; Link, Thomas M

    2007-03-01

    MR imaging of bone marrow infiltration by hematologic malignancies provides non-invasive assays of bone marrow cellularity and vascularity to supplement the information provided by bone marrow biopsies. This article will review the MR imaging findings of bone marrow infiltration by hematologic malignancies with special focus on treatment effects. MR imaging findings of the bone marrow after radiation therapy and chemotherapy will be described. In addition, changes in bone marrow microcirculation and metabolism after anti-angiogenesis treatment will be reviewed. Finally, new specific imaging techniques for the depiction of regulatory events that control blood vessel growth and cell proliferation will be discussed. Future developments are directed to yield comprehensive information about bone marrow structure, function and microenvironment. PMID:17021706

  16. Gene therapy vectors: the prospects and potentials of the cut-and-paste transposons

    Microsoft Academic Search

    Corentin Claeys Bouuaert; Ronald M. Chalmers

    2010-01-01

    Gene therapy applications require efficient tools for the stable delivery of genetic information into eukaryotic genomes.\\u000a Most current gene delivery strategies are based on viral vectors. However, a number of drawbacks, such as the limited cargo\\u000a capacity, host immune response and mutational risks, highlight the need for alternative gene delivery tools. A comprehensive\\u000a gene therapy tool kit should contain a

  17. Efficacious and Safe Tissue-Selective Controlled Gene Therapy Approaches for the Cornea

    Microsoft Academic Search

    Rajiv R. Mohan; Sunilima Sinha; Ashish Tandon; Rangan Gupta; Jonathan C. K. Tovey; Ajay Sharma; Neeraj Vij

    2011-01-01

    Untargeted and uncontrolled gene delivery is a major cause of gene therapy failure. This study aimed to define efficient and safe tissue-selective targeted gene therapy approaches for delivering genes into keratocytes of the cornea in vivo using a normal or diseased rabbit model. New Zealand White rabbits, adeno-associated virus serotype 5 (AAV5), and a minimally invasive hair-dryer based vector-delivery technique

  18. Radiologists' leading position in image-guided therapy.

    PubMed

    Helmberger, Thomas; Martí-Bonmatí, Luis; Pereira, Philippe; Gillams, Alice; Martínez, Jose; Lammer, Johannes; Malagari, Katarina; Gangi, Afshin; de Baere, Thierry; Adam, E Jane; Rasch, Coen; Budach, Volker; Reekers, Jim A

    2013-02-01

    Image-guided diagnostic and therapeutic procedures are related to, or performed under, some kind of imaging. Such imaging may be direct inspection (as in open surgery) or indirect inspection as in endoscopy or laparoscopy. Common to all these techniques is the transformation of optical and visible information to a monitor or the eye of the operator. Image-guided therapy (IGT) differs by using processed imaging data acquired before, during and after a wide range of different imaging techniques. This means that the planning, performing and monitoring, as well as the control of the therapeutic procedure, are based and dependent on the "virtual reality" provided by imaging investigations. Since most of such imaging involves radiology in the broadest sense, there is a need to characterise IGT in more detail. In this paper, the technical, medico-legal and medico-political issues will be discussed. The focus will be put on state-of-the-art imaging, technical developments, methodological and legal requisites concerning radiation protection and licensing, speciality-specific limitations and crossing specialty borders, definition of technical and quality standards, and finally to the issue of awareness of IGT within the medical and public community. The specialty-specific knowledge should confer radiologists with a significant role in the overall responsibility for the imaging-related processes in various non-radiological specialties. These processes may encompass purchase, servicing, quality management, radiation protection and documentation, also taking responsibility for the definition and compliance with the legal requirements regarding all radiological imaging performed by non-radiologists. PMID:23325609

  19. 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

  20. Gastric inhibitory polypeptide receptor (GIPR) is a promising target for imaging and therapy in neuroendocrine tumors

    PubMed Central

    Sherman, Scott K.; Carr, Jennifer C.; Wang, Donghong; O’Dorisio, M. Sue; O’Dorisio, Thomas M.; Howe, James R.

    2013-01-01

    Background Ligands binding the somatostatin receptor type 2 (SSTR2) are useful for imaging and treatment of neuroendocrine tumors (NETs), but not all tumors express high levels of these receptors. The aim of this study was to evaluate gene expression of new therapeutic targets in NETs relative to SSTR2. Methods RNA was extracted from 103 primary small bowel (SBNET) and pancreatic neuroendocrine tumors (PNET), matched normal tissue, and 123 metastases. Expression of 12 candidate genes was measured by quantitative PCR normalized to internal controls; candidate gene expression was compared to SSTR2. Results Relative to normal tissue, primary NET expression of SSTR2, GPR98, BRS3, GIPR, GRM1, and OPRK1 were increased by 3, 8, 13, 13, 17, and 20-fold, respectively. Similar changes were found in metastases. While most candidate genes showed lower absolute expression than SSTR2, absolute GIPR expression was closest to SSTR2 (mean dCT 3.6 vs. 2.7, p=0.01). Absolute OPRK1 and OXTR expression varied significantly by primary tumor type and was close to SSTR2 in SBNETs but not PNETs. Conclusions Compared to the current treatment standard SSTR2, GIPR has only somewhat lower absolute gene expression in tumor tissue but much lower expression in normal tissue, making it a promising new target for NET imaging and therapy. PMID:24238043

  1. 256. Importance of Temporal Control of HSVtk Gene Therapy in Combination with T Cell Based Therapies for Cancer

    Microsoft Academic Search

    Luis A. Sanchez-Perez; Michael Gough; Jill Thompson; Richard G. Vile

    2004-01-01

    Many cancer gene therapy strategies rely upon the ability to deliver genes to tumors in vivo leading to the direct killing of tumor cells. We have shown previously, using the B16\\/HSVtk melanoma model, that in situ tumor cell death can be immunogenic due to recruitment, loading and activation of antigen presenting cells with released tumor antigens. We have now focused

  2. Theranostic applications of nanomaterials in cancer: drug delivery, image-guided therapy, and multifunctional platforms.

    PubMed

    Fernandez-Fernandez, Alicia; Manchanda, Romila; McGoron, Anthony J

    2011-12-01

    Successful cancer management depends on accurate diagnostics along with specific treatment protocols. Current diagnostic techniques need to be improved to provide earlier detection capabilities, and traditional chemotherapy approaches to cancer treatment are limited by lack of specificity and systemic toxicity. This review highlights advances in nanotechnology that have allowed the development of multifunctional platforms for cancer detection, therapy, and monitoring. Nanomaterials can be used as MRI, optical imaging, and photoacoustic imaging contrast agents. When used as drug carriers, nanoformulations can increase tumor exposure to therapeutic agents and result in improved treatment effects by prolonging circulation times, protecting entrapped drugs from degradation, and enhancing tumor uptake through the enhanced permeability and retention effect as well as receptor-mediated endocytosis. Multiple therapeutic agents such as chemotherapy, antiangiogenic, or gene therapy agents can be simultaneously delivered by nanocarriers to tumor sites to enhance the effectiveness of therapy. Additionally, imaging and therapy agents can be co-delivered to provide seamless integration of diagnostics, therapy, and follow-up, and different therapeutic modalities such as chemotherapy and hyperthermia can be co-administered to take advantage of synergistic effects. Liposomes, metallic nanoparticles, polymeric nanoparticles, dendrimers, carbon nanotubes, and quantum dots are examples of nanoformulations that can be used as multifunctional platforms for cancer theranostics. Nanomedicine approaches in cancer have great potential for clinically translatable advances that can positively impact the overall diagnostic and therapeutic process and result in enhanced quality of life for cancer patients. However, a concerted scientific effort is still necessary to fully explore long-term risks, effects, and precautions for safe human use. PMID:21947761

  3. Theranostic applications of nanomaterials in cancer: Drug delivery, image-guided therapy and multifunctional platforms

    PubMed Central

    Fernandez-Fernandez, Alicia; Manchanda, Romila

    2011-01-01

    Successful cancer management depends on accurate diagnostics along with specific treatment protocols. Current diagnostic techniques need to be improved to provide earlier detection capabilities, and traditional chemotherapy approaches to cancer treatment are limited by lack of specificity and systemic toxicity. This review highlights advances in nanotechnology that have allowed the development of multifunctional platforms for cancer detection, therapy, and monitoring. Nanomaterials can be used as MRI, optical imaging, and photoacoustic imaging contrast agents. When used as drug carriers, nanoformulations can increase tumor exposure to therapeutic agents and result in improved treatment effects by prolonging circulation times, protecting entrapped drugs from degradation, and enhancing tumor uptake through the EPR effect as well as receptor-mediated endocytosis. Multiple therapeutic agents such as chemotherapy, antiangiogenic, or gene therapy agents can be simultaneously delivered by nanocarriers to tumor sites to enhance the effectiveness of therapy. Additionally, imaging and therapy agents can be co-delivered to provide seamless integration of diagnostics, therapy and follow-up, and different therapeutic modalities such as chemotherapy and hyperthermia can be coadministered to take advantage of synergistic effects. Liposomes, metallic nanoparticles, polymeric nanoparticles, dendrimers, carbon nanotubes, and quantum dots are examples of nanoformulations that can be used as multifunctional platforms for cancer theranostics. Nanomedicine approaches in cancer have great potential for clinically translatable advances that can positively impact the overall diagnostic and therapeutic process, and result in enhanced quality of life for cancer patients. However, a concerted scientific effort is still necessary to fully explore long-term risks, effects, and precautions for safe human use. PMID:21947761

  4. AAV-Mediated Liver-Directed Gene Therapy

    PubMed Central

    Sands, Mark S.

    2014-01-01

    The liver is directly or indirectly involved in many essential processes and is affected by numerous inherited diseases. Therefore, many inherited diseases could be effectively treated by targeting the liver using gene transfer approaches. The challenges associated with liver-directed gene therapy are efficient targeting of hepatocytes, stability of the vector genome, and persistent high level expression. Many of these obstacles can be overcome with adeno-associated viral (AAV) gene transfer vectors. The first AAV gene transfer vector developed for in vivo use was based on the AAV2 serotype. AAV2 has a broad tropism and transduces many cell types, including hepatocytes, relatively efficiently in vivo. The capsid protein confers the serological profile and at least 12 primate AAV serotypes have already been characterized. Importantly, pseudotyping a recombinant AAV vector with different capsid proteins can dramatically alter the tropism. Both AAV8 and AAV9 have higher affinities for hepatocytes when compared to AAV2. In particular, AAV8 can transduce 3–4 fold more hepatocytes and deliver 3–4 fold more genomes per transduced cell when compared to AAV2. Depending on the dose, AAV8 can transduce up to 90–95% of hepatocytes in the mouse liver following intraportal vein injection. Interestingly, comparable levels of transduction can be achieved following intravenous injection. Direct intraparenchymal injection of an AAV vector also mediates relatively high level long term expression. Additional specificity can be conferred by using liver-specific promoters in conjunction with AAV8 capsid proteins. In addition to treating primary hepatocyte defects, immune reactions to transgene products can be minimized by circumventing the fixed tissue macrophages of the liver, Kupffer cells, and limiting expression to hepatocytes. The ability to target hepatocytes by virtue of the AAV serotype and the use of liver-specific promoters allows investigators to test novel therapeutic approaches and answer basic clinical and biological questions. PMID:22034029

  5. [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

  6. Gene therapy in glaucoma-part 2: Genetic etiology and gene mapping

    PubMed Central

    Mahdy, Mohamed Abdel-Monem Soliman

    2010-01-01

    Glaucoma diagnosis, identification of people at risk, initiation of treatment and timing of surgical intervention remains a problem. Despite new and improving diagnostic and therapeutic options for glaucoma, blindness from glaucoma is increasing and glaucoma remains a major public health problem. The role of heredity in ocular disease is attracting greater attention as the knowledge and recent advances of Human Genome Project and the HapMap Project have made genetic analysis of many human disorders possible. Glaucoma offers a variety of potential targets for gene therapy. All risk factors for glaucoma and their underlying causes are potentially susceptible to modulation by gene transfer. The discovery of genes responsible for glaucoma has led to the development of new methods of Deoxyribonucleic acid (DNA)-based diagnosis and treatment. As genetic defects responsible for glaucoma are identified and the biochemical mechanisms underlying the disease are recognized, new methods of therapy can be developed. It is of utmost importance for the ophthalmologists and glaucoma specialists to be familiar with and understand the basic molecular mechanisms, genes responsible for glaucoma and the ways of genetic treatment. Method of Literature Search The literature was searched on the Medline database, using the PubMed interface. PMID:21217896

  7. A new colloidal lipidic system for gene therapy.

    PubMed

    Fahr, A; Müller, K; Nahde, Th; Müller, Rolf; Brüsselbach, Sabine

    2002-01-01

    A novel type of liposomal vector for gene therapy is described (Artificial Virus Particles; AVPs). This vector is based on the composition of retroviral envelopes, serum-resistant and non-toxic and smaller than 200 nm in size. The DNA is condensed using low molecular weight branched PEI. Equipment of these particles with a cyclic RGD peptide ligand as targeting device renders them selective for tumor endothelial and melanoma cells expressing high levels of alphavbeta3-integrins, and allows for an efficient delivery of the enclosed genetic material. The specificity of the vector system for melanoma cells could be further improved by using a melanocyte-specific tyrosinase promoter to drive transgene expression. PMID:12604036

  8. Improved virus purification processes for vaccines and gene therapy.

    PubMed

    Nestola, Piergiuseppe; Peixoto, Cristina; Silva, Ricardo R J S; Alves, Paula M; Mota, José P B; Carrondo, Manuel J T

    2015-05-01

    The downstream processing of virus particles for vaccination or gene therapy is becoming a critical bottleneck as upstream titers keep improving. Moreover, the growing pressure to develop cost-efficient processes has brought forward new downstream trains. This review aims at analyzing the state-of-the-art in viral downstream purification processes, encompassing the classical unit operations and their recent developments. Emphasis is given to novel strategies for process intensification, such as continuous or semi-continuous systems based on multicolumn technology, opening up process efficiency. Process understanding in the light of the pharmaceutical quality by design (QbD) initiative is also discussed. Finally, an outlook of the upcoming breakthrough technologies is presented. Biotechnol. Bioeng. 2015;112: 843-857. © 2015 Wiley Periodicals, Inc. PMID:25677990

  9. Gene Therapy and Virotherapy of Gastric Cancer: Preclinical Results and Clinical Developments

    Microsoft Academic Search

    Daniëlle A. M. Heideman

    2004-01-01

    Despite advances in current treatment modalities, the clinical outcome of gastric cancer remains dismal. New treatment modalities are urgently required to improve the prognosis of patients with gastric cancer. Cancer gene therapy and virotherapy comprise a potential category of new therapeutics and will be discussed in this review. To date, various gene therapy strategies have been developed, but first clinical

  10. RESEARCH ARTICLE A model for the analysis of nonviral gene therapy

    E-print Network

    RESEARCH ARTICLE A model for the analysis of nonviral gene therapy GA Banks1 , RJ Roselli1 , R Chen to produce clinical applications of gene therapy. The compartmental and computational model designed between two cellular studies were held constant, varying only the cell type, to investigate how the rates

  11. 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

  12. Gene Therapy in the Neuroendocrine System: Its Implementation in Experimental Models Using Viral Vectors

    Microsoft Academic Search

    Federico Bolognani; Rodolfo G. Goya

    2001-01-01

    Gene therapy, the transfer of genetic material for therapeutic purposes, has undergone an explosive development in the last few years. Within this context, development of gene therapy approaches for the neuroendocrine system, while incipient, has already generated a core of results which emerge as a promising area of research in neuroendocrinology. The present review presents a brief description of the

  13. HUMAN GENE THERAPY 12:563573 (March 20, 2001) Mary Ann Liebert, Inc.

    E-print Network

    Ponder, Katherine P.

    ,4 and KATHERINE PARKER PONDER1,5 ABSTRACT Although AAV vectors show promise for hepatic gene therapy, the optimal, St. Louis, MO 63110. 2Powell Gene Therapy Center, Genetics Institute, University of Florida of Genetics, Washington University School of Medicine, St. Louis, MO 63110. 5Department of Biochemistry

  14. Prospects for cationic polymers in gene and oligonucleotide therapy against cancer

    Microsoft Academic Search

    Thomas Merdan; Thomas Kissel

    2002-01-01

    Gene and antisense\\/ribozyme therapy possesses tremendous potential for the successful treatment of genetically based diseases, such as cancer. Several cancer gene therapy strategies have already been realized in vitro, as well as in vivo. A few have even reached the stage of clinical trials, most of them phase I, while some antisense strategies have advanced to phase II and III

  15. Progress and problems with the use of viral vectors for gene therapy

    Microsoft Academic Search

    Clare E. Thomas; Anja Ehrhardt; Mark A. Kay

    2003-01-01

    Gene therapy has a history of controversy. Encouraging results are starting to emerge from the clinic, but questions are still being asked about the safety of this new molecular medicine. With the development of a leukaemia-like syndrome in two of the small number of patients that have been cured of a disease by gene therapy, it is timely to contemplate

  16. A Look to Future Directions in Gene Therapy Research for Monogenic Diseases

    Microsoft Academic Search

    Matthew H. Porteus; Jon P. Connelly; Shondra M. Pruett

    2006-01-01

    The concept of gene therapy has long appealed to biomedical researchers and clinicians because it promised to treat certain diseases at their origins. In the last several years, there have been several trials in which patients have benefited from gene therapy protocols. This progress, however, has revealed important problems, including the problem of insertional oncogenesis. In this review, which focuses

  17. Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Gene therapy for hemophilia

    E-print Network

    Ponder, Katherine P.

    . Gene therapy for hemophilia Katherine P. Ponder Purpose of review This review will highlight the progress achieved in the past 2 years on using gene therapy to treat hemophilia in animals and humans with hemophilia. Novel approaches for hemophilia A in mice include expression of Factor VIII in blood cells

  18. Center for Gene Therapy of Cystic Fibrosis Call for Pilot Grant Applications

    E-print Network

    Center for Gene Therapy of Cystic Fibrosis Call for Pilot Grant Applications http://genetherapy.genetics.uiowa.edu/ The University of Iowa Center for Gene Therapy of Cystic Fibrosis is accepting applications for pilot of cystic fibrosis and disease pathophysiology in cystic fibrosis. Pilot grants, with budgets of up to $75

  19. 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

    The Food and Drug Administration (FDA) is announcing the availability of a document entitled ``Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products'' dated January 2011. The guidance document provides manufacturers of cellular and gene therapy (CGT) products with recommendations for developing tests to measure potency. The recommendations are intended to clarify the potency......

  20. 721. Measles Virus for Cancer Gene Therapy of Primary Liver Tumors

    Microsoft Academic Search

    Boris R. A. Blechacz; Patrick Splinter; Greiner Suzanne; Mark J. Federspiel; Kah-Whye Peng; Nicholas F. LaRusso; Stephen J. Russell

    2005-01-01

    Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer mortality worldwide, causing nearly 1 million deaths annually. Its therapy is mainly based on surgery, local-regional therapy and chemotherapy. Despite a variety of different new therapeutic approaches, its prognosis remains poor with a median survival of <10 months. Therefore, there is an urgent need for new therapeutic approaches.Gene therapy

  1. Liposomal DNA vectors for cystic fibrosis gene therapy. Current applications, limitations, and future directions

    Microsoft Academic Search

    Hans Schreier; Susan M. Sawyer

    1996-01-01

    The etiology of cystic fibrosis (CF), current therapies, and recent experimental molecular based therapies are briefly described including the use of recombinant human deoxyribonuclease I (rhDNase), nonsteroidal antiinflammatory drugs (ibuprofen), the sodium channel blocking diuretic amiloride, and uridine triphosphate (UTP), a chloride secretagogue. The original approach to CF gene therapy using recombinant replication defective adenovirus and its potential benefits as

  2. Diffusion Imaging for Therapy Response Assessment of Brain Tumor

    PubMed Central

    Chenevert, Thomas L.; Ross, Brian D.

    2014-01-01

    Advanced imaging provides insight into biophysical, physiologic, metabolic, or functional properties of tissues. Since water mobility is sensitive to cellular homeostasis, cellular density and microstructural organization, it is considered a valuable tool in the advanced imaging arsenal. This article briefly summarizes diffusion imaging concepts and highlights clinical applications of diffusion MRI for oncologic imaging. The inverse relationship between water mobility and density of cellular elements has been exploited in attempts to characterize and grade brain tumor based on apparent diffusion coefficient (ADC), as well as distinguish tumor from peritumoral edema. Diffusion tensor imaging and its derivative maps of diffusion anisotropy allow assessment of tumor compression or destruction of adjacent normal tissue anisotropy thus may aid to assess tumor infiltration and aid pre-surgical planning. A variety of preclinical studies on treated tumor models demonstrate ADC is sensitive to therapeutic alteration of tumor by effective cytotoxic agents, and that ADC changes are measurable before the lesion shrinks in size. In corresponding clinical studies, these ADC changes have been detected before completion of fractionated chemo-radiation schedules thus diffusion-based biomarkers of response have the potential to be used to intervene and individualize therapy delivery. Several methods to distill diffusion information into quantitative biomarkers have been proposed and include tumor summary statistics of baseline ADC/FA values and their change with time, as well as production of voxel-by-voxel response maps that reflect the relative volume of responding tumor. The voxel-based methods require coregistration of image volumes but this approach may also have value to guide spatially-directed therapies. PMID:19959005

  3. [Advances of driver gene and targeted therapy of non-small cell lung cancer].

    PubMed

    Zhang, Dan; Huang, Yan; Wang, Hongyang

    2014-10-20

    Lung cancer is the leading cause of cancer-related mortality in the worldwide. The discovery of drive gene makes tumor treatment is no longer "one-size-fits-all". Targeted therapy to change the present situation of cancer drugs become "bullet" with eyes, the effect is visible and bring a revolution in the treatment of lung cancer. The diver gene and targeted therapy have became the new cedule of non-small cell lung cancer (NSCLC). Society of Clinical Oncology (ASCO) has showed 11 kinds of diver genes. Here, we review the functional and structural characteristics and the targeted therapy in the 11 kinds of driver gene mutations. PMID:25342042

  4. Optimization of PAMAM-gold nanoparticle conjugation for gene therapy

    PubMed Central

    Yan, Jiaxi; Luo, Laureen; Foster, Aaron E.; Drezek, Rebekah A.

    2014-01-01

    The development of efficient and biocompatible non-viral vectors for gene therapy remains a great challenge, and exploiting the properties of both nanoparticle carriers and cationic polymers is an attractive approach. In this work, we have developed gold nanoparticle (AuNP) polyamidoamine (PAMAM) conjugates for use as non-viral transfection agents. AuPAMAM conjugates were prepared by crosslinking PAMAM dendrimers to carboxylic-terminated AuNPs via EDC and sulfo-NHS chemistry. EDC and sulfo-NHS have been utilized widely and in numerous applications such as amino acid coupling; however, their use in the coupling of PAMAM dendrimers to AuNPs presents new challenges to form effective and stable constructs for delivery that have not yet been examined. Enhanced colloidal stability and DNA condensation ability was established by probing two critical synthetic parameters: the reaction rate of the PAMAM crosslinking step, and the amine to carboxyl ratio. Based on this work, increasing the amine to carboxyl ratio during conjugation of PAMAM onto AuNPs yielded the optimal vector with respect to colloidal stability and transfection efficiency in vitro. AuPAMAM conjugates present attractive candidates for non-viral gene delivery due to their commercial availability, ease of fabrication and scale-up, high yield, high transfection efficiency and low cytotoxicity. PMID:24286816

  5. Optimization of PAMAM-gold nanoparticle conjugation for gene therapy.

    PubMed

    Figueroa, Elizabeth R; Lin, Adam Y; Yan, Jiaxi; Luo, Laureen; Foster, Aaron E; Drezek, Rebekah A

    2014-02-01

    The development of efficient and biocompatible non-viral vectors for gene therapy remains a great challenge, and exploiting the properties of both nanoparticle carriers and cationic polymers is an attractive approach. In this work, we have developed gold nanoparticle (AuNP) polyamidoamine (PAMAM) conjugates for use as non-viral transfection agents. AuPAMAM conjugates were prepared by crosslinking PAMAM dendrimers to carboxylic-terminated AuNPs via EDC and sulfo-NHS chemistry. EDC and sulfo-NHS have been utilized widely and in numerous applications such as amino acid coupling; however, their use in the coupling of PAMAM dendrimers to AuNPs presents new challenges to form effective and stable constructs for delivery that have not yet been examined. Enhanced colloidal stability and DNA condensation ability was established by probing two critical synthetic parameters: the reaction rate of the PAMAM crosslinking step, and the amine to carboxyl ratio. Based on this work, increasing the amine to carboxyl ratio during conjugation of PAMAM onto AuNPs yielded the optimal vector with respect to colloidal stability and transfection efficiency in vitro. AuPAMAM conjugates present attractive candidates for non-viral gene delivery due to their commercial availability, ease of fabrication and scale-up, high yield, high transfection efficiency and low cytotoxicity. PMID:24286816

  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. 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

  8. 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.

  9. Polymeric Micelles in Anticancer Therapy: Targeting, Imaging and Triggered Release

    PubMed Central

    Bult, Wouter; Bos, Mariska; Storm, Gert; Nijsen, J. Frank W.; Hennink, Wim E.

    2010-01-01

    ABSTRACT Micelles are colloidal particles with a size around 5–100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a ‘magic bullet’ a major step forward. PMID:20725771

  10. Alkylphosphocholine Analogs for Broad-Spectrum Cancer Imaging and Therapy

    PubMed Central

    Weichert, Jamey P.; Clark, Paul A.; Kandela, Irawati K.; Vaccaro, Abram M.; Clarke, William; Longino, Marc A.; Pinchuk, Anatoly N.; Farhoud, Mohammed; Swanson, Kyle I.; Floberg, John M.; Grudzinski, Joseph; Titz, Benjamin; Traynor, Anne M.; Chen, Hong-En; Hall, Lance T.; Pazoles, Christopher J.; Pickhardt, Perry J.; Kuo, John S.

    2015-01-01

    Many solid tumors contain an overabundance of phospholipid ethers relative to normal cells. Capitalizing on this difference, we created cancer-targeted alkylphosphocholine (APC) analogs through structure-activity analyses. Depending on the iodine isotope used, radioiodinated APC analog CLR1404 was used as either a positron emission tomography (PET) imaging (124I) or molecular radiotherapeutic (131I) agent. CLR1404 analogs displayed prolonged tumor-selective retention in 55 in vivo rodent and human cancer and cancer stem cell models. 131I-CLR1404 also displayed efficacy (tumor growth suppression and survival extension) in a wide range of human tumor xenograft models. Human PET/CT (computed tomography) and SPECT (single-photon emission computed tomography)/CT imaging in advanced-cancer patients with 124I-CLR1404 or 131I-CLR1404, respectively, demonstrated selective uptake and prolonged retention in both primary and metastatic malignant tumors. Combined application of these chemically identical APC-based radioisosteres will enable personalized dual modality cancer therapy of using molecular 124I-CLR1404 tumor imaging for planning 131I-CLR1404 therapy. PMID:24920661

  11. Interleukin 12 Gene Therapy of MHC-negative Murine Melanoma Métastases1

    Microsoft Academic Search

    Patrizia Nanni; Carla De Giovanni; Lorena Landuzzi; Giordano Nicoletti; Antonella Stoppacciaro; Marii-Ila Parenza; Mario P. Colombo; Pier-Luigi Lollini

    Immunological gene therapy of cancer relies heavily on the activation of T cells, but tumors with defects in MHC gene expression are not recog nized by MHC-restricted T cells. To investigate the potential of cytokine genes for the therapy of MHC-negative tumors, we transduced B78H1, a class I-negative murine melanoma clone, with a polycistronic vector car rying murine interleukin (II.I-I2

  12. Adeno-associated virus (AAV) based gene therapy for eye diseases

    Microsoft Academic Search

    Shuang Wang; Peng Liu; Lei Song; Lei Lu; Wensong Zhang; Yazhen Wu

    2011-01-01

    Gene therapy emerged as important approach in treatment for many inborn disorders caused by genetic defects, as well as other\\u000a diseases. This manuscript focused on Adeno-associated virus (AAV) based gene therapy to eye diseases. The paper firstly introduced\\u000a the AAV vectors and the techniques of eye delivery, then summarized some tested genes that were used in past treatment to\\u000a retinal

  13. New Insights and Unresolved Issues Regarding Insertional Mutagenesis in X-linked SCID Gene Therapy

    Microsoft Academic Search

    Karin Pike-Overzet; Mirjam van der Burg; Gerard Wagemaker; Jacques JM van Dongen; Frank JT Staal; Frank J. T. Staal

    2007-01-01

    The oncogenic potential of retrovirus-mediated gene therapy has been re-emphasized because four patients developed T-cell acute lymphoblastic leukemia (T-ALL)-like disease from an otherwise successful gene therapy trial for X-linked severe combined immunodeficiency (X-linked SCID). X-linked SCID, a disease caused by inactivating mutations in the IL2R? gene, is part of a heterogeneous group of SCIDs characterized by the lack of T

  14. 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

  15. Prior image constrained scatter correction in cone-beam computed tomography image-guided radiation therapy

    PubMed Central

    Brunner, Stephen; Nett, Brian E; Tolakanahalli, Ranjini; Chen, Guang-Hong

    2012-01-01

    X-ray scatter is a significant problem in cone-beam computed tomography when thicker objects and larger cone angles are used, as scattered radiation can lead to reduced contrast and CT number inaccuracy. Advances have been made in x-ray computed tomography (CT) by incorporating a high quality prior image into the image reconstruction process. In this paper, we extend this idea to correct scatter-induced shading artifacts in cone-beam CT image-guided radiation therapy. Specifically, this paper presents a new scatter correction algorithm which uses a prior image with low scatter artifacts to reduce shading artifacts in cone-beam CT images acquired under conditions of high scatter. The proposed correction algorithm begins with an empirical hypothesis that the target image can be written as a weighted summation of a series of basis images that are generated by raising the raw cone-beam projection data to different powers, and then, reconstructing using the standard filtered backprojection algorithm. The weight for each basis image is calculated by minimizing the difference between the target image and the prior image. The performance of the scatter correction algorithm is qualitatively and quantitatively evaluated through phantom studies using a Varian 2100 EX System with an on-board imager. Results show that the proposed scatter correction algorithm using a prior image with low scatter artifacts can substantially mitigate scatter-induced shading artifacts in both full-fan and half-fan modes. PMID:21258140

  16. 78 FR 26794 - Prospective Grant of Start-Up Exclusive Evaluation Option License Agreement: Gene Therapy and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-08

    ...Option License Agreement: Gene Therapy and Cell-Based Therapy for Cardiac Arrhythmias...may be limited to ``Gene therapy and cell-based therapy for cardiac arrhythmias...activated adenylyl cyclase, as well as cardiac cells or cardiac-like cells derived from...

  17. Gene Therapy (2002) 9, 713718 2002 Nature Publishing Group All rights reserved 0969-7128/02 $25.00

    E-print Network

    Warburton, Peter E.

    Gene Therapy (2002) 9, 713­718 2002 Nature Publishing Group All rights reserved 0969-7128/02 $25.00 www.nature.com/gt Chromosome engineering: prospects for gene therapy BR Grimes1 , PE Warburton2 and CJ and the potential for downstream applications in gene therapy were presented at the Artificial Chromosome Session

  18. [CANCER RESEARCH 62, 42734281, August 1, 2002] Adenoviral Gene Therapy for Renal Cancer Requires Retargeting to Alternative

    E-print Network

    Hemminki, Akseli

    [CANCER RESEARCH 62, 4273­4281, August 1, 2002] Adenoviral Gene Therapy for Renal Cancer Requires and David T. Curiel2 Division of Human Gene Therapy, Departments of Medicine, Pathology, and Surgery, and Gene Therapy Center [Y. S. H., J. L. B., A. K., P. N., V. K., I. D., M. W., X. L., A. H., D. T. C

  19. Suppression and Replacement Gene Therapy for Autosomal Dominant Disease in a Murine Model of Dominant Retinitis Pigmentosa

    Microsoft Academic Search

    Sophia Millington-Ward; Naomi Chadderton; Mary O'Reilly; Arpad Palfi; Tobias Goldmann; Claire Kilty; Marian Humphries; Uwe Wolfrum; Jean Bennett; Peter Humphries; Paul F Kenna; G Jane Farrar

    2011-01-01

    For dominantly inherited disorders development of gene therapies, targeting the primary genetic lesion has been impeded by mutational heterogeneity. An example is rhodopsin-linked autosomal dominant retinitis pigmentosa with over 150 mutations in the rhodopsin gene. Validation of a mutation-independent suppression and replacement gene therapy for this disorder has been undertaken. The therapy provides a means of correcting the genetic defect

  20. The American Society of Gene Therapy 244 www.moleculartherapy.org vol.16no.2,244251feb.2008

    E-print Network

    Cai, Long

    advantage observed in animal pharmacokinetic studies.4,5 IP delivery of gene therapy vectors is particularly© 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

  1. Cell and gene therapies in epilepsy--promising avenues or blind alleys?

    PubMed

    Löscher, Wolfgang; Gernert, Manuela; Heinemann, Uwe

    2008-02-01

    The past decades have brought several advances to the treatment of epilepsy. However, despite the continued development and release of new antiepileptic drugs (AEDs), more than one-third of patients are resistant to pharmacological treatment. Furthermore, current AEDs do not prevent the development and progression of epilepsy. Thus, there is an urgent need to develop new therapies for AED-resistant patients, for prevention of epilepsy in patients at risk and for disease modification. Cell replacement and gene therapies have been proposed to offer potential approaches for improvements in therapy, but are such approaches really more promising than new pharmacological strategies? Here we critically review and discuss data from epilepsy models and human tissue studies indicating that cell and gene therapies might provide alternative therapeutic approaches for AED-resistant focal epilepsies and might have antiepileptogenic or disease-modifying potential. However, several crucial issues remain to be resolved to develop cell and gene therapies into effective and safe therapies. PMID:18201772

  2. 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

  3. The European hospital exemption clause-new option for gene therapy?

    PubMed

    Buchholz, Christian J; Sanzenbacher, Ralf; Schüle, Silke

    2012-01-01

    Gene-therapy medicinal products are currently applied to patients enrolled in authorized clinical trials to demonstrate safety and efficacy. Given a positive outcome, marketing authorization can subsequently be achieved via the centralized procedure coordinated by the European Medicines Agency. With Regulation (EC) No. 1394/2007 in force, advanced therapy medicinal products, including gene- and cell-therapy products, can be excepted from the obligation of obtaining a marketing authorization via the centralized procedure under specific conditions (so-called "hospital exemption"). This hospital exemption allows the application of gene-therapy medicinal products prepared on a non-routine basis for an individual patient and used under the exclusive professional responsibility of a medical practitioner. Here, we explain the requirements to be fulfilled in order to fall under this exemption, the implementation of this regulation into the German national legislation, and its impact on gene-therapy product development in the future. PMID:22247961

  4. Combined Multi-modal Optical Imaging and Targeted Gene Silencing Using Stimuli-transforming Nanotheragnostics

    PubMed Central

    Shim, Min Suk; Kim, Chang Soo; Ahn, Yeh-Chan; Chen, Zhongping; Kwon, Young Jik

    2010-01-01

    Combined diagnosis and therapy for cancer has been of great interest in medicine. Small interference RNA (siRNA)-encapsulating polyplexes were covalently coated with small gold nanoparticles (Au NPs) via acid-cleavable linkages in order to explore the possibility of achieving combined stimuli-responsive multi-modal optical imaging and stimuli-enhanced gene silencing. In a mildly acidic tumor environment, Au NPs are dissociated from the siRNA-carrying polyplexes, generating various optical signal changes such as diminished scattering intensity, increased variance of Doppler frequency, and blue-shifted UV absorbance (stimuli-responsive imaging). Simultaneously, Au NP dissociation exposes the siRNA-carrying polyplex with elevated surface charge and results in enhanced cellular uptake and transfection (stimuli-enhanced therapy). In this study, the feasibility of achieving combined diagnosis and therapy for cancer (theragnostics) is demonstrated by 1) microscopic and spectrophotometric confirmation of acid-transformation of the nanoparticles, 2) reduced scattering intensity and increased variance of Doppler frequency in an acidic pH upon the nanoparticle’s transformation, and 3) simultaneous optical signal changes and gene silencing in vitro under a tumor pH-mimicking condition. This novel type of stimuli-responsive nanotheragnostics will provide a new paradigm for pinpointed, multi-modal, and combined imaging and therapy for cancer. PMID:20518502

  5. 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

  6. HUMAN GENE THERAPY 19:12611271 (November 2008) Mary Ann Liebert, Inc.

    E-print Network

    Paris-Sud XI, Université de

    of tissues. 1261 Introduction THE CONCEPT OF GENE ELECTROTRANSFER has developed from the first in vitroHUMAN GENE THERAPY 19:1261­1271 (November 2008) © Mary Ann Liebert, Inc. DOI: 10.1089/hum.2008.060 Efficiency of High- and Low-Voltage Pulse Combinations for Gene Electrotransfer in Muscle, Liver, Tumor

  7. HUMAN GENE THERAPY 19:12491260 (November 2008) Mary Ann Liebert, Inc.

    E-print Network

    Paris-Sud XI, Université de

    treatment (Mir et al., 2005). In fact, the first clinical trials with gene electrotransfer to human in the first pioneering study of in vivo gene elec- trotransfer (Titomirov et al., 1991). Comparison of trainsHUMAN GENE THERAPY 19:1249­1260 (November 2008) © Mary Ann Liebert, Inc. DOI: 10.1089/hum.2008

  8. RNAi based gene therapy for Spinocerebellar ataxia-7 HHMI Med-Into-Grad Proposal

    E-print Network

    Gleeson, Joseph G.

    RNAi based gene therapy for Spinocerebellar ataxia-7 Lisa Kurtz HHMI Med-Into-Grad Proposal dominant mutations that lead to expanded polyglutamine repeat regions in specific genes. Individuals of disease. In addition, because a different gene is mutated in each specific form of SCA, each has a unique

  9. Survival of thefittest: in vivo selection and stem cell gene therapy

    Microsoft Academic Search

    Tobias Neff; Brian C. Beard; Hans-Peter Kiem

    2006-01-01

    human stem cells has long been the most prominent obstacle to widespread clinical application of stem cell gene therapy. A solution to this problem has been in vivo selection. In vivo selection increases the proportion of circulating gene-corrected cells by conferring a selective growth and\\/or survival advantage to the corrected cell population. While improvements in gene transfer technology did contribute,

  10. In Vivo Gene Therapy of Hemophilia B: Sustained Partial Correction in Factor IX-Deficient Dogs

    Microsoft Academic Search

    Mark A. Kay; Steven Rothenberg; Charles N. Landen; Dwight A. Bellinger; Frances Leland; Carol Toman; Milton Finegold; Arthur R. Thompson; M. S. Read; Kenneth M. Brinkhous; Savio L. C. Woo

    1993-01-01

    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

  11. Genomic Context Vectors and Artificial Chromosomes for Cystic Fibrosis Gene Therapy

    Microsoft Academic Search

    Massimo Conese; A. Christopher Boyd; Sante Di Gioia; Cristina Auriche; Fiorentina Ascenzioni

    2007-01-01

    Cystic fibrosis (CF) is caused by mutations of the CF transmembrane conductance regulator (CFTR) gene, which encodes a cAMP dependent chloride channel whose expression is finely tuned in space and time. Gene therapy ap- proaches to CF lung disease have demonstrated partial efficacy and short-lived CFTR expression in the airways. Draw- backs in the use of classical gene transfer vectors

  12. 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.

  13. 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

  14. Gene therapy to rescue retinal degeneration caused by mutations in rhodopsin.

    PubMed

    Rossmiller, Brian P; Ryals, Renee C; Lewin, Alfred S

    2015-01-01

    Retinal gene therapy has proven safe and at least partially successful in clinical trials and in numerous animal models. Gene therapy requires characterization of the progression of the disease and understanding of its genetic cause. Testing gene therapies usually requires an animal model that recapitulates the key features of the human disease, though photoreceptors and cells of the retinal pigment epithelium produced from patient-derived stem cells may provide an alternative test system for retinal gene therapy. Gene therapy also requires a delivery system that introduces the therapeutic gene to the correct cell type and does not cause unintended damage to the tissue. Current systems being tested in the eye are nanoparticles, pseudotyped lentiviruses, and adeno-associated virus (AAV) of various serotypes. Here, we describe the techniques of AAV vector design as well as the in vivo and ex vivo tests necessary for assessing the efficacy of retinal gene therapy to treat retinal degeneration caused by mutations in the rhodopsin gene. PMID:25697537

  15. 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

  16. Autoradiography Imaging in Targeted Alpha Therapy with Timepix Detector

    PubMed Central

    AL 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

  17. In vivo quantitative noninvasive imaging of gene transfer by single-photon emission computerized tomography.

    PubMed

    Auricchio, Alberto; Acton, Paul D; Hildinger, Markus; Louboutin, Jean-Pierre; Plössl, Karl; O'Connor, Erin; Kung, Hank F; Wilson, James M

    2003-02-10

    Systems aimed at detecting gene expression noninvasively in vivo are desirable for evaluating the outcome of gene transfer in clinical trials. Several approaches have been exploited using magnetic resonance imaging and spectroscopy ((31)P MRS), positron emission tomography (PET), single-photon emission tomography (SPECT), and detection of bioluminescent signals. An ideal system is based on transfer of a marker gene, the activity of which can be detected against a background from the target tissue without interfering with normal physiology or eliciting an immune response. The majority of approaches described to date use genes encoding a nonmammalian protein that can elicit immune responses or a transmembrane receptor as a marker gene whose ectopic expression may cause aberrant signaling in the target cell through binding to endogenous ligands. The dopamine transporter (DAT) is normally expressed at high levels, mainly in the dopaminergic neurons of the central nervous system. We previously synthesized a radioactive ligand, [(99m)Tc]TRODAT-1, that binds with high affinity to the dopamine transporter, allowing for SPECT imaging of the striatum in normal control subjects and individuals affected with Parkinson's disease. Here we describe a strategy to monitor gene transfer based on adeno-associated viral vector (AAV)-mediated transduction of DAT in murine muscle followed by [(99m)Tc]TRODAT-1 imaging by SPECT of cells expressing the transgene. We show that quantitative, noninvasive imaging of gene transfer is successfully achieved in vivo, using a single-photon computed tomography camera. This system employs a reporter gene encoding a mammalian protein that is absent in most tissues, has no enzymatic activity, and does not activate intracellular pathways. This should be useful to monitor gene transfer in the settings of gene therapy. PMID:12639305

  18. Noise evaluation of Compton camera imaging for proton therapy

    NASA Astrophysics Data System (ADS)

    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.

    2015-02-01

    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.

  19. 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

    2015-02-21

    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

  20. Subthalamic hGAD65 Gene Therapy and Striatum TH Gene Transfer in a Parkinson’s Disease Rat Model

    PubMed Central

    Zheng, Deyu; Jiang, Xiaohua; Zhao, Junpeng; Duan, Deyi; Zhao, Huanying; Xu, Qunyuan

    2013-01-01

    The aim of the present study is to detect a combination method to utilize gene therapy for the treatment of Parkinson’s disease (PD). Here, a PD rat model is used for the in vivo gene therapy of a recombinant adeno-associated virus (AAV2) containing a human glutamic acid decarboxylase 65 (rAAV2-hGAD65) gene delivered to the subthalamic nucleus (STN). This is combined with the ex vivo gene delivery of tyrosine hydroxylase (TH) by fibroblasts injected into the striatum. After the treatment, the rotation behavior was improved with the greatest efficacy in the combination group. The results of immunohistochemistry showed that hGAD65 gene delivery by AAV2 successfully led to phenotypic changes of neurons in STN. And the levels of glutamic acid and GABA in the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNr) were obviously lower than the control groups. However, hGAD65 gene transfer did not effectively protect surviving dopaminergic neurons in the SNc and VTA. This study suggests that subthalamic hGAD65 gene therapy and combined with TH gene therapy can alleviate symptoms of the PD model rats, independent of the protection the DA neurons from death. PMID:23738148