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1

Human gene therapy and imaging: cardiology  

Microsoft Academic Search

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

Joseph C. Wu; Seppo Yla-Herttuala

2005-01-01

2

In Vivo Noninvasive Imaging for Gene Therapy  

PubMed Central

Gene therapy is reaching a stage where some clinical benefits have been demonstrated on patients involved in phase I/II clinical trials. However, in many cases, the clinical benefit is hardly measurable and progress in the improvement of gene therapy formulations is hampered by the lack of objective clinical endpoints to measure transgene delivery and to quantitate transgene expression. However, these endpoints rely almost exclusively on the analysis of biopsies by molecular and histopathological methods. These methods provide only a limited picture of the situation. Therefore, there is a need for a technology that would allow precise, spacio-temporal measurement of gene expression on a whole body scale upon administration of the gene delivery vector. In the field of gene therapy, a considerable effort is being invested in the development of noninvasive imaging of gene expression and this review presents the various strategies currently being developed.

2003-01-01

3

Molecular imaging of gene therapy for cancer  

Microsoft Academic Search

Gene therapy of cancer has been one of the most exciting and elusive areas of scientific and clinical research in the past decade. One of the most critical issues for ensuring success of this therapy is the development of technology for noninvasive monitoring of the location, magnitude and duration of vector-mediated gene expression, as well as the distribution and targeting

K. Shah; A. Jacobs; X. O. Breakefield; R. Weissleder

2004-01-01

4

The Application of Nanoparticles in Gene Therapy and Magnetic Resonance Imaging  

PubMed Central

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.

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

2012-01-01

5

Gene Therapy  

PubMed Central

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.

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

2009-01-01

6

Characterization of Response to Radiation Mediated Gene Therapy via Multi-Modality Imaging  

PubMed Central

Imaging techniques are under development to facilitate early analysis of spatial patterns of tumor response to combined radiation and antivascular gene therapy. A genetically modified, replication defective adenoviral vector (Ad.EGR-TNF?), injected intratumorally, mediates infected cells to express tumor necrosis factor alpha (TNF?), which is increased following exposure to radiation. The goal of this study was to characterize an image based “signature” for response to this combined radiation and gene therapy in mice with human prostate xenografts. This study is part of an imaged guided therapy project where such a signature would be useful in guiding subsequent treatments. Changes in the tumor micro-environment were assessed using MRI registered with electron paramagnetic resonance imaging which provides images of tissue oxygenation. Dynamic contrast-enhanced MRI was used to assess tissue perfusion. When compared to null vector (control) treatment, the ratio of contrast agent (Gd-DTPA-BMA) washout rate to uptake rate was lower (p = 0.001) after treatment, suggesting a more balanced perfusion. Concomitantly, oxygenation significantly increased in the treated animals and decreased or did not change in the control animals (p < 0.025). This is the first report of minimally invasive, quantitative, absolute oxygen measurements correlated with tissue perfusion in vivo.

Haney, Chad R.; Parasca, Adrian D.; Fan, Xiaobing; Bell, Rebecca M.; Zamora, Marta A.; Karczmar, Gregory S.; Mauceri, Helena J.; Halpern, Howard J.; Weichselbaum, Ralph R.; Pelizzari, Charles A.

2009-01-01

7

Integrating Molecular Imaging Approaches to Monitor Prostate Targeted Suicide and Anti-angiogenic Gene Therapy.  

National Technical Information Service (NTIS)

To develop safe and efficient gene therapy protocol for advanced stages of prostate cancer, we aimed to combine the selective suicide and anti- angiogenic gene therapy approaches into an effective targeted treatment for prostate cancer. We propose to inco...

M. Sato

2005-01-01

8

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

PubMed Central

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

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

2010-01-01

9

Dual-therapeutic reporter genes fusion for enhanced cancer gene therapy and imaging.  

PubMed

Two of the successful gene-directed enzyme prodrug therapies include herpes simplex virus-thymidine kinase (HSV1-TK) enzyme-ganciclovir prodrug and the Escherichia coli nitroreductase (NTR) enzyme-CB1954 prodrug strategies; these enzyme-prodrug combinations produce activated cytotoxic metabolites of the prodrugs capable of tumor cell death by inhibiting DNA synthesis and killing quiescent cells, respectively. Both these strategies also affect significant bystander cell killing of neighboring tumor cells that do not express these enzymes. We have developed a dual-combination gene strategy, where we identified HSV1-TK and NTR fused in a particular orientation can effectively kill tumor cells when the tumor cells are treated with a fusion HSV1-TK-NTR gene- along with a prodrug combination of GCV and CB1954. In order to determine whether the dual-system demonstrate superior therapeutic efficacy than either HSV1-TK or NTR systems alone, we conducted both in vitro and in vivo tumor xenograft studies using triple negative SUM159 breast cancer cells, by evaluating the efficacy of cell death by apoptosis and necrosis upon treatment with the dual HSV1-TK genes-GCV-CB1954 prodrugs system, and compared the efficiency to HSV1-TK-GCV and NTR-CB1954. Our cell-based studies, tumor regression studies in xenograft mice, histological analyses of treated tumors and bystander studies indicate that the dual HSV1-TK-NTR-prodrug system is two times more efficient even with half the doses of both prodrugs than the respective single gene-prodrug system, as evidenced by enhanced apoptosis and necrosis of tumor cells in vitro in culture and xenograft of tumor tissues in animals. PMID:22914496

Sekar, T V; Foygel, K; Willmann, J K; Paulmurugan, R

2013-05-01

10

Myocardial gene therapy  

NASA Astrophysics Data System (ADS)

Gene therapy is proving likely to be a viable alternative to conventional therapies in coronary artery disease and heart failure. Phase 1 clinical trials indicate high levels of safety and clinical benefits with gene therapy using angiogenic growth factors in myocardial ischaemia. Although gene therapy for heart failure is still at the pre-clinical stage, experimental data indicate that therapeutic angiogenesis using short-term gene expression may elicit functional improvement in affected individuals.

Isner, Jeffrey M.

2002-01-01

11

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

PubMed Central

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.

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

2012-01-01

12

Molecular Imaging of Biological Gene Delivery Vehicles for Targeted Cancer Therapy: Beyond Viral Vectors  

Microsoft Academic Search

Cancer persists as one of the most devastating diseases in the world. Problems including metastasis and tumor resistance to\\u000a chemotherapy and radiotherapy have seriously limited the therapeutic effects of present clinical treatments. To overcome these\\u000a limitations, cancer gene therapy has been developed over the last two decades for a broad spectrum of applications, from gene\\u000a replacement and knockdown to vaccination,

Jung-Joon Min; Vu H. Nguyen; Sanjiv S. Gambhir

2010-01-01

13

Hypoxia imaging predicts success of hypoxia-induced cytosine deaminase/5-fluorocytosine gene therapy in a murine lung tumor model.  

PubMed

Tc-99m-HL91 is a hypoxia imaging biomarker. The aim of this study was to investigate the value of Tc-99m-HL91 imaging for hypoxia-induced cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy in a murine lung tumor model. C57BL/6 mice were implanted with Lewis lung carcinoma cells transduced with the hypoxia-inducible promoter-driven CD gene (LL2/CD) or luciferase gene (LL2/Luc) serving as the control. When tumor volumes reached 100?mm(3), pretreatment images were acquired after injection of Tc-99m-HL91. The mice were divided into low and high hypoxic groups based on the tumor-to-non-tumor ratio of Tc-99m-HL91. They were injected daily with 5-FC (500?mg?kg(-1)) or the vehicle for 1 week. When tumor volumes reached 1000?mm(3), autoradiography and histological examinations were performed. Treatment with 5-FC delayed tumor growth and enhanced the survival of mice bearing high hypoxic LL2/CD tumors. The therapeutic effect of hypoxia-induced CD/5-FC gene therapy was more pronounced in high hypoxic tumors than in low hypoxic tumors. This study provides the first evidence that Tc-99m-HL91 can serve as an imaging biomarker for predicting the treatment responses of hypoxia-regulated CD/5-FC gene therapy in animal tumor models. Our results suggest that hypoxia imaging using Tc-99m-HL91 has the predictive value for the success of hypoxia-directed treatment regimens. PMID:22281757

Lee, B-F; Lee, C-H; Chiu, N-T; Hsia, C-C; Shen, L-H; Shiau, A-L

2012-04-01

14

Gene therapy for arthritis  

Microsoft Academic Search

\\u000a Gene therapy has a potential for effective therapeutic intervention in rheumatoid arthritis (RA). Proof of concept has been\\u000a demonstrated in animal models, either through local gene delivery to the joint space or through systemic gene delivery for\\u000a immune intervention. This chapter reviews how certain clinical applications of gene therapy would be beneficial for RA patients\\u000a and discusses the roadblocks that

Florence Apparailly; Paul Peter Tak; Christian Jorgensen

15

Image-guided, Tumor Stroma-targeted 131I Therapy of Hepatocellular Cancer After Systemic Mesenchymal Stem Cell-mediated NIS Gene Delivery  

Microsoft Academic Search

Due to its dual role as reporter and therapy gene, the sodium iodide symporter (NIS) allows noninvasive imaging of functional NIS expression by 123I-scintigraphy or 124I-PET imaging before the application of a therapeutic dose of 131I. NIS expression provides a novel mechanism for the evaluation of mesenchymal stem cells (MSCs) as gene delivery vehicles for tumor therapy. In the current

Kerstin Knoop; Marie Kolokythas; Kathrin Klutz; Michael J. Willhauck; Nathalie Wunderlich; Dan Draganovici; Christian Zach; Franz-Josef Gildehaus; Guido Böning; Burkhard Göke; Ernst Wagner; Peter J. Nelson; Christine Spitzweg

2011-01-01

16

Sodium iodide symporter for nuclear molecular imaging and gene therapy: from bedside to bench and back.  

PubMed

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

Ahn, Byeong-Cheol

2012-01-01

17

Parkinson's Disease: Gene Therapies  

PubMed Central

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.

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

2012-01-01

18

DNA Micelle Flares for Intracellular mRNA Imaging and Gene Therapy  

PubMed Central

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.

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

2013-01-01

19

Gene therapy for haemophilia  

PubMed Central

The ultimate goal of gene therapy is the replacement of a defective gene sequence with a corrected version to eliminate disease for the lifetime of the patient. This challenging task is not yet accomplished, however significant progress is evident. An initial spate of clinical trials attempting the treatment of haemophilia with gene transfer primarily resulted in the demonstration of good safety profiles, but without efficacy. Subsequent reengineering of vector plasmids and delivery systems resulted in markedly improved outcomes in animal models of the disease. The most recent clinical trial for the treatment of haemophilia B with gene transfer showed transient achievement of efficacy in the highest dose cohort tested, but also exposed a previously hidden barrier to the future success of these treatments. The progress and problems of gene therapies for haemorrhagic disorders will be discussed. This review will concentrate on approaches in or near clinical application.

Murphy, Samuel L; High, Katherine A

2008-01-01

20

Gene therapy for arthritis  

PubMed Central

Arthritis is among the leading causes of disability in the developed world. There remains no cure for this disease and the current treatments are only modestly effective at slowing the disease's progression and providing symptomatic relief. The clinical effectiveness of current treatment regimens has been limited by short half-lives of the drugs and the requirement for repeated systemic administration. Utilizing gene transfer approaches for the treatment of arthritis may overcome some of the obstacles associated with current treatment strategies. The present review examines recent developments in gene therapy for arthritis. Delivery strategies, gene transfer vectors, candidate genes, and safety are also discussed.

Traister, Russell S.

2008-01-01

21

Gene Therapy for Hypertension  

Microsoft Academic Search

Despite several drugs for the treatment of hypertension, there are many patients with poorly controlled high blood pressure. This is partly because all of the available drugs are short-lasting ( #24 hours), have side effects, and are not highly specific. Gene therapy offers a possibility of producing longer-lasting effects with precise specificity based on the genetic design. Preclinical studies on

M. Ian Phillips

2010-01-01

22

Homologous Recombination Based Gene Therapy  

Microsoft Academic Search

Background\\/Aims: Most of the current expression vector based gene therapy protocols fail to achieve clinically significant transgene expression required for treating genetic diseases. Homologous recombination, initially considered to be of limited use for gene therapy because of its low frequency in mammalian cells, has recently emerged as a potential strategy for developing gene therapy. Methods: Six recent studies of homologous

Li-Wen Lai; Yeong-Hau H. Lien

1999-01-01

23

Optical image-guided cancer therapy.  

PubMed

Optical molecular imaging holds great promise for image guiding cancer therapy. The non-invasive guidance of therapeutic strategies would enable the removal of cancerous tissue while avoiding side effects and systemic toxicity, preventing damage of healthy tissues and decreasing the risk of postoperative problems. This review article highlights the advantages and disadvantages of the optical imaging techniques that are currently available, including their recent applications in image-guided cancer therapy. Three approaches for optical image-guided cancer therapy were discussed in this review, namely, bioluminescence imaging (BLI), fluorescence imaging (FI) and Cerenkov luminescence imaging (CLI). BLI is always used in small animal imaging for the in vivo tracking of therapeutic gene expression and cell-based therapy. To the contrary, FI display high promising for clinical translation. The applications of FI include image-guided surgery, radiotherapy, gene therapy, drug delivery and sentinel lymph node fluorescence mapping. CLI is a novel radioactive optical hybrid imaging strategy and its use for animal and clinical translation was also discussed. Perspectives on the translation of optical image-guided cancer therapy into clinical practice were provided. PMID:24372233

Bu, Lihong; Ma, Xiaowei; Tu, Yingfeng; Shen, Baozhong; Cheng, Zhen

2014-10-01

24

Gene therapy in diabetes  

PubMed Central

Type 1 diabetes (T1D) is a chronic autoimmune disease, whereby auto-reactive cytotoxic T cells target and destroy insulin-secreting ?-cells in pancreatic islets leading to insulin deficiency and subsequent hyperglycemia. These individuals require multiple daily insulin injections every day of their life without which they will develop life-threatening diabetic ketoacidosis (DKA) and die. Gene therapy by viral vector and non-viral transduction may be useful techniques to treat T1D as it can be applied from many different angles; such as the suppression of autoreactive T cells to prevent islet destruction (prophylactic) or the replacement of the insulin gene (post-disease). The need for a better method for providing euglycemia arose from insufficient numbers of cadaver islets for transplantation and the immunosuppression required post-transplant. Ectopic expression of insulin or islet modification have been examined, but not perfected. This review examines the various gene transfer methods, gene therapy techniques used to date and promising novel techniques for the maintenance of euglycemia in the treatment of T1D.

Wong, Mary S; Hawthorne, Wayne J

2010-01-01

25

Cardiac Gene Therapy  

PubMed Central

Heart failure is a chronic progressive disorder where frequent and recurrent hospitalizations are associated with high mortality and morbidity. The incidence and the prevalence of this disease will increase with the increase in the number of the aging population of the United States. Understanding the molecular pathology and pathophysiology of this disease will uncover novel targets and therapies that can restore the function or attenuate the damage of malfunctioning cardiomyocytes by gene therapy that becomes an interesting and a promising field for the treatment of heart failure as well as other diseases in the future. Of equal importance is developing vectors and delivery methods that can efficiently transduce the majority of the cardiomyocytes, that can offer a long term expression and that can escape the host immune response. Recombinant adeno-associated virus vectors have the potential to become a promising novel therapeutic vehicles for molecular medicine in the future.

Chaanine, Antoine H.; Kalman, Jill; Hajjar, Roger J.

2010-01-01

26

Image-guided, Tumor Stroma-targeted 131I Therapy of Hepatocellular Cancer After Systemic Mesenchymal Stem Cell-mediated NIS Gene Delivery  

PubMed Central

Due to its dual role as reporter and therapy gene, the sodium iodide symporter (NIS) allows noninvasive imaging of functional NIS expression by 123I-scintigraphy or 124I-PET imaging before the application of a therapeutic dose of 131I. NIS expression provides a novel mechanism for the evaluation of mesenchymal stem cells (MSCs) as gene delivery vehicles for tumor therapy. In the current study, we stably transfected bone marrow–derived CD34? MSCs with NIS cDNA (NIS-MSC), which revealed high levels of functional NIS protein expression. In mixed populations of NIS-MSCs and hepatocellular cancer (HCC) cells, clonogenic assays showed a 55% reduction of HCC cell survival after 131I application. We then investigated body distribution of NIS-MSCs by 123I-scintigraphy and 124I-PET imaging following intravenous (i.v.) injection of NIS-MSCs in a HCC xenograft mouse model demonstrating active MSC recruitment into the tumor stroma which was confirmed by immunohistochemistry and ex vivo ?-counter analysis. Three cycles of systemic MSC-mediated NIS gene delivery followed by 131I application resulted in a significant delay in tumor growth. Our results demonstrate tumor-specific accumulation and therapeutic efficacy of radioiodine after MSC-mediated NIS gene delivery in HCC tumors, opening the prospect of NIS-mediated radionuclide therapy of metastatic cancer using MSCs as gene delivery vehicles.

Knoop, Kerstin; Kolokythas, Marie; Klutz, Kathrin; Willhauck, Michael J.; Wunderlich, Nathalie; Draganovici, Dan; Zach, Christian; Gildehaus, Franz-Josef; Boning, Guido; Goke, Burkhard; Wagner, Ernst; Nelson, Peter J.; Spitzweg, Christine

2011-01-01

27

Gene therapy for psychiatric disorders.  

PubMed

Gene therapy has become of increasing interest in clinical neurosurgery with the completion of numerous clinical trials for Parkinson disease, Alzheimer disease, and pediatric genetic disorders. With improved understanding of the dysfunctional circuitry mediating various psychiatric disorders, deep brain stimulation for refractory psychiatric diseases is being increasingly explored in human patients. These factors are likely to facilitate development of gene therapy for psychiatric diseases. Because delivery of gene therapy agents would require the same surgical techniques currently being employed for deep brain stimulation, neurosurgeons are likely to lead the development of this field, as has occurred in other areas of clinical gene therapy for neurologic disorders. We review the current state of gene therapy for psychiatric disorders and focus specifically on particular areas of promising research that may translate into human trials for depression, drug addiction, obsessive-compulsive disorder, and schizophrenia. Issues that are relatively unique to psychiatric gene therapy are also discussed. PMID:23268195

Gelfand, Yaroslav; Kaplitt, Michael G

2013-01-01

28

Gene Therapy for Chronic Pain  

Microsoft Academic Search

\\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

William R. Lariviere; Doris K. Cope

29

Hematopoietic Stem Cell Gene Therapy  

Microsoft Academic Search

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

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

2002-01-01

30

Gene therapy for Deafness  

PubMed Central

Hearing loss is the most common sensory deficit in humans and can result from genetic, environmental, or combined etiologies that prevent normal function of the cochlea, the peripheral sensory organ. Recent advances in understanding the genetic pathways that are critical for the development and maintenance of cochlear function, as well as the molecular mechanisms that underlie cell trauma and death have provided exciting opportunities for modulating these pathways to correct genetic mutations, to enhance endogenous protective pathways for hearing preservation and to regenerate lost sensory cells with the possibility of ameliorating hearing loss. A number of recent animal studies have used gene-based therapies in innovative ways toward realizing these goals. With further refinement, some of the protective and regenerative approaches reviewed here may become clinically applicable.

Kohrman, David C.; Raphael, Yehoash

2014-01-01

31

Gene therapy for ocular diseases  

PubMed Central

The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.

Liu, Melissa M; Tuo, Jingsheng; Chan, Chi-Chao

2011-01-01

32

Long-term in vivo imaging of translated RNAs for gene therapy.  

PubMed

To determine the potential of RNA for transient expression, we followed its translational efficiency and expression kinetics in vivo in mouse skin. Three RNA species were delivered in vivo with differing 5' and 3' ends, as well as with different structures that are known to influence their translation fate, such as an internal ribosome entry site (IRES), a cap or a poly(A) tail. RNAs were transferred by electropermeabilization, and each encoded the firefly luciferase enzyme to allow monitoring of translational efficiency by in vivo bioluminescence imaging. We show that all types of naked RNAs delivered into mouse skin are efficient for transient protein expression in vivo. Expression could be achieved with some differences in efficiency and time course, using either capped/polyadenylated RNAs or RNAs containing HCV IRES structures with or without a poly(A) tail. Our data reveal expression occurring up to 2 weeks, suggesting that electroporated RNA has high stability in vivo, particularly capped and polyadenylated RNAs. Our study shows that RNA molecules are efficient tools for the transient expression of proteins in vivo and that they can be used for therapeutic purposes. Changes in RNA features may be used to modulate both expression efficiency and kinetics. PMID:24430234

Pinel, K; Lacoste, J; Plane, G; Ventura, M; Couillaud, F

2014-04-01

33

GENE THERAPY FOR LUNG NEOPLASMS  

PubMed Central

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

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

2011-01-01

34

Prospects for Human Gene Therapy  

Microsoft Academic Search

Procedures have now been developed for inserting functional genes into the bone marrow of mice. The most effective delivery system at present uses retroviral-based vectors to transfer a gene into murine bone marrow cells in culture. The genetically altered bone marrow is then implanted into recipient animals. These somatic cell gene therapy techniques are becoming increasingly efficient. Their future application

W. French Anderson

1984-01-01

35

Gene therapy in cystic fibrosis.  

PubMed

The principal cause of morbidity and mortality in cystic fibrosis (CF) is pulmonary disease, so the focus of new treatments in this condition is primarily targeted at the lungs. Since the cloning of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene in 1989, there has been significant interest in the possibility of gene therapy as a treatment for CF. Early studies using viral vectors carrying a healthy CFTR plasmid highlighted the difficulties with overcoming the body's host defences. This article reviews the work on gene therapy in CF to date and describes the ongoing work of the UK CF Gene Therapy Consortium in investigating the potential of gene therapy as a treatment for patients with CF. PMID:24464978

Armstrong, David K; Cunningham, Steve; Davies, Jane C; Alton, Eric W F W

2014-05-01

36

Gene Therapy for Parkinson's Disease  

PubMed Central

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.

Denyer, Rachel; Douglas, Michael R.

2012-01-01

37

Prospects for Human Gene Therapy.  

National Technical Information Service (NTIS)

In this taped lecture Dr. Anderson reviews the currently most promising means for using gene therapy in managing various disease states. He outlines a technique by which genetically modified calls can be used in a specific cancer chemotherapy protocol, an...

1994-01-01

38

Gene therapy on the move  

PubMed Central

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.

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

2013-01-01

39

Arthritis gene therapy's first death  

PubMed Central

In July 2007 a subject died while enrolled in an arthritis gene therapy trial. The study was placed on clinical hold while the circumstances surrounding this tragedy were investigated. Early in December 2007 the Food and Drug Administration removed the clinical hold, allowing the study to resume with minor changes to the protocol. In the present article we collate the information we were able to obtain about this clinical trial and discuss it in the wider context of arthritis gene therapy.

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

2008-01-01

40

Gene Therapy for Pituitary Tumors  

PubMed Central

Pituitary tumors are the most common primary intracranial neoplasms. Although most pituitary tumors are considered typically benign, others can cause severe and progressive disease. The principal aims of pituitary tumor treatment are the elimination or reduction of the tumor mass, normalization of hormone secretion and preservation of remaining pituitary function. In spite of major advances in the therapy of pituitary tumors, for some of the most difficult tumors, current therapies that include medical, surgical and radiotherapeutic methods are often unsatisfactory and there is a need to develop new treatment strategies. Gene therapy, which uses nucleic acids as drugs, has emerged as an attractive therapeutic option for the treatment of pituitary tumors that do not respond to classical treatment strategies if the patients become intolerant to the therapy. The development of animal models for pituitary tumors and hormone hypersecretion has proven to be critical for the implementation of novel treatment strategies and gene therapy approaches. Preclinical trials using several gene therapy approaches for the treatment of anterior pituitary diseases have been successfully implemented. Several issues need to be addressed before clinical implementation becomes a reality, including the development of more effective and safer viral vectors, uncovering novel therapeutic targets and development of targeted expression of therapeutic transgenes. With the development of efficient gene delivery vectors allowing long-term transgene expression with minimal toxicity, gene therapy will become one of the most promising approaches for treating pituitary adenomas.

Seilicovich, Adriana; Pisera, Daniel; Sciascia, Sandra A.; Candolfi, Marianela; Puntel, Mariana; Xiong, Weidong; Jaita, Gabriela; Castro, Maria G.

2009-01-01

41

PET imaging of adoptive progenitor cell therapies  

Microsoft Academic Search

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

Gelovani; Juri G

2008-01-01

42

GENE THERAPY FOR VENTRICULAR TACHYARRHYTHMIAS  

PubMed Central

Cardiac arrest is the leading cause of death in the United States and other developed countries. Ventricular tachyarrhythmias are the most prominent cause of cardiac arrest, and patients with structural heart disease are at increased risk for these abnormal heart rhythms. Drug and device therapy have important limitations that make them inadequate to meet this challenge. We and others have proposed development of arrhythmia gene therapy as an alternative to current treatment methods. In this review, I discuss the basic mechanisms of ventricular arrhythmias and summarize the literature on the use of gene therapy for ventricular tachyarrhythmias.

Donahue, J. Kevin

2013-01-01

43

Nanobiodevice based single cell imaging for cancer diagnosis and in vivo imaging for stem cell therapy  

Microsoft Academic Search

The lecture will describe new synthetic method for quantum dots (QDs) and their applications to the single molecular real-time imaging of enzymatic reaction, single cancer cell and cancer stem cell imaging, stem cell in vivo imaging, imaging of single QD tracking in a single living cell for cancer diagnosis, stem cell therapy, and gene delivery therapy.

Y. Baba

2010-01-01

44

Gene therapy\\/cell therapy for lysosomal storage disease  

Microsoft Academic Search

Lysosomal storage diseases (LSD) are considered to be appropriate disorders for gene therapy\\/cell therapy. We are attempting to treat one of these disorders using a mouse model, the Sly mouse. This is an authentic model for human ß-glucuronidase deficiency, MPS VII. We have carried out two types of experimental protocols; in vivo gene therapy and ex vivo gene therapy using

Y. Eto; T. Ohashi

2000-01-01

45

for Hemophilia B Gene Therapy  

Microsoft Academic Search

Adeno-associated viral (AAV) vector is attracting significant interest for use in gene therapy for genetic diseases, because of its unique and advantageous characteristics, compared to other currently available viral vectors. Eight natural serotypes of AAV have been identified, of which AAV serotype 2 is the one best characterized and most widely used in current gene delivery studies. The application of

HENGJUN CHAO; CHRISTOPHER E. WALSH

46

Switching on the Lights for Gene Therapy  

PubMed Central

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 expression of any type of gene after in vivo transduction by versatile vectors is feasible, we generated regulatable herpes simplex virus type 1 (HSV-1) amplicon vectors carrying hormone (mifepristone) or antibiotic (tetracycline) regulated promoters driving the proportional co-expression of two marker genes. Regulated gene expression was monitored by fluorescence microscopy in culture and by positron emission tomography (PET) or bioluminescence (BLI) in vivo. The induction levels evaluated in glioma models varied depending on the dose of inductor. With fluorescence microscopy and BLI being the tools for assessing gene expression in culture and animal models, and with PET being the technology for possible application in humans, the generated vectors may serve to non-invasively monitor the dynamics of any gene of interest which is proportionally co-expressed with the respective imaging marker gene in research applications aiming towards translation into clinical application.

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

2007-01-01

47

Gene therapy in status epilepticus.  

PubMed

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

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

2013-09-01

48

Gene Therapy for Heart Failure  

PubMed Central

Congestive heart failure accounts for half a million deaths per year in the US. Despite its place among the leading causes of morbidity, pharmcalogical and mechanic remedies have been able to slow the progression of the disease, today’s science has yet to provide a cure and there are few therapeutic modalities available for patients with advanced heart failure. There is a critical need to explore new therapeutic approaches in heart failure and gene therapy has emerged as a viable alternative. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, has placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) along with the start of more recent phase 1 trials opens a new era for gene therapy for the treatment of heart failure.

Tilemann, Lisa; Ishikawa, Kiyotake; Weber, Thomas; Hajjar, Roger J.

2012-01-01

49

Delivery systems for gene therapy  

PubMed Central

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

Mali, Shrikant

2013-01-01

50

Gene therapy for pancreatitis pain.  

PubMed

Pancreatic cancer and chronic pancreatitis are clinical syndromes associated with severe pain that is difficult to manage. Thus, seeking additional pain reduction therapies is warranted. Excessive alcohol consumption over an extended period of time is the primary causal agent in pancreatitis. The efficacy of a replication defective Herpes (HSV-1, DPE) viral vector construct encoding the human preproenkephalin gene (HSV-Enk), used as a molecular therapy for alleviation of pancreatitis pain, is reviewed here. The characteristics of the gene therapy treatment for inflammation and pain-related behavior in two alcoholic pancreatitis animal models is described. Significant analgesia and protection of pancreatic tissue was provided for the duration of the transgene expression (approximately 4-6 weeks). These studies establish a basis for use of HSV-based gene therapy for chronic visceral pain. Targeted enkephalin gene therapy approaches are providing clear promise for pain control. As innovative means of significantly reducing pancreatic inflammation and preserving tissue architecture, they may extend their clinical usefulness for pancreatitis and pancreatic cancer pain patients. PMID:19262610

Westlund, K N

2009-04-01

51

Gene therapy in clinical medicine  

PubMed Central

Although the field of gene therapy has experienced significant setbacks and limited success, it is one of the most promising and active research fields in medicine. Interest in this therapeutic modality is based on the potential for treatment and cure of some of the most malignant and devastating diseases affecting humans. Over the next decade, the relevance of gene therapy to medical practices will increase and it will become important for physicians to understand the basic principles and strategies that underlie the therapeutic intervention. This report reviews the history, basic strategies, tools, and several current clinical paradigms for application.

Selkirk, S

2004-01-01

52

Gene Therapy for Erectile Dysfunction  

Microsoft Academic Search

Our current understanding of the underlying mechanisms of erectile dysfunction suggests that gene therapy will become a therapeutic\\u000a treatment in the near future. Over the past decade, erectile dysfunction has been ameliorated in animal models using viral-and\\u000a plasmid-based vectors. Genes that stimulate smooth muscle cell relaxation, such as neuronal, inducible, and endothelial nitric\\u000a oxide synthase, or that inhibit smooth muscle

Thomas R. Magee; Jacob Rajfer; Nestor F. Gonzalez-Cadavid

53

Gene Therapy of Brain and Endocrine Tumors  

Microsoft Academic Search

Gene therapy of cancer has become a major interest of medical research since more than 60% of the ongoing gene therapy protocols today involve cancer patients. To increase the therapeutic index of cancer gene therapy, targeting strategies have been developed to ensure that the expression of therapeutic genes is restricted exclusively to the tissue of interest. An attractive approach lies

Giorgio Palù; Roberta Bonaguro; Elisa Gnatta; Elisa Franchin; Luisa Barzon

54

Orthopedic Gene Therapy in 2008  

Microsoft Academic Search

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

Christopher H Evans; Steven C Ghivizzani; Paul D Robbins

2009-01-01

55

Ethics of Gene Therapy Debated.  

ERIC Educational Resources Information Center

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)

Borman, Stu

1991-01-01

56

Prospects for human gene therapy.  

PubMed

Procedures have now been developed for inserting functional genes into the bone marrow of mice. The most effective delivery system at present uses retroviral-based vectors to transfer a gene into murine bone marrow cells in culture. The genetically altered bone marrow is then implanted into recipient animals. These somatic cell gene therapy techniques are becoming increasingly efficient. Their future application in humans should result in at least partial correction of a number of genetic disorders. However, the safety of the procedures must still be established by further animal studies before human clinical trials would be ethical. PMID:6093246

Anderson, W F

1984-10-26

57

Gene therapy in Parkinson's disease.  

PubMed

Gene therapy in Parkinson's disease appears to be at the brink of the clinical study phase. Future gene therapy protocols will be based on a substantial amount of preclinical data regarding the use of ex vivo and in vivo genetic modifications with the help of viral or non-viral vectors. To date, the supplementation of neurotrophic factors and substitution for the dopaminergic deficit have formed the focus of trials to achieve relief in animal models of Parkinson's disease. Newer approaches include attempts to influence detrimental cell signalling pathways and to inhibit overactive basal ganglia structures. Nevertheless, current models of Parkinson's disease do not mirror all aspects of the human disease, and important issues with respect to long-term protein expression, choice of target structures and transgenes and safety remain to be solved. Here, we thoroughly review available animal data of gene transfer in models of Parkinson's disease. PMID:15322915

Eberhardt, O; Schulz, J B

2004-10-01

58

Combination of Gene Therapy with Radiation  

Microsoft Academic Search

To date tremendous progress has been made in the field of cancer gene therapy. Strategies have been explored for achieving\\u000a therapeutic benefit using various genes and several clinical trials for cancer gene therapy have been carried out demonstrating\\u000a that gene therapy is well tolerated. However, in most cases the efficacy of gene transfer has been very limited. As an alternative,

Anupama Munshi; Raymond E. Meyn

59

Muscle Gene Therapy for Hemophilia  

PubMed Central

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.

Sabatino, Denise E.; Arruda, Valder R.

2013-01-01

60

Gene Therapy for Primary Immunodeficiencies  

PubMed Central

Abstract For over 40 years, primary immunodeficiencies (PIDs) have featured prominently in the development and refinement of human allogeneic hematopoietic stem cell transplantation. More recently, ex vivo somatic gene therapy using autologous cells has provided remarkable evidence of clinical efficacy in patients without HLA-matched stem cell donors and in whom toxicity of allogeneic procedures is likely to be high. Together with improved preclinical models, a wealth of information has accumulated that has allowed development of safer, more sophisticated technologies and protocols that are applicable to a much broader range of diseases. In this review we summarize the status of these gene therapy trials and discuss the emerging application of similar strategies to other PIDs.

Rivat, Christine; Santilli, Giorgia; Gaspar, H. Bobby

2012-01-01

61

Phoenix rising: gene therapy makes a comeback.  

PubMed

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

Limberis, Maria P

2012-08-01

62

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

PubMed

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

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

2013-08-10

63

Advancement and prospects of tumor gene therapy  

PubMed Central

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

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

2011-01-01

64

Gene therapy and its implications in Periodontics  

PubMed Central

Gene therapy is a field of Biomedicine. With the advent of gene therapy in dentistry, significant progress has been made in the control of periodontal diseases and reconstruction of dento-alveolar apparatus. Implementation in periodontics include: -As a mode of tissue engineering with three approaches: cell, protein-based and gene delivery approach. -Genetic approach to Biofilm Antibiotic Resistance. Future strategies of gene therapy in preventing periodontal diseases: -Enhances host defense mechanism against infection by transfecting host cells with an antimicrobial peptide protein-encoding gene. -Periodontal vaccination. Gene therapy is one of the recent entrants and its applications in the field of periodontics are reviewed in general here.

Mahale, Swapna; Dani, Nitin; Ansari, Shumaila S.; Kale, Triveni

2009-01-01

65

Cancer Treatment with Gene Therapy and Radiation Therapy  

PubMed Central

Radiation therapy methods have evolved remarkably in recent years which have resulted in more effective local tumor control with negligible toxicity of surrounding normal tissues. However, local recurrence and distant metastasis often occur following radiation therapy mostly due to the development of radioresistance through the deregulation of the cell cycle, apoptosis, and inhibition of DNA damage repair mechanisms. Over the last decade, extensive progress in radiotherapy and gene therapy combinatorial approaches has been achieved to overcome resistance of tumor cells to radiation. In this review, we summarize the results from experimental cancer therapy studies on the combination of radiation therapy and gene therapy.

Kaliberov, Sergey A.; Buchsbaum, Donald J.

2013-01-01

66

Gene Therapy in Oral Cancer: A Review  

PubMed Central

Gene therapy is the use of DNA as an agent to treat disease. Gene therapy aims at the insertion of a functional gene into the cells of a patient for the correction of an inborn error of metabolism, to alter or repair an acquired genetic abnormality, and to provide new function to the cell. Many experiments have been done with respect to its application in various diseases.Today, most of the gene therapy studies are aimed at cancer and hereditary diseases which are linked to genetic defects. Cancer usually occurs due to the production of multiple mutations in a single cell which cause it to proliferate out of control. Several methods such as surgery, radiation therapy and chemotherapy have been used widely to treat cancers. But, the cancer patients who are not helped by these therapies can be treated by gene therapy. The purpose of this article is to review the use and purpose of gene therapy in oral cancer.

Kumar, M. Sathish; Masthan, K.M.K.; Babu, N. Aravindha; Dash, Kailash Chandra

2013-01-01

67

Gene therapy in oral cancer: a review.  

PubMed

Gene therapy is the use of DNA as an agent to treat disease. Gene therapy aims at the insertion of a functional gene into the cells of a patient for the correction of an inborn error of metabolism, to alter or repair an acquired genetic abnormality, and to provide new function to the cell. Many experiments have been done with respect to its application in various diseases.Today, most of the gene therapy studies are aimed at cancer and hereditary diseases which are linked to genetic defects. Cancer usually occurs due to the production of multiple mutations in a single cell which cause it to proliferate out of control. Several methods such as surgery, radiation therapy and chemotherapy have been used widely to treat cancers. But, the cancer patients who are not helped by these therapies can be treated by gene therapy. The purpose of this article is to review the use and purpose of gene therapy in oral cancer. PMID:23905156

Kumar, M Sathish; Masthan, K M K; Babu, N Aravindha; Dash, Kailash Chandra

2013-06-01

68

PET imaging of adoptive progenitor cell therapies.  

SciTech Connect

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.

Gelovani, Juri G.

2008-05-13

69

Translational considerations for CNS gene therapy.  

PubMed

Gene transfer is being rigorously evaluated in the laboratory in the preparation for the development of clinical therapies. Many CNS diseases, which have proved more challenging to treat than peripheral disorders, are prime candidates for gene therapy. However, there are numerous considerations in the development of gene therapy, including delivery, maintenance of expression, transgene level regulation, toxicity of the viral vector system and safety of the gene product. The authors review these issues and discuss various approaches used in preclinical studies. Alzheimer's and Parkinson's disease are employed as models, in which much research has already been performed, to address disease-specific questions about gene therapy approaches. PMID:17309323

Ryan, Deborah A; Federoff, Howard J

2007-03-01

70

Hematopoietic Stem Cell Expansion and Gene Therapy  

PubMed Central

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

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

2012-01-01

71

[Gene therapy for Parkinson's disease].  

PubMed

Parkinson's disease is a chronic and progressive disorder whose treatment does not prevent middle term appearance of invalidating motor and psychic complications. Gene therapy techniques which are increasingly applied in the field of neurodegenerative diseases are added to the possibility of treatment of this disease. Among the existing modalities, the in vivo strategies that use potent viral vectors are those which have obtained the best results in the different existing models of the disease. This article aims to review the information regarding the use of these latter techniques, the therapeutic trials that have been conducted and the advantages and disadvantages that the use of the different vectors have. PMID:17315100

Gómez Gallego, M; Fernández Barreiro, A

2007-01-01

72

Non-invasive in vivo imaging with radiolabelled FIAU for monitoring cancer gene therapy using herpes simplex virus type 1 thymidine kinase and ganciclovir.  

PubMed

An experimental cancer gene therapy model was employed to develop a non-invasive imaging procedure using radiolabelled 2'-fluoro-2'-deoxy-5-iodo-1-beta- d-arabinofuranosyluracil (FIAU) as an enzyme substrate for monitoring retroviral vector-mediated herpes simplex virus type 1 thymidine kinase gene ( HSV1-tk) transgene expression. Iodine-131 labelled FIAU was prepared by a no-carrier-added (n.c.a.) synthesis process and lyophilised to give "hot kits". The labelling yield was over 95%, with a radiochemical purity of more than 98%. The stability of [(131)I]FIAU in the form of lyophilised powder (the hot kit) was much better than that in the normal saline solution. The shelf life of the final [(131)I]FIAU hot kit product is as long as 4 weeks. Cellular uptake of [(131)I]FIAU after different periods of storage was investigated in vitro with HSV1-tk-retroviral vector transduced NG4TL4-STK and parental non-transduced NG4TL4 murine sarcoma cell lines over an 8-h incubation period. The NG4TL4-STK cells accumulated more radioactivity than NG4TL4 cells in all conditions, and accumulation increased with time up to 8 h. The kinetic profile of the cellular uptake of n.c.a. [(131)I]FIAU formulated from the lyophilised hot kit or from the stock solution was qualitatively similar. For animal model cancer gene therapy studies, FVB/N mice were inoculated subcutaneously with the HSV1-tk(+) and tk(-) sarcoma cells into the flank to produce tumours. Biodistribution studies showed that tumour/blood ratios were 2, 3.5, 8.2 and 386.8 at 1, 4, 8 and 24 h post injection, respectively, for the HSV1-tk(+) tumours, and 0.5, 0.5, 0.7 and 5.4, respectively, for the HSV1-tk(-) tumours. Radiotracer clearance from blood was completed in 24 h and was bi-exponential. A significant difference in radioactivity accumulation was revealed among the HSV1-tk(+) tumours, the tk(-) tumours and other tissues. At 24 h p.i., higher activity retention was observed in HSV1-tk(+) tumours (9.67%+/-3.89%ID/g) than in HSV1-tk(-) tumours (0.48%+/-0.19%ID/g). After seven consecutive daily treatments with the prodrug ganciclovir, planar gamma camera imaging showed HSV1-tk(+) tumour regression at day 4, and complete tumour regression at day 7. These results clearly demonstrate that the simplified n.c.a. synthesis process developed in this study is reliable and that the [(131)I]FIAU product is useful for in vivo monitoring of HSV1-tk gene transfer, expression and gene therapy. PMID:14513292

Deng, Win-Ping; Yang, Wen K; Lai, Wen-Fu; Liu, Ren-Shyan; Hwang, Jeng-Jong; Yang, Den-Mei; Fu, Ying-Kai; Wang, Hsin-Ell

2004-01-01

73

Gene therapy for childhood immunological diseases  

Microsoft Academic Search

Gene therapy using autologous hematopoietic stem cells (HSC) that are corrected with the normal gene may have a beneficial effect on blood cell production or function, without the immunologic complications of allogeneic HSC transplantation. Childhood immunological diseases are highly favorable candidates for responses to gene therapy using HSC. Hemoglobinopathies, lysosomal and metabolic disorders and defects of hematopoietic stem and progenitor

D B Kohn

2008-01-01

74

Cancer Imaging: Gene Transcription-Based Imaging and Therapeutic Systems  

PubMed Central

Molecular-genetic imaging of cancer is in its infancy. Over the past decade gene reporter systems have been optimized in preclinical models and some have found their way into the clinic. The search is on to find the best combination of gene delivery vehicle and reporter imaging system that can be translated safely and quickly. The goal is to have a combination that can detect a wide variety of cancers with high sensitivity and specificity in a way that rivals the current clinical standard, positron emission tomography with [18F]fluorodeoxyglucose. To do so will require systemic delivery of reporter genes for the detection of micrometastases, and a nontoxic vector, whether viral or based on nanotechnology, to gain widespread acceptance by the oncology community. Merger of molecular-genetic imaging with gene therapy, a strategy that has been employed in the past, will likely be necessary for such imaging to reach widespread clinical use.

Bhang, Hyo-eun C.; Pomper, Martin G.

2012-01-01

75

Gene delivery and gene therapy of prostate cancer.  

PubMed

Surgery, radiation or hormonal therapy are not adequate to control prostate cancer. Clearly, other novel treatment approaches, such as gene therapy, for advanced/recurrent disease are desperately needed to achieve long-term local control and particularly to develop effective systemic therapy for metastatic prostate cancer. In the last decade, significant progress in gene therapy for the treatment of localised prostate cancer has been demonstrated. A broad range of different gene therapy approaches, including cytolytic, immunological and corrective gene therapy, have been successfully applied for prostate cancer treatment in animal models, with translation into early clinical trials. In addition, a wide variety of viral and nonbiological gene delivery systems are available for basic and clinical research. Gene therapy approaches that have been developed for the treatment of prostate cancer are summarised. PMID:16370939

Kaliberov, Sergey A; Buchsbaum, Donald J

2006-01-01

76

Nonviral gene therapy targeting cardiovascular system.  

PubMed

The goal of gene therapy is either to introduce a therapeutic gene into or replace a defective gene in an individual's cells and tissues. Gene therapy has been urged as a potential method to induce therapeutic angiogenesis in ischemic myocardium and peripheral tissues after extensive investigation in recent preclinical and clinical studies. A successful gene therapy mainly relies on the development of the gene delivery vector. Developments in viral and nonviral vector technology including cell-based gene transfer will further improve transgene delivery and expression efficiency. Nonviral approaches as alternative gene delivery vehicles to viral vectors have received significant attention. Recently, a simple and safe approach of gene delivery into target cells using naked DNA has been improved by combining several techniques. Among the physical approaches, ultrasonic microbubble gene delivery, with its high safety profile, low costs, and repeatable applicability, can increase the permeability of cell membrane to macromolecules such as plasmid DNA by its bioeffects and can provide as a feasible tool in gene delivery. On the other hand, among the promising areas for gene therapy in acquired diseases, ischemic cardiovascular diseases have been widely studied. As a result, gene therapy using advanced technology may play an important role in this regard. The aims of this review focus on understanding the cellular and in vivo barriers in gene transfer and provide an overview of currently used chemical vectors and physical tools that are applied in nonviral cardiovascular gene transfer. PMID:22821991

Su, Cheng-Huang; Wu, Yih-Jer; Wang, Hsueh-Hsiao; Yeh, Hung-I

2012-09-15

77

Gene therapy for the treatment of cancer.  

PubMed

The delineation of the molecular basis of neoplasia provides the possibility of specific intervention by gene therapy through the introduction of genetic material for therapeutic purposes. In this regard, several gene therapy approaches have been developed for the treatment of cancer: mutation compensation, genetic immunopotentiation, molecular chemotherapy, inhibition of angiogenesis, replicative vector oncolysis, and chemosensitization or radiosensitization. Clinical trials have been initiated to evaluate safety, toxicity, and efficacy of each of these approaches, based on promising preclinical results. Various limitations that have been identified include lack of in vivo selective tumor delivery of vectors, minimal expression of therapeutic genes, immune response against vectors, and normal tissue toxicity. Combined modality therapy with gene therapy and chemotherapy or radiation therapy has shown promising results. It is expected that as new therapeutic targets and approaches are identified, combined with advances in vector design, that gene therapy will play an increasing role in clinical cancer treatment. PMID:11602998

Buchsbaum, D J; Curiel, D T

2001-08-01

78

Adenoviral Gene Therapy, Radiation, and Prostate Cancer  

PubMed Central

Viral gene therapy has exceptional potential as a specifically tailored cancer treatment. However, enthusiasm for cancer gene therapy has varied over the years, partly owing to safety concerns after the death of a young volunteer in a clinical trial for a genetic disease. Since this singular tragedy, results from numerous clinical trials over the past 10 years have restored the excellent safety profile of adenoviral vectors. These vectors have been extensively studied in phase I and II trials as intraprostatically administered agents for patients with locally recurrent and high-risk local prostate cancer. Promising therapeutic responses have been reported in several studies with both oncolytic and suicide gene therapy strategies. The additional benefit of combining gene therapy with radiation therapy has also been realized; replicating adenoviruses inhibit DNA repair pathways, resulting in a synergistic sensitization to radiation. Other, nonreplicating suicide gene therapy strategies are also significantly enhanced with radiation. Combined radiation/gene therapy is currently being studied in phase I and II clinical trials and will likely be the first adenoviral gene therapy mechanism to become available to urologists in the clinic. Systemic gene therapy for metastatic disease is also a major goal of the field, and clinical trials are currently under way for hormone-resistant metastatic prostate cancer. Second- and third-generation “re-targeted” viral vectors, currently being developed in the laboratory, are likely to further improve these systemic trials.

Lupold, Shawn E; Rodriguez, Ronald

2005-01-01

79

Transcriptionally targeted gene therapy to detect and treat cancer  

PubMed Central

The greatest challenge in cancer treatment is to achieve the highest levels of specificity and efficacy. Cancer gene therapy could be designed specifically to express therapeutic genes to induce cancer cell destruction. Cancer-specific promoters are useful tools to accomplish targeted expression; however, high levels of gene expression are needed to achieve therapeutic efficacy. Incorporating an imaging reporter gene in tandem with the therapeutic gene will allow tangible proof of principle that gene expression occurs at the correct location and at a sufficient level. Gene-based imaging can advance cancer detection and diagnosis. By combining the cancer-targeted imaging and therapeutic strategies, the exciting prospect of a ‘one-two punch’ to find hidden, disseminated cancer cells and destroy them simultaneously can potentially be realized.

Wu, Lily; Johnson, Mai; Sato, Makoto

2010-01-01

80

Republished review: Gene therapy for ocular diseases  

PubMed Central

The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.

Liu, Melissa M; Tuo, Jingsheng; Chan, Chi-Chao

2011-01-01

81

Gene Therapy For Ischemic Heart Disease  

PubMed Central

Current pharmacologic therapy for ischemic heart disease suffers multiple limitations such as compliance issues and side effects of medications. Revascularization procedures often end with need for repeat procedures. Patients remain symptomatic despite maximal medical therapy. Gene therapy offers an attractive alternative to current pharmacologic therapies and may be beneficial in refractory disease. Gene therapy with isoforms of growth factors such as VEGF, FGF and HGF induces angiogenesis, decreases apoptosis and leads to protection in the ischemic heart. Stem cell therapy augmented with gene therapy used for myogenesis has proven to be beneficial in numerous animal models of myocardial ischemia. Gene therapy coding for antioxidants, eNOS, HSP, mitogen-activated protein kinase and numerous other anti apoptotic proteins have demonstrated significant cardioprotection in animal models. Clinical trials have demonstrated safety in humans apart from symptomatic and objective improvements in cardiac function. Current research efforts are aimed at refining various gene transfection techniques and regulation of gene expression in vivo in the heart and circulation to improve clinical outcomes in patients that suffer from ischemic heart disease. In this review article we will attempt to summarize the current state of both preclinical and clinical studies of gene therapy to combat myocardial ischemic disease.

Lavu, Madhav; Gundewar, Susheel; Lefer, David J.

2010-01-01

82

Gene therapy approaches for spinal cord injury  

Microsoft Academic Search

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

Corinne Bright

2005-01-01

83

Antiangiogenic gene therapy of cancer: recent developments  

PubMed Central

With the role of angiogenesis in tumor growth and progression firmly established, considerable effort has been directed to antiangiogenic therapy as a new modality to treat human cancers. Antiangiogenic agents have recently received much widespread attention but strategies for their optimal use are still being developed. Gene therapy represents an attractive alternative to recombinant protein administration for several reasons. This review evaluates the potential advantages of gene transfer for antiangiogenic cancer therapy and describes preclinical gene transfer work with endogenous angiogenesis inhibitors demonstrating the feasibility of effectively suppressing and even eradicating tumors in animal models. Additionally, we describe the advantages and disadvantages of currently available gene transfer vectors and update novel developments in this field. In conclusion, gene therapy holds great promise in advancing antiangiogenesis as an effective cancer therapy and will undoubtedly be evaluated in human clinical trials in the near future.

Tandle, Anita; Blazer, Dan G; Libutti, Steven K

2004-01-01

84

Recent advances in fetal gene therapy.  

PubMed

Over the first decade of this new millennium gene therapy has demonstrated clear clinical benefits in several diseases for which conventional medicine offers no treatment. Clinical trials of gene therapy for single gene disorders have recruited predominantly young patients since older subjects may have suffered irrevocablepathological changes or may not be available because the disease is lethal relatively early in life. The concept of fetal gene therapy is an extension of this principle in that diseases in which irreversible changes occur at or beforebirth can be prevented by gene supplementation or repair in the fetus or associated maternal tissues. This article ccnsiders the enthusiasm and skepticism held for fetal gene therapy and its potential for clinical application. It coversa spectrum of candidate diseases for fetal gene therapy including Pompe disease, Gaucher disease, thalassemia, congenital protein C deficiency and cystic fibrosis. It outlines successful and not-so-successful examples of fetal gene therapy in animal models. Finally the application and potential of fetal gene transfer as a fundamental research tool for developmental biology and generation of somatic transgenic animals is surveyed. PMID:22826854

Buckley, Suzanne M K; Rahim, Ahad A; Chan, Jerry K Y; David, Anna L; Peebles, Donald M; Coutelle, Charles; Waddingtont, Simon N

2011-04-01

85

Gene Therapy for Chronic Granulomatous Disease  

Microsoft Academic Search

Identification of gene mutations responsible for leukocyte dysfunction along with the application of gene transfer technology has made genetic correction of such disorders possible. Much of the research into molecular therapy for inherited disorders of phagocytes has been focused on chronic granulomatous disease (CGD). CGD results from mutations in any one of the four genes encoding essential subunits of respiratory

W. Scott Goebel; Mary C. Dinauer

2003-01-01

86

FUNCTIONAL NANOPARTICLES FOR MOLECULAR IMAGING GUIDED GENE DELIVERY  

PubMed Central

Gene therapy has great potential to bring tremendous changes in treatment of various diseases and disorders. However, one of the impediments to successful gene therapy is the inefficient delivery of genes to target tissues and the inability to monitor delivery of genes and therapeutic responses at the targeted site. The emergence of molecular imaging strategies has been pivotal in optimizing gene therapy; since it can allow us to evaluate the effectiveness of gene delivery noninvasively and spatiotemporally. Due to the unique physiochemical properties of nanomaterials, numerous functional nanoparticles show promise in accomplishing gene delivery with the necessary feature of visualizing the delivery. In this review, recent developments of nanoparticles for molecular imaging guided gene delivery are summarized.

Liu, Gang; Swierczewska, Magdalena; Lee, Seulki; Chen, Xiaoyuan

2010-01-01

87

Phenotyping Cardiac Gene Therapy in Mice  

PubMed Central

Heart disease is the leading health problem of industrialized countries. The development of gene therapies tailored towards the heart has grown exponentially over the past decade. Murine models of heart diseases have played a pivotal role in testing novel cardiac gene therapy approaches. Unfortunately, the small body size and rapid heart rate of mice present a great challenge to heart function evaluation. Here we outline the commonly used cardiac phenotyping methods of treadmill exercise regimen, full 12-lead electrocardiographic assay and left ventricular catheterization hemodynamic assay. Application of these protocols will allow critical testing of gene therapy efficacy in mouse models of heart diseases.

Bostick, Brian; Yue, Yongping; Duan, Dongsheng

2011-01-01

88

[Gene therapy of neurological diseases].  

PubMed

In hereditary neurological diseases, gene transfer into neurons is made difficult by: the nature of the cells (postmitotic cells, that cannot be cultured, genetically modified ex vivo, then retransplanted), sometimes, their widespread localization, the blood-brain barrier. However, three viral vectors derived from adenovirus, Herpes simplex virus and adeno-associated virus have been shown to be very efficient in transferring DNA into brain cells. All of these vectors can infect resting cells, especially neurons, and are efficient in vivo. Retroviral vectors which can infect dividing cells only are mainly used for ex vivo genetic modification of cells (neural progenitor cells, myoblasts, fibroblasts) followed by intracerebral transplantation. Alternatively, genetically modified cells can be transplanted in a peripheral site if the transgene product is able to cross the blood-brain barrier or to be transported retrogradely from the nerve terminals. We have especially investigated the potential interest of adenoviral vectors to transfer foreign genes into brain cells and to treat animal models of neurological diseases. These vectors allowed us to transfer the lacZ gene into any neural cell type, including neurons, glia, photoreceptors and olfactory receptors, ex vivo, in cell culture, and in vivo, by stereotactic administration. In addition, axonal transport of adenoviral vectors has been demonstrated, e.g. in the substantia nigra after injection into the striatum, in the olfactory bulb after intranasal instillation and in spinal motor neurons after intramuscular injection. After intracerebroventricular injection, ependymal cells are massively infected and express the transgene for several months, as this is also observed in neurons. Through the spinal canal and cerebrospinal fluid, the vector can diffuse to a considerable distance from the injection point, e.g. to the lumbar spinal cord after injection in the suboccipital region. To test the biological function of transgenes transferred through adenoviral vectors, we have constructed vectors with cDNAs or genes for various neutrophic factors: CNTF, NT3, BDNF and GDNF. These vectors were biologically active on target cells, ex vivo and in vivo. In the pmn mouse model of progressive motor neuronal degeneration, some of these vectors, alone or combined, allowed for prolongation of life of homozygous animals by more than two fold, and for decrease in the demyelination of phrenic nerve axons. Finally, we have also constructed an adenoviral vector carrying the alpha-hexosaminidase cDNA, encoding the enzyme subunit deficient in Tay Sachs patients. This vector permitted to normalize ganglioside metabolism in Tay Sachs fibroblasts and is currently tested in knock out mice deficient in hexosaminidase A. In spite of all these encouraging results, we are nevertheless aware that progress in vector design and delivery strategies will be needed before gene therapy can become a realistic therapeutical strategy in humans. PMID:8881264

Kahn, A; Haase, G; Akli, S; Guidotti, J E

1996-01-01

89

Image-Guided Tumor-Selective Radioiodine Therapy of Liver Cancer After Systemic Nonviral Delivery of the Sodium Iodide Symporter Gene  

PubMed Central

Abstract We reported the induction of tumor-selective iodide uptake and therapeutic efficacy of 131I in a hepatocellular carcinoma (HCC) xenograft mouse model, using novel polyplexes based on linear polyethylenimine (LPEI), shielded by polyethylene glycol (PEG), and coupled with the epidermal growth factor receptor-specific peptide GE11 (LPEI-PEG-GE11). The aim of the current study in the same HCC model was to evaluate the potential of biodegradable nanoparticle vectors based on pseudodendritic oligoamines (G2-HD-OEI) for systemic sodium iodide symporter (NIS) gene delivery and to compare efficiency and tumor specificity with LPEI-PEG-GE11. Transfection of HCC cells with NIS cDNA, using G2-HD-OEI, resulted in a 44-fold increase in iodide uptake in vitro as compared with a 22-fold increase using LPEI-PEG-GE11. After intravenous application of G2-HD-OEI/NIS HCC tumors accumulated 6–11% ID/g 123I (percentage of the injected dose per gram tumor tissue) with an effective half-life of 10?hr (tumor-absorbed dose, 281?mGy/MBq) as measured by 123I scintigraphic gamma camera or single-photon emission computed tomography computed tomography (SPECT CT) imaging, as compared with 6.5–9% ID/g with an effective half-life of only 6?hr (tumor-absorbed dose, 47?mGy/MBq) for LPEI-PEG-GE11. After only two cycles of G2-HD-OEI/NIS/131I application, a significant delay in tumor growth was observed with markedly improved survival. A similar degree of therapeutic efficacy had been observed after four cycles of LPEI-PEG-GE11/131I. These results clearly demonstrate that biodegradable nanoparticles based on OEI-grafted oligoamines show increased efficiency for systemic NIS gene transfer in an HCC model with similar tumor selectivity as compared with LPEI-PEG-GE11, and therefore represent a promising strategy for NIS-mediated radioiodine therapy of HCC.

Klutz, Kathrin; Willhauck, Michael J.; Dohmen, Christian; Wunderlich, Nathalie; Knoop, Kerstin; Zach, Christian; Senekowitsch-Schmidtke, Reingard; Gildehaus, Franz-Josef; Ziegler, Sibylle; Furst, Sebastian; Goke, Burkhard; Wagner, Ernst

2011-01-01

90

Image-guided tumor-selective radioiodine therapy of liver cancer after systemic nonviral delivery of the sodium iodide symporter gene.  

PubMed

We reported the induction of tumor-selective iodide uptake and therapeutic efficacy of (131)I in a hepatocellular carcinoma (HCC) xenograft mouse model, using novel polyplexes based on linear polyethylenimine (LPEI), shielded by polyethylene glycol (PEG), and coupled with the epidermal growth factor receptor-specific peptide GE11 (LPEI-PEG-GE11). The aim of the current study in the same HCC model was to evaluate the potential of biodegradable nanoparticle vectors based on pseudodendritic oligoamines (G2-HD-OEI) for systemic sodium iodide symporter (NIS) gene delivery and to compare efficiency and tumor specificity with LPEI-PEG-GE11. Transfection of HCC cells with NIS cDNA, using G2-HD-OEI, resulted in a 44-fold increase in iodide uptake in vitro as compared with a 22-fold increase using LPEI-PEG-GE11. After intravenous application of G2-HD-OEI/NIS HCC tumors accumulated 6-11% ID/g (123)I (percentage of the injected dose per gram tumor tissue) with an effective half-life of 10?hr (tumor-absorbed dose, 281?mGy/MBq) as measured by (123)I scintigraphic gamma camera or single-photon emission computed tomography computed tomography (SPECT CT) imaging, as compared with 6.5-9% ID/g with an effective half-life of only 6?hr (tumor-absorbed dose, 47?mGy/MBq) for LPEI-PEG-GE11. After only two cycles of G2-HD-OEI/NIS/(131)I application, a significant delay in tumor growth was observed with markedly improved survival. A similar degree of therapeutic efficacy had been observed after four cycles of LPEI-PEG-GE11/(131)I. These results clearly demonstrate that biodegradable nanoparticles based on OEI-grafted oligoamines show increased efficiency for systemic NIS gene transfer in an HCC model with similar tumor selectivity as compared with LPEI-PEG-GE11, and therefore represent a promising strategy for NIS-mediated radioiodine therapy of HCC. PMID:21851208

Klutz, Kathrin; Willhauck, Michael J; Dohmen, Christian; Wunderlich, Nathalie; Knoop, Kerstin; Zach, Christian; Senekowitsch-Schmidtke, Reingard; Gildehaus, Franz-Josef; Ziegler, Sibylle; Fürst, Sebastian; Göke, Burkhard; Wagner, Ernst; Ogris, Manfred; Spitzweg, Christine

2011-12-01

91

Targeted Gene Therapies: Tools, Applications, Optimization  

PubMed Central

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.

Humbert, Olivier; Davis, Luther; Maizels, Nancy

2012-01-01

92

Getting arthritis gene therapy into the clinic  

PubMed Central

Gene transfer technologies enable the controlled, targeted and sustained expression of gene products at precise anatomical locations, such as the joint. In this way, they offer the potential for more-effective, less-expensive treatments of joint diseases with fewer extra-articular adverse effects. A large body of preclinical data confirms the utility of intra-articular gene therapy in animal models of rheumatoid arthritis and osteoarthritis. However, relatively few clinical trials have been conducted, only one of which has completed phase II. This article summarizes the status in 2010 of the clinical development of gene therapy for arthritis, identifies certain constraints to progress and suggests possible solutions.

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

2012-01-01

93

Gene Therapy for Diseases and Genetic Disorders  

MedlinePLUS

... notable advancements are the following: Gene Therapy for Genetic Disorders Severe Combined Immune Deficiency (ADA-SCID) ADA-SCID ... in preclinical animal models of this disease. Other genetic disorders After many years of laboratory and preclinical research ...

94

International progress in cancer gene therapy  

Microsoft Academic Search

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

B A Guinn; R Mulherkar

2008-01-01

95

Cardiovascular gene therapy for myocardial infarction  

PubMed Central

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

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

2014-01-01

96

Strategies in Gene Therapy for Glioblastoma  

PubMed Central

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.

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

2013-01-01

97

Gene therapy for primary immunodeficiencies: Part 1.  

PubMed

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

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

2012-10-01

98

An overview of gene therapy in head and neck cancer  

PubMed Central

Gene therapy is a new treatment modality in which new gene is introduced or existing gene is manipulated to cause cancer cell death or slow the growth of the tumor. In this review, we have discussed the different treatment approaches for cancer gene therapy; gene addition therapy, immunotherapy, gene therapy using oncolytic viruses, antisense ribonucleic acid (RNA) and RNA interference-based gene therapy. Clinical trials to date in head and neck cancer have shown evidence of gene transduction and expression, mediation of apoptosis and clinical response including pathological complete responses. The objective of this article is to provide an overview of the current available gene therapies for head and neck cancer.

Bali, Amit; Bali, Deepika; Sharma, Ashutosh

2013-01-01

99

Evolution of a Gene Therapy Clinical Trial  

Microsoft Academic Search

Developing and conducting gene therapy clinical trials poses unique challenges which must be addressed to satisfy regulatory requirements and, most importantly, to protect human subjects. Experimental products used for gene transfer studies, such as viral vectors, are often complex and cannot be sterilized or completely characterized to the extent of a typical pharmaceutical. Thus, quality and characterization must be built

Laura K. Aguilar; Estuardo Aguilar-Cordova

2003-01-01

100

Optimizing Ribozymes for Somatic Cell Gene Therapy  

Microsoft Academic Search

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

Andrea D. Branch; Paul E. Klotman

1998-01-01

101

Human gene therapy and slippery slope arguments.  

PubMed Central

Any suggestion of altering the genetic makeup of human beings through gene therapy is quite likely to provoke a response involving some reference to a 'slippery slope'. In this article the author examines the topography of two different types of slippery slope argument, the logical slippery slope and the rhetorical slippery slope argument. The logical form of the argument suggests that if we permit somatic cell gene therapy then we are committed to accepting germ line gene therapy in the future because there is no logically sustainable distinction between them. The rhetorical form posits that allowing somatic cell therapy now will be taking the first step on a slippery slope which will ultimately lead to the type of genocide perpetrated by the Nazis. The author tests the validity of these lines of argument against the facts of human gene therapy and concludes that because of their dependence on probabilities that cannot be empirically proven they should be largely disregarded in the much more important debate on moral line-drawing in gene therapy.

McGleenan, T

1995-01-01

102

[Gene therapy--hopes and fears].  

PubMed

Gene therapy assumes the correction of a genetic defect by the delivery of a correct DNA sequence to the target cells. Depending on the target cells two types gene therapy have been defined: somatic and germinal. By July 1998, 351 protocols of somatic therapy were approved by the Recombinant DNA Advisory Committee. The majority of protocols focus on cancer therapy and monogenic diseases. By now, still there is more unfulfilled expectation than clinically sound achievements, since no effective prevention or successful treatment for genetic diseases or cancer have been developed. Germline genetic modification is considered as the treatment of choice for such a diseases like retinoblastoma. Tay-Sachs, Lesch-Nyhan and metachromatic leuko-dystrophy. This approach which is still illegal or prohibited by rules in many European countries, is gathering more and more advocates. Once we learn how to control gene expression the perspectives for clinical application of gene therapy might be enormous. The safety of genetic modification of gametes or embryonal stem cells remains to be properly addressed and successfully solved. The ethical issues of germinal gene therapy are still the subject of controversial opinions among the scientists, lawyers and philosophers. PMID:10816964

Pietrzyk, J J

1998-01-01

103

Gene replacement therapy for hereditary emphysema  

SciTech Connect

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.

Skolnick, A.

1989-11-10

104

Transcriptional Targeting in Cancer Gene Therapy  

PubMed Central

Cancer gene therapy has been one of the most exciting areas of therapeutic research in the past decade. In this review, we discuss strategies to restrict transcription of transgenes to tumour cells. A range of promoters which are tissue-specific, tumour-specific, or inducible by exogenous agents are presented. Transcriptional targeting should prevent normal tissue toxicities associated with other cancer treatments, such as radiation and chemotherapy. In addition, the specificity of these strategies should provide improved targeting of metastatic tumours following systemic gene delivery. Rapid progress in the ability to specifically control transgenes will allow systemic gene delivery for cancer therapy to become a real possibility in the near future.

2003-01-01

105

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.

106

Gene Therapy for Liver Disease  

Microsoft Academic Search

With major advances in biomedical science over the last 2 decades, the possibility of treating human disease at a genetic level has become a tantalizing possibility. As a result, a growing number of investigators are focusing on the development of techniques to deliver therapeutic genes into cells. The liver has been a model organ in the development of this gene

Timothy J. Davern II; Bruce F. Scharschmidt

1998-01-01

107

Current status of haemophilia gene therapy.  

PubMed

After many reports of successful gene therapy studies in small and large animal models of haemophilia, we have, at last, seen the first signs of success in human patients. These very encouraging results have been achieved with the use of adeno-associated viral (AAV) vectors in patients with severe haemophilia B. Following on from these initial promising studies, there are now three ongoing trials of AAV-mediated gene transfer in haemophilia B all aiming to express the factor IX gene from the liver. Nevertheless, as discussed in the first section of this article, there are still a number of significant hurdles to overcome if haemophilia B gene therapy is to become more widely available. The second section of this article deals with the challenges relating to factor VIII gene transfer. While the recent results in haemophilia B are extremely encouraging, there is, as yet, no similar data for factor VIII gene therapy. It is widely accepted that this therapeutic target will be significantly more problematic for a variety of reasons including accommodating the larger factor VIII cDNA, achieving adequate levels of transgene expression and preventing the far more frequent complication of antifactor VIII immunity. In the final section of the article, the alternative approach of lentiviral vector-mediated gene transfer is discussed. While AAV-mediated approaches to transgene delivery have led the way in clinical haemophilia gene therapy, there are still a number of potential advantages of using an alternative delivery vehicle including the fact that ex vivo host cell transduction will avoid the likelihood of immune responses to the vector. Overall, these are exciting times for haemophilia gene therapy with the likelihood of further clinical successes in the near future. PMID:24762274

High, K H; Nathwani, A; Spencer, T; Lillicrap, D

2014-05-01

108

Proton therapy verification with PET imaging.  

PubMed

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

Zhu, Xuping; El Fakhri, Georges

2013-01-01

109

Virus production for clinical gene therapy.  

PubMed

Gene therapy is becoming increasingly relevant for the treatment of prominent human diseases. Viral vectors are currently used in more than 50% of the gene therapy clinical trials, most of them aimed at cancer diseases. Clearly, the increasing needs of high-quality viral preparations require the elimination of process bottlenecks, streamlining the development of a viral vector into a real-world clinical tool. Virus production for clinical gene therapy can be a limiting step because many virus generation protocols rely on labor-intensive, bench-scale methods; robust, cost-effective strategies for the delivery of clinical-grade viruses are thus essential for the future of gene therapy. A comprehensive picture of key aspects on the integration of upstream and downstream processing is addressed in this chapter, by describing the case study of recombinant budded baculoviruses for gene therapy; scalable methods are described in detail as well as mandatory characterization techniques for a proper and complete quality assessment of the viral vectors. PMID:19565917

Vicente, Tiago; Peixoto, Cristina; Carrondo, Manuel J T; Alves, Paula M

2009-01-01

110

A Comprehensive Review of Retinal Gene Therapy  

PubMed Central

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

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

2013-01-01

111

Gene therapy for the inner ear  

PubMed Central

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.

Fukui, Hideto; Raphael, Yehoash

2012-01-01

112

Development of gene therapy for thalassemia.  

PubMed

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

Nienhuis, Arthur W; Persons, Derek A

2012-11-01

113

Theranostic agents for intracellular gene delivery with spatiotemporal imaging  

PubMed Central

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.

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

2013-01-01

114

Moving forward: cystic fibrosis gene therapy.  

PubMed

Since cloning of the CFTR gene more than 20 years ago a large number of pre-clinical and clinical CF gene therapy studies have been performed and a vast amount of information and know-how has been generated. Here, we will review key studies with a particular emphasis on clinical findings. We have learnt that the lung is a more difficult target than originally anticipated, and we describe the strength and weaknesses of the most commonly used airway gene transfer agents (GTAs). In our view, one of the most significant developments in recent years is the generation of lentiviral vectors, which efficiently transduce lung tissue. However, focused and co-ordinated efforts assessing lentiviral vector safety and scaling up of production will be required to move this vector into clinical lung gene therapy studies. PMID:23918661

Griesenbach, Uta; Alton, Eric W F W

2013-10-15

115

Prospects for gene therapy in Parkinson's disease.  

PubMed

Numerous advances in in vivo and ex vivo gene-therapy approaches to Parkinson's disease offer promise for direct clinical trials in patients in the next several years. These systems are predicated on introducing gene that encode enzymes responsible for dopamine biosynthesis or neurotrophic factors that may delay nigrostriatal degeneration or facilitate regeneration. We review the current status of experimental approaches to gene therapy for Parkinson's disease. Comparative advantages and disadvantages of each system are enumerated, and preclinical trials of some of the systems are evaluated. Although the specific in vivo or ex vivo methods used for gene transfer into the brain are likely to be supplanted by newer technology over the next decade, the principles and approaches developed in current studies likely will remain the same. PMID:8866488

Freese, A; Stern, M; Kaplitt, M G; O'Connor, W M; Abbey, M V; O'Connor, M J; During, M J

1996-09-01

116

New strategies for cardiovascular gene therapy  

Microsoft Academic Search

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

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

2006-01-01

117

Gene Therapy and Targeted Toxins for Glioma  

PubMed Central

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.

King, Gwendalyn D.; Curtin, James F.; Candolfi, Marianela; Kroeger, Kurt; Lowenstein, Pedro R.; Castro, Maria G.

2006-01-01

118

Immunotherapy and Gene Therapy of Cancer1  

Microsoft Academic Search

In the past decade, immunothérapies have been developed that are capable of causing prolonged cancer regressions in selected patients with advanced metastatic disease. In the past year, attempts at the gene therapy of cancer have begun. These experimental cancer treatments deserve vigorous exploration. The last decade has witnessed the rise of new biological treatments for cancer based on stimulating natural

Steven A. Rosenberg

1991-01-01

119

An update on gene therapy programs.  

PubMed

This commentary discusses the most significant advances that were presented at the 12th Annual Meeting of the American Society of Gene Therapy. Many reports focused on clinical trials for the treatment of cancer and other pathological conditions, preclinical studies for various diseases, genetic immunization protocols and improvement of vector design. In this respect, a major emphasis was placed on safety issues. PMID:19890502

Romano, Gaetano

2009-09-01

120

Retroviral Integrations in Gene Therapy Trials  

Microsoft Academic Search

?-Retroviral and lentiviral vectors allow the permanent integration of a therapeutic transgene in target cells and have provided in the last decade a delivery platform for several successful gene therapy (GT) clinical approaches. However, the occurrence of adverse events due to insertional mutagenesis in GT treated patients poses a strong challenge to the scientific community to identify the mechanisms at

Luca Biasco; Cristina Baricordi; Alessandro Aiuti

2012-01-01

121

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.

122

The gene therapy revolution in ophthalmology.  

PubMed

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

Al-Saikhan, Fahad I

2013-04-01

123

Clinical aspects of intratumoral gene therapy.  

PubMed

One of the major obstacles to the development of gene therapy for cancer is our inability to deliver genes to all targets within the body. Thus, effective methodology does not exist to deliver a gene intravenously with the expectation that it will selectively localize within the target tumor, will not localize in other tissues and will be expressed efficiently. While one can take advantage of tissue-specific promoters to activate the gene only in a given target tissue, only a small fraction of the vector will be taken up in the target tissue and expressed. Consequently, since accessible local or regional tumor masses are a major problem in many cancers, there has been a strong emphasis on clinical trials in intratumoral and peritumoral gene delivery. PMID:11713758

Akporiaye, E T; Hersh, E

1999-08-01

124

Gene Therapy: Implications for Craniofacial Regeneration  

PubMed Central

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.

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

2011-01-01

125

Gene therapy for hemoglobinopathies: progress and challenges  

PubMed Central

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.

Dong, Alisa; Rivella, Stefano; Breda, Laura

2013-01-01

126

Delivery of Gene and Cellular Therapies for Heart Disease  

Microsoft Academic Search

Although there has been considerable interest in the utilization of gene and cellular therapy for heart disease in recent\\u000a years, there remain critical questions prior to widespread promotion of therapy, and key among these issues is the delivery\\u000a method used for both gene therapy and cellular therapy. Much of the failure of gene and cellular therapy can be explained\\u000a by

Justin A. Mariani; David M. Kaye

2010-01-01

127

Gene therapy approaches to regenerating bone  

PubMed Central

Bone formation and regeneration therapies continue to require optimization and improvement because many skeletal disorders remain undertreated. Clinical solutions to nonunion fractures and osteoporotic vertebral compression fractures, for example, remain suboptimal and better therapeutic approaches must be created. The widespread use of recombinant human bone morphogenetic proteins (rhBMPs) for spine fusion was recently questioned by a series of reports in a special issue of The Spine Journal, which elucidated the side effects and complications of direct rhBMP treatments. Gene therapy—both direct (in vivo) and cell-mediated (ex vivo)—has long been studied extensively to provide much needed improvements in bone regeneration. In this article, we review recent advances in gene therapy research whose aims are in vivo or ex vivo bone regeneration or formation. We examine appropriate vectors, safety issues, and rates of bone formation. The use of animal models and their relevance for translation of research results to the clinical setting are also discussed in order to provide the reader with a critical view. Finally, we elucidate the main challenges and hurdles faced by gene therapy aimed at bone regeneration as well as expected future trends in this field.

Bleich, Nadav Kimelman; Kallai, Ilan; Lieberman, Jay R.; Schwarz, Edward M.; Pelled, Gadi; Gazit, Dan

2013-01-01

128

Engineering HSV-1 vectors for gene therapy.  

PubMed

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

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

2014-01-01

129

Gene Therapy for Inborn and Acquired Immune Deficiency Disorders  

Microsoft Academic Search

Gene therapy has been under development as a way to correct inborn errors for over 20 years. Immune deficiencies are favorable candidates for gene therapy because of the potential selective advantage of genetically corrected cells in these conditions. Gene therapy for immune deficiencies has been the only application to show incontrovertible benefit in clinical trials to date. Despite the success

Barbara C. Engel; Donald B. Kohn

2003-01-01

130

Newer Gene Editing Technologies toward HIV Gene Therapy  

PubMed Central

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.

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

2013-01-01

131

Fetal muscle gene therapy/gene delivery in large animals.  

PubMed

Gene delivery to the fetal muscles is a potential strategy for the early treatment of muscular dystrophies. In utero muscle gene therapy can also be used to treat other genetic disorders such as hemophilia, where the missing clotting proteins may be secreted from the treated muscle. In the past few years, studies in small animal models have raised the hopes that a phenotypic cure can be obtained after fetal application of gene therapy. Studies of efficacy and safety in large animals are, however, essential before clinical application can be considered in the human fetus. For this reason, the development of clinically applicable strategies for the delivery of gene therapy to the fetal muscles is of prime importance. In this chapter, we describe the protocols for in utero ultrasound-guided gene delivery to the ovine fetal muscle in early gestation. In particular, procedures to inject skeletal muscle groups such as the thigh and thoracic musculature and targeting the diaphragm in the fetus are described in detail. PMID:21194032

Abi-Nader, Khalil N; David, Anna L

2011-01-01

132

Bacterial Systems for Tumor-Specific Gene Therapy  

Microsoft Academic Search

This chapter describes the power of genetically engineered bacteria in cancer therapy. In the applications we consider, the\\u000a bacteria are genetically engineered to carry a specific gene into tumors, and on this basis, it can be considered gene therapy.\\u000a However, if gene therapy is defined as the introduction of a gene, or part of a gene, into the cancer cells

J. Martin Brown; Shie-Chau Liu; Jan Theys; Philippe Lambin

133

Cocaine hydrolase gene therapy for cocaine abuse  

PubMed Central

Rapid progress in the past decade with re-engineering of human plasma butyrylcholinesterase has led to enzymes that destroy cocaine so efficiently that they prevent or interrupt drug actions in the CNS even though confined to the blood stream. Over the same time window, improved gene-transfer technology has made it possible to deliver such enzymes by endogenous gene transduction at high levels for periods of a year or longer after a single treatment. This article reviews recent advances in this field and considers prospects for development of a robust therapy aimed at aiding recovering drug users avoid addiction relapse.

Brimijoin, Stephen; Gao, Yang

2013-01-01

134

Glucagon-Like Peptide-1 Gene Therapy  

PubMed Central

Glucagon-like peptide 1 (GLP-1) is a small peptide component of the prohormone, proglucagon, that is produced in the gut. Exendin-4, a GLP-1 receptor agonist originally isolated from the saliva of H. suspectum or Gila monster, is a peptide that shares sequence and functional homology with GLP-1. Both peptides have been demonstrated to stimulate insulin secretion, inhibit glucagon secretion, promote satiety and slow gastric emptying. As such, GLP-1 and Exendin-4 have become attractive pharmaceutical targets as an adjunctive therapy for individuals with type II diabetes mellitus, with several products currently available clinically. Herein we summarize the cell biology leading to GLP-1 production and secretion from intestinal L-cells and the endocrine functions of this peptide and Exendin-4 in humans. Additionally, gene therapeutic applications of GLP-1 and Exendin-4 are discussed with a focus on recent work using the salivary gland as a gene therapy target organ for the treatment of diabetes mellitus.

Rowzee, Anne M.; Cawley, Niamh X.; Chiorini, John A.; Di Pasquale, Giovanni

2011-01-01

135

Pluripotent Stem Cells and Gene Therapy  

PubMed Central

Human pluripotent stem cells represent an accessible cell source for novel cell-based clinical research and therapies. With the realization of induced pluripotent stem cells (iPSCs), it is possible to produce almost any desired cell type from any patient's cells. Current developments in gene modification methods have opened the possibility for creating genetically corrected human iPSCs for certain genetic diseases that could be used later in autologous transplantation. Promising preclinical studies have demonstrated correction of disease-causing mutations in a number of hematological, neuronal and muscular disorders. This review aims to summarize these recent advances with a focus on iPSC generation techniques, as well as gene modification methods. We will then further discuss some of the main obstacles remaining to be overcome before successful application of human pluripotent stem cell-based therapy arrives in the clinic and what the future of stem cell research may look like.

Simara, Pavel; Motl, Jason A.; Kaufman, Dan S.

2013-01-01

136

Cardiac Gene Therapy: From Concept to Reality  

PubMed Central

Heart failure is increasing in incidence throughout the world, especially in industrialized countries. Although the current therapeutic modalities have been successful in stabilizing the course of heart failure, morbidity and mortality remain quite high and there remains a great need for innovative breakthroughs that will offer new treatment strategies for patients with advanced forms of the disease. The past few years have witnessed a greater understanding of the molecular underpinnings of the failing heart, paving the way for novel strategies in modulating the cellular environment. As such, gene therapy has recently emerged as a powerful tool offering the promise of a new paradigm for alleviating heart failure. Current gene therapy research for heart failure is focused on exploring potential cellular targets and preclinical and clinical studies are ongoing toward the realization of this goal. Efforts also include the development of sophisticated viral vectors and vector delivery methods for efficient transduction of cardiomyocytes.

Kratlian, Razmig Garo

2012-01-01

137

Gene therapy: no new ethical issues.  

PubMed

This letter was drafted as a result of a dayschool sponsored by the Human Reproduction Study Group of the British Sociological Association. The meeting considered the findings of the Report of the Committee on the Ethics of Gene Therapy, the Clothier Report (see Bulletin 75). Held at Manchester Town Hall on 9th May, the meeting was attended by participants representing various professions and academic disciplines. PMID:16144145

1992-06-01

138

Gene Therapy for Allergic Airway Diseases  

Microsoft Academic Search

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

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

2011-01-01

139

Synthesis and evaluation of a 18F-labeled 4-ipomeanol as an imaging agent for CYP4B1 gene prodrug activation therapy.  

PubMed

We report the development of a (18)F-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. [(18)F]F-4-IM ([(18)F]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 [(18)F]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 [(18)F]F-4-IM in these cells was compared with that in parental controls. The uptake ratio of [(18)F]F-4-IM was 2.8-fold higher in C6-CYP4B1 compared with that in parental cells at 1 hour, whereas [(3)H]4-IM was taken up at similar rates in both cell lines after 6 hours. These results suggest that [(18)F]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

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

2013-10-01

140

Ex vivo gene therapy and vision.  

PubMed

Ex vivo gene therapy, a technique where genetic manipulation of cells is undertaken remotely and more safely since it is outside the body, is an emerging therapeutic strategy particularly well suited to targeting a specific organ rather than for treating a whole organism. The eye and visual pathways therefore make an attractive target for this approach. With blindness still so prevalent worldwide, new approaches to treatment would also be widely applicable and a significant advance in improving quality of life. Despite being a relatively new approach, ex vivo gene therapy has already achieved significant advances in the treatment of blindness in pre-clinical trials. In particular, advances are being achieved in corneal disease, glaucoma, retinal degeneration, stroke and multiple sclerosis through genetic re-programming of cells to replace degenerate cells and through more refined neuroprotection, modulation of inflammation and replacement of deficient protein. In this review we discuss the latest developments in ex vivo gene therapy relevant to the visual pathways and highlight the challenges that need to be overcome for progress into clinical trials. PMID:22424554

Gregory-Evans, Kevin; Bashar, A M A Emran; Tan, Malcolm

2012-04-01

141

Gene therapy approaches for spinal cord injury  

NASA Astrophysics Data System (ADS)

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

Bright, Corinne

142

Frontiers in Suicide Gene Therapy of Cancer  

PubMed Central

The National Cancer Institute (NCI) and the American Cancer Society (ACS) predict that 1,638,910 men and women will be diagnosed with cancer in the USA in 2012. Nearly 577,190 patients will die of cancer of all sites this year. Patients undergoing current systemic therapies will suffer multiple side effects from nausea to infertility. Potential parents, when diagnosed with cancer, will have to deposit oocytes or sperm prior to starting systemic radiation or chemo-therapy for the future genetic testing and in vitro fertilization, while trying to avoid risks of iatrogenic mutations in their germ cells. Otherwise, children of parents treated with systemic therapies, will be at high risk of developing genetic disorders. According to these predictions, this year will carry another, very poor therapeutic record again. The ultimate goal of cancer therapy is the complete elimination of all cancer cells, while leaving all healthy cells unharmed. One of the most promising therapeutic strategies in this regard is cancer suicide gene therapy (CSGT), which is rapidly progressing into new frontiers. The therapeutic success, in CSGT, is primarily contingent upon precision in delivery of the therapeutic transgenes to the cancer cells only. This is addressed by discovering and targeting unique or / and over-expressed biomarkers displayed on the cancer cells and cancer stem cells. Specificity of cancer therapeutic effects is further enhanced by designing the DNA constructs, which put the therapeutic genes under the control of the cancer cell specific promoters. The delivery of the suicidal genes to the cancer cells involves viral, as well as synthetic vectors, which are guided by cancer specific antibodies and ligands. The delivery options also include engineered stem cells with tropisms towards cancers. Main mechanisms inducing cancer cells’ deaths include: transgenic expression of thymidine kinases, cytosine deaminases, intracellular antibodies, telomeraseses, caspases, DNases. Precautions are undertaken to eliminate the risks associated with transgenesis. Progress in genomics and proteomics should help us in identifying the cancer specific biomarkers and metabolic pathways for developing new strategies towards clinical trials of targeted and personalized gene therapy of cancer.

Malecki, Marek

2012-01-01

143

Concepts in Gene Therapy for Cartilage Repair  

PubMed Central

Summary Once articular cartilage is injured, it has a very limited capacity for self-repair. Although current surgical therapeutic procedures to cartilage repair are clinically useful, they cannot restore a normal articular surface. Current research offers a growing number of bioactive reagents, including proteins and nucleic acids, that may be used to augment different aspects of the repair process. As these agents are difficult to administer effectively, gene transfer approaches are being developed to provide their sustained synthesis at sites of repair. To augment regeneration of articular cartilage, therapeutic genes can be delivered to the synovium, or directly to the cartilage lesion. Gene delivery to the cells of the synovial lining is generally considered more suitable for chondroprotective approaches, based on the expression of anti-inflammatory mediators. Gene transfer targeted to cartilage defects can be achieved by either direct vector administration to cells located at or surrounding the defects, or by transplantation of genetically modified chondrogenic cells into the defect. Several studies have shown that exogenous cDNAs encoding growth factors can be delivered locally to sites of cartilage damage, where they are expressed at therapeutically relevant levels. Furthermore, data is beginning to emerge indicating, that efficient delivery and expression of these genes is capable of influencing a repair response toward the synthesis of a more hyaline cartilage repair tissue in vivo. This review presents the current status of gene therapy for cartilage healing and highlights some of the remaining challenges.

Steinert, Andre F.; Noth, Ulrich; Tuan, Rocky S.

2009-01-01

144

Nanoarchitectonics in cancer therapy and imaging diagnosis.  

PubMed

Nanoarchitectonics has gained remarkable importance due to the fabrication of various recent nanostructures with the capability of being used in biomedical science, particularly in cancer diagnosis and treatment. These nanosized structures possess unique physical and optical properties that can be exploited for cancer therapeutics, and so nanoarchitectonics is popularly known as nanomedicine. The goal of this review is to discuss the latest findings in nanostructures research including nanocrystals, nanotubes, nanoshells, nanopillars, nanoballs, nanoflowers, nanorods, nanocontainers, nanobelts, nanocages, nanodiscs, nanodots, nanoprisms, nanoplates, nanorings, nanocubes, nanobranches, nanospheres, nanorattles, nanostars, nanotrees, nanowires, nanowalls, nanodiamonds, nanosheets, layered nanostructures, quantum dots, mesoporous nanostructures etc. in the field of cancer therapy and imaging. This review further highlights brief information about use of radionuclide in cancer. Lastly, different nanoformulations that are available in the market or are under clinical trials for cancer therapy and imaging are discussed. PMID:24730301

Pandey, Abhijeet P; Girase, Nayandip M; Patil, Mahendra D; Patil, Pravin O; Patil, Dilip A; Deshmukh, Prashant K

2014-01-01

145

Nanomaterials for Cancer Therapy and Imaging  

PubMed Central

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.

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

2011-01-01

146

Gene-modified bone marrow cell therapy for prostate cancer  

Microsoft Academic Search

There is a critical need to develop new and effective cancer therapies that target bone, the primary metastatic site for prostate cancer and other malignancies. Among the various therapeutic approaches being considered for this application, gene-modified cell-based therapies may have specific advantages. Gene-modified cell therapy uses gene transfer and cell-based technologies in a complementary fashion to chaperone appropriate gene expression

H Wang; T C Thompson

2008-01-01

147

Gene therapy of primary T cell immunodeficiencies.  

PubMed

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

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

2013-08-10

148

Gene therapy: X-SCID transgene leukaemogenicity.  

PubMed

Gene therapy has been remarkably effective for the immunological reconstitution of patients with severe combined immune deficiency, but the occurrence of leukaemia in a few patients has stimulated debate about the safety of the procedure and the mechanisms of leukaemogenesis. Woods et al. forced high expression of the corrective therapeutic gene IL2RG, which encodes the gamma-chain of the interleukin-2 receptor, in a mouse model of the disease and found that tumours appeared in a proportion of cases. Here we show that transgenic IL2RG does not necessarily have potent intrinsic oncogenic properties, and argue that the interpretation of this observation with respect to human trials is overstated. PMID:16988659

Thrasher, Adrian J; Gaspar, H Bobby; Baum, Christopher; Modlich, Ute; Schambach, Axel; Candotti, Fabio; Otsu, Makoto; Sorrentino, Brian; Scobie, Linda; Cameron, Ewan; Blyth, Karen; Neil, Jim; Abina, Salima Hacein-Bey; Cavazzana-Calvo, Marina; Fischer, Alain

2006-09-21

149

Coaxial electrospray for multimodal imaging and image-guided therapy  

NASA Astrophysics Data System (ADS)

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

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

2012-02-01

150

Application of SFHR to gene therapy of monogenic disorders  

Microsoft Academic Search

Gene therapy treatment of disease will be greatly facilitated by the identification of genetic mutations through the Human Genome Project. The specific treatment will ultimately depend on the type of mutation as different genetic lesions will require different gene therapies. For example, large rearrangements and translocations may call for complementation with vectors containing the cDNA for the wild-type (wt) gene.

K K Goncz; N L Prokopishyn; B L Chow; B R Davis; D C Gruenert

2002-01-01

151

Gene Therapy for Cancer Treatment: Past, Present and Future  

Microsoft Academic Search

The broad field of gene therapy promises a number of innovative treatments that are likely to become important in preventing deaths from cancer. In this review, we discuss the history, highlights and future of three different gene therapy treatment approaches: immunotherapy, oncolytic virotherapy and gene transfer. Immunotherapy uses genetically modified cells and viral particles to stimulate the immune system to

Deanna Cross; James K. Burmester

2006-01-01

152

Gene therapy for malignant mesothelioma: beyond the infant years  

Microsoft Academic Search

Mesothelioma may be particularly well suited for gene therapy treatment owing to its accessibility, allowing both intrapleural and intratumoral gene delivery. At least four gene therapy trials have been carried out in mesothelioma patients, using different vector systems (adenovirus, vaccinia virus, irradiated tumor cells), and different transgenes (herpes simplex virus thymidine kinase (HSVtk) combined with ganciclovir, IL-2, IFN-?). Although small

R G van der Most; B W S Robinson; D J Nelson; RG van der Most

2006-01-01

153

Cystic Fibrosis Gene Therapy: Key Questions and Prospects  

Microsoft Academic Search

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

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

2006-01-01

154

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

Microsoft Academic Search

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

Eric Alton

2007-01-01

155

The promise of gene therapy in gastrointestinal and liver diseases  

PubMed Central

Gene therapy consists of the transfer of genetic material to cells to achieve a therapeutic goal. In the field of gastroenterology and hepatology gene therapy has produced considerable expectation as a potential tool in the management of conditions that lack effective therapy including non-resectable neoplasms of the liver, pancreas and gastrointestinal tract, chronic viral hepatitis unresponsive to interferon therapy, liver cirrhosis, and inflammatory bowel disease.

Prieto, J; Herraiz, M; Sangro, B; Qian, C; Mazzolini, G; Melero, I; Ruiz, J

2003-01-01

156

Gene therapy in animal models of autosomal dominant retinitis pigmentosa  

PubMed Central

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.

Rossmiller, Brian; Mao, Haoyu

2012-01-01

157

Chimeric RNA\\/DNA oligonucleotide-based gene therapy  

Microsoft Academic Search

Chimeric RNA\\/DNA oligonucleotide-based gene therapy.BackgroundChimeric RNA\\/DNA oligonucleotides, emerging as a potential strategy for gene therapy, have been shown to induce site-specific correction of point mutations in several genetic disease models.MethodsSix recent studies of chimeric RNA\\/DNA oligonucleotide-based gene therapy in genetic disease models are reviewed. Chimeric RNA\\/DNA oligonucleotides, complementary to 25 to 30 residues of genomic DNA flanking the mutation site

Li-Wen Lai; Yeong-Hau H. Lien

2002-01-01

158

Tripartite Meeting in Gene and Cell Therapy, 2008: Irish Society for Gene and Cell Therapy, British Society for Gene Therapy, and International Society for Cell and Gene Therapy of Cancer  

Microsoft Academic Search

The second annual meeting of the Irish Society for Gene and Cell Therapy was held in Cork, Ireland on May 15 and 16, 2008 (http:\\/\\/crr.ucc.ie\\/isgct\\/). The meeting was jointly organized with the British Society for Gene Therapy and the International Society for Cell and Gene Therapy of Cancer. Because of the location of the con- ference and the co-organization of

Barbara Guinn; Garrett Casey; Sara Collins; Tim O'Brien; M. Yvonne Alexander; Mark Tangney

2008-01-01

159

Gene Therapy for Malignant Glioma: Current Clinical Status  

Microsoft Academic Search

Glioblastoma is an aggressive brain tumor with a dismal prognosis. Gene therapy may offer a new option for the treatment of these patients. Several gene therapy approaches have shown anti-tumor efficiency in experimental studies, and the first clinical trials for the treatment of malignant glioma were conducted in the 1990s. HSV-tk gene therapy has been the pioneering and most commonly

Kalevi J. Pulkkanen; Seppo Yla-Herttuala

2005-01-01

160

Stem Cell Gene Therapy for Fanconi Anemia: Report from the 1st International Fanconi Anemia Gene Therapy Working Group Meeting  

Microsoft Academic Search

Survival rates after allogeneic hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) have increased dramatically since 2000. However, the use of autologous stem cell gene therapy, whereby the patient's own blood stem cells are modified to express the wild-type gene product, could potentially avoid the early and late complications of allogeneic HCT. Over the last decades, gene therapy has experienced

Jakub Tolar; Jennifer E Adair; Michael Antoniou; Cynthia C Bartholomae; Pamela S Becker; Bruce R Blazar; Juan Bueren; Thomas Carroll; Marina Cavazzana-Calvo; D Wade Clapp; Robert Dalgleish; Anne Galy; H Bobby Gaspar; Helmut Hanenberg; Christof Von Kalle; Hans-Peter Kiem; Dirk Lindeman; Luigi Naldini; Susana Navarro; Raffaele Renella; Paula Rio; Julián Sevilla; Manfred Schmidt; Els Verhoeyen; John E Wagner; David A Williams; Adrian J Thrasher

2011-01-01

161

Liver-directed Gene Therapy for Dyslipidemia and Diabetes  

PubMed Central

This article provides an update of liver-directed gene therapy for dyslipidemia, reviewing papers published since 2002 and summarizing progress in gene transfer vectors. Despite the availability of polypharmacy and other therapeutic interventions, the treatment of severe dyslipidemia remains a challenge and continues to be an important target for experimental gene therapy. Gene therapy strategies that focus on long-term therapeutic efficacy of different regimens are emerging from small animal experiments, and new therapeutic genes and/or new approaches have been developed. A novel strategy for gene therapy for diabetes was published recently. Gene therapy for dyslipidemia and diabetes is still in its infancy. Nonetheless, recent progress in this area is encouraging and bodes well for the future.

Oka, Kazuhiro; Chan, Lawrence

2005-01-01

162

Gene therapy for gastric cancer: Is it promising?  

PubMed Central

Gastric cancer is one of the most common tumors worldwide. The therapeutic outcome of conventional therapies is inefficient. Thus, new therapeutic strategies are urgently needed. Gene therapy is a promising molecular alternative in the treatment of gastric cancer, including the replacement of defective tumor suppressor genes, the inactivation of oncogenes, the introduction of suicide genes, genetic immunotherapy, anti-angiogenetic gene therapy, and virotherapy. Improved molecular biological techniques and a better understanding of gastric carcinogenesis have allowed us to validate a variety of genes as molecular targets for gene therapy. This review provides an update of the new developments in cancer gene therapy, new principles, techniques, strategies and vector systems, and shows how they may be applied in the treatment of gastric cancer.

Sutter, Andreas P; Fechner, Henry

2006-01-01

163

Potential of gene therapy as a treatment for heart failure  

PubMed Central

Advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, make gene-based therapy a promising treatment option for heart conditions. Cardiovascular gene therapy has benefitted from recent advancements in vector technology, design, and delivery modalities. There is a critical need to explore new therapeutic approaches in heart failure, and gene therapy has emerged as a viable alternative. Advances in understanding of the molecular basis of myocardial dysfunction, together with the development of increasingly efficient gene transfer technology, has placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting the cardiac sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump (SERCA2a) has the potential to open a new era for gene therapy for heart failure.

Hajjar, Roger J.

2013-01-01

164

Interactive Fly: Early Zygotic Gene Expression Images  

NSDL National Science Digital Library

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.

PhD Thomas B Brody (NIH Laboratory of Neurochemistry)

2006-12-12

165

Nanoparticle PEGylation for imaging and therapy  

PubMed Central

Nanoparticles are an essential component in the emerging field of nanomedical imaging and therapy. When deployed in vivo, these materials are typically protected from the immune system by polyethylene glycol (PEG). A wide variety of strategies to coat and characterize nanoparticles with PEG has established important trends on PEG size, shape, density, loading level, molecular weight, charge and purification. Strategies to incorporate targeting ligands are also prevalent. This article presents a background to investigators new to stealth nanoparticles, and suggests some key considerations needed prior to designing a nanoparticle PEGylation protocol and characterizing the performance features of the product.

Jokerst, Jesse V; Lobovkina, Tatsiana; Zare, Richard N; Gambhir, Sanjiv S

2011-01-01

166

Radioiodine therapy of thyroid carcinoma following Pax-8 gene transfer.  

PubMed

The thyroid transcription factor Pax-8 could bind with the promoter/enhancer of thyroid-specific genes such as thyroglobulin (Tg), thyroperoxidase (TPO) and sodium iodide symporter (NIS), and regulate the expression of these proteins in thyrocyte. Promoting iodide accumulation in tumor cells by re-expression of Pax-8 provides a possible strategy for radioiodine therapy of tumor. Therefore, we investigated the effect of Pax-8 gene transfer on radioiodine therapy of thyroid carcinoma. The human Pax-8 gene was transfected into the human thyroid carcinoma (K1 and F133) cells by the recombinant adenovirus vector. Although the NIS mRNA was not detected, the expression of mRNA and proteins of Tg and TPO in AdPax-8-infected F133 cells were activated by Pax-8. Iodide uptake in thyroid carcinoma cells was reactivated by Pax-8 (increasing 3.3-fold in K1 cells and 5.7-fold in F133 cells). Moreover, Pax-8 promoted iodide organification and the retention time of iodine in Pax-8-expressing cells apparently prolonged in vitro and in vivo (P<0.05). Pax-8-expressing thyroid carcinoma cells were selectively killed by radioiodine. The AdPax-8-infected tumors in vivo clearly visualized in scanning images at 12?h after administration of radioiodine. These results indicate that Pax-8 can promote iodide uptake, and specifically prolong the retention time of iodide in thyroid cancer in vitro and in vivo by promoting the expression of TPO and Tg proteins. Pax-8 gene transfection may lead to effective radioiodine therapy of tumor. PMID:21833035

Mu, D; Huang, R; Ma, X; Li, S; Kuang, A

2012-04-01

167

Successful Gene Therapy in Utero for Lethal Murine Hypophosphatasia  

PubMed Central

Abstract Hypophosphatasia (HPP), caused by mutations in the gene ALPL encoding tissue-nonspecific alkaline phosphatase (TNALP), is an inherited systemic skeletal disease characterized by mineralization defects of bones and teeth. The clinical severity of HPP varies widely, from a lethal perinatal form to mild odontohypophosphatasia showing only dental manifestations. HPP model mice (Akp2?/?) phenotypically mimic the severe infantile form of human HPP; they appear normal at birth but die by 2 weeks of age because of growth failure, hypomineralization, and epileptic seizures. In the present study, we investigated the feasibility of fetal gene therapy using the lethal HPP model mice. On day 15 of gestation, the fetuses of HPP model mice underwent transuterine intraperitoneal injection of adeno-associated virus serotype 9 (AAV9) expressing bone-targeted TNALP. Treated and delivered mice showed normal weight gain and seizure-free survival for at least 8 weeks. Vector sequence was detected in systemic organs including bone at 14 days of age. ALP activities in plasma and bone were consistently high. Enhanced mineralization was demonstrated on X-ray images of the chest and forepaw. Our data clearly demonstrate that systemic injection of AAV9 in utero is an effective strategy for the treatment of lethal HPP mice. Fetal gene therapy may be an important choice after prenatal diagnosis of life-threatening HPP.

Sugano, Hanako; Matsumoto, Tae; Miyake, Koichi; Watanabe, Atsushi; Iijima, Osamu; Migita, Makoto; Narisawa, Sonoko; Millan, Jose Luis; Fukunaga, Yoshitaka

2011-01-01

168

Prospectives for gene therapy of retinal degenerations.  

PubMed

Retinal degenerations encompass a large number of diseases in which the retina and associated retinal pigment epithelial (RPE) cells progressively degenerate leading to severe visual disorders or blindness. Retinal degenerations can be divided into two groups, a group in which the defect has been linked to a specific gene and a second group that has a complex etiology that includes environmental and genetic influences. The first group encompasses a number of relatively rare diseases with the most prevalent being Retinitis pigmentosa that affects approximately 1 million individuals worldwide. Attempts have been made to correct the defective gene by transfecting the appropriate cells with the wild-type gene and while these attempts have been successful in animal models, human gene therapy for these inherited retinal degenerations has only begun recently and the results are promising. To the second group belong glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). These retinal degenerations have a genetic component since they occur more often in families with affected probands but they are also linked to environmental factors, specifically elevated intraocular pressure, age and high blood sugar levels respectively. The economic and medical impact of these three diseases can be assessed by the number of individuals affected; AMD affects over 30 million, DR over 40 million and glaucoma over 65 million individuals worldwide. The basic defect in these diseases appears to be the relative lack of a neurogenic environment; the neovascularization that often accompanies these diseases has suggested that a decrease in pigment epithelium-derived factor (PEDF), at least in part, may be responsible for the neurodegeneration since PEDF is not only an effective neurogenic and neuroprotective agent but also a potent inhibitor of neovascularization. In the last few years inhibitors of vascularization, especially antibodies against vascular endothelial cell growth factors (VEGF), have been used to prevent the neovascularization that accompanies AMD and DR resulting in the amelioration of vision in a significant number of patients. In animal models it has been shown that transfection of RPE cells with the gene for PEDF and other growth factors can prevent or slow degeneration. A limited number of studies in humans have also shown that transfection of RPE cells in vivo with the gene for PEDF is effective in preventing degeneration and restore vision. Most of these studies have used virally mediated gene delivery with all its accompanying side effects and have not been widely used. New techniques using non-viral protocols that allow efficient delivery and permanent integration of the transgene into the host cell genome offer novel opportunities for effective treatment of retinal degenerations. PMID:23372421

Thumann, Gabriele

2012-08-01

169

Imaging of enzyme replacement therapy using PET  

PubMed Central

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.

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

2010-01-01

170

Cerenkov Luminescence Imaging (CLI) for cancer therapy monitoring.  

PubMed

In molecular imaging, positron emission tomography (PET) and optical imaging (OI) are two of the most important and thus most widely used modalities. PET is characterized by its excellent sensitivity and quantification ability while OI is notable for non-radiation, relative low cost, short scanning time, high throughput, and wide availability to basic researchers. However, both modalities have their shortcomings as well. PET suffers from poor spatial resolution and high cost, while OI is mostly limited to preclinical applications because of its limited tissue penetration along with prominent scattering optical signals through the thickness of living tissues. Recently a bridge between PET and OI has emerged with the discovery of Cerenkov Luminescence Imaging (CLI). CLI is a new imaging modality that harnesses Cerenkov Radiation (CR) to image radionuclides with OI instruments. Russian Nobel laureate Alekseyevich Cerenkov and his colleagues originally discovered CR in 1934. It is a form of electromagnetic radiation emitted when a charged particle travels at a superluminal speed in a dielectric medium. The charged particle, whether positron or electron, perturbs the electromagnetic field of the medium by displacing the electrons in its atoms. After passing of the disruption photons are emitted as the displaced electrons return to the ground state. For instance, one (18)F decay was estimated to produce an average of 3 photons in water. Since its emergence, CLI has been investigated for its use in a variety of preclinical applications including in vivo tumor imaging, reporter gene imaging, radiotracer development, multimodality imaging, among others. The most important reason why CLI has enjoyed much success so far is that this new technology takes advantage of the low cost and wide availability of OI to image radionuclides, which used to be imaged only by more expensive and less available nuclear imaging modalities such as PET. Here, we present the method of using CLI to monitor cancer drug therapy. Our group has recently investigated this new application and validated its feasibility by a proof-of-concept study. We demonstrated that CLI and PET exhibited excellent correlations across different tumor xenografts and imaging probes. This is consistent with the overarching principle of CR that CLI essentially visualizes the same radionuclides as PET. We selected Bevacizumab (Avastin; Genentech/Roche) as our therapeutic agent because it is a well-known angiogenesis inhibitor. Maturation of this technology in the near future can be envisioned to have a significant impact on preclinical drug development, screening, as well as therapy monitoring of patients receiving treatments. PMID:23183774

Xu, Yingding; Liu, Hongguang; Chang, Edwin; Jiang, Han; Cheng, Zhen

2012-01-01

171

Bystander effect caused by suicide gene expression indicates the feasibility of gene therapy for hepatocellular carcinoma  

Microsoft Academic Search

In the field of gene therapy using retroviral vectors, it appears impossible to introduce a foreign gene into all target cells. Therefore adjacent cell killing, the so-called bystander effect, caused by genetically modified cells provides therapeutic advantages for gene therapy against cancers. We retrovirally transduced the herpes simplex virus thymidine kinase (HSV-tk) gene into murine and rat hepatocellular carcinoma (HCC)

Shigeki Kuriyama; Toshiya Nakatani; Kazuhiro Masui; Takemi Sakamoto; Kentarou Tominaga; Masahide Yoshikawa; Hiroshi Fukui; Kazuhiro Ikenaka; Tadasu Tsujii

1995-01-01

172

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

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

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

2006-01-01

173

New development and application of ultrasound targeted microbubble destruction in gene therapy and drug delivery.  

PubMed

Ultrasound is a common used technique for clinical imaging. In recent years, with the advances in preparation technology of microbubbles and the innovations in ultrasound imaging, ultrasound is no longer confined to detection of tissue perfusion, but extends to specific ultrasound molecular imaging and target therapy gradually. With the development of research, ultrasound molecular imaging and target therapy have made great progresses. Targeted microbubbles for molecular imaging are achieved by binding target molecules, specific antibody or ligand to the surface of microbubbles to obtain specific imaging by attaching to target tissues. Meanwhile, it can also achieve targeting gene therapy or drug delivery by ultrasound targeted microbubble destruction (UTMD) mediating genes or drugs to specific target sites. UTMD has a number of advantages, such as target-specific, highly effective, non-invasivity, relatively low-cost and no radiation, and has broad application prospects, which is regarded as one hot spot in medical studies. We reviewed the new development and application of UTMD in gene therapy and drug delivery in this paper. With further development of technology and research, the gene or drug delivery system and related methods will be widely used in application and researches. PMID:23721204

Chen, Zhi-Yi; Yang, Feng; Lin, Yan; Zhang, Jin-Shan; Qiu, Ri-Xiang; Jiang, Lan; Zhou, Xing-Xing; Yu, Jiang-Xiu

2013-08-01

174

Viability of long-term gene therapy in the cochlea.  

PubMed

Gene therapy has been investigated as a way to introduce a variety of genes to treat neurological disorders. An important clinical consideration is its long-term effectiveness. This research aims to study the long-term expression and effectiveness of gene therapy in promoting spiral ganglion neuron survival after deafness. Adenoviral vectors modified to express brain derived neurotrophic factor or neurotrophin-3 were unilaterally injected into the guinea pig cochlea one week post ototoxic deafening. After six months, persistence of gene expression and significantly greater neuronal survival in neurotrophin-treated cochleae compared to the contralateral cochleae were observed. The long-term gene expression observed indicates that gene therapy is potentially viable; however the degeneration of the transduced cells as a result of the original ototoxic insult may limit clinical effectiveness. With further research aimed at transducing stable cochlear cells, gene therapy may be an efficacious way to introduce neurotrophins to promote neuronal survival after hearing loss. PMID:24751795

Atkinson, Patrick J; Wise, Andrew K; Flynn, Brianna O; Nayagam, Bryony A; Richardson, Rachael T

2014-01-01

175

Viability of Long-Term Gene Therapy in the Cochlea  

PubMed Central

Gene therapy has been investigated as a way to introduce a variety of genes to treat neurological disorders. An important clinical consideration is its long-term effectiveness. This research aims to study the long-term expression and effectiveness of gene therapy in promoting spiral ganglion neuron survival after deafness. Adenoviral vectors modified to express brain derived neurotrophic factor or neurotrophin-3 were unilaterally injected into the guinea pig cochlea one week post ototoxic deafening. After six months, persistence of gene expression and significantly greater neuronal survival in neurotrophin-treated cochleae compared to the contralateral cochleae were observed. The long-term gene expression observed indicates that gene therapy is potentially viable; however the degeneration of the transduced cells as a result of the original ototoxic insult may limit clinical effectiveness. With further research aimed at transducing stable cochlear cells, gene therapy may be an efficacious way to introduce neurotrophins to promote neuronal survival after hearing loss.

Atkinson, Patrick J.; Wise, Andrew K.; Flynn, Brianna O.; Nayagam, Bryony A.; Richardson, Rachael T.

2014-01-01

176

Preclinical Evaluation of Gene Therapy for NF2 Lesions in Mouse Models Using Amplicon Vectors and Prodrug Activation.  

National Technical Information Service (NTIS)

These studies were designed to characterize tumors in mouse models of NF2 and to evaluate vector mediated therapy. Magnetic resonance, bioluminescence and near-infrared imaging were used in monitoring changes in tumor volume and in tracking gene delivery ...

X. O. Breakefield

2003-01-01

177

Will gene therapy trump factor treatment in hemophilia?  

PubMed

Hemophilia treatment is entering a new phase, with the exciting possibility of gene therapy promising a cure. Novel gene transfer strategies are being considered for patients with inhibitors.Improvement of factor-replacement therapy is being aggressively pursued with long-acting factor concentrates, many of which are in clinical trials. Whether gene therapy will be safe and cost effective to eventually supersede factor-replacement therapy is yet to be determined. It is hoped that with the profusion of clinical trial programs in hemophilia care, it will eventually provide affordable treatment to many patients who currently cannot access adequate treatment in the developing countries. PMID:23373779

Rangarajan, Savita; Aledort, Louis

2013-02-01

178

A snapshot of gene therapy in Latin America  

PubMed Central

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

Linden, Rafael; Matte, Ursula

2014-01-01

179

Gene and Cell Therapy in Germany and the EU  

Microsoft Academic Search

:  Gene and somatic cell therapy medicinal products as well as tissue engineered products are summarized under the term advanced\\u000a therapy medicinal products in the EU. The Paul-Ehrlich-Institut has established a specialized division with various sections\\u000a providing scientific advice and clinical trial authorization to applicants, thereby protecting patients’ health and supporting\\u000a product development. Gene therapy medicinal products include products suitable for

Klaus Cichutek

2008-01-01

180

Current status of gene therapy for muscle diseases.  

PubMed

The progress made in vector technology and preclinical evaluation of molecular and gene therapy for inherited muscle diseases led to initiation of the first clinical trials using plasmid and adeno-associated virus vectors, as well as antisense oligonucleotides. The scope of this review is to discuss the current status of gene therapy for muscular dystrophy and to highlight recent advances in viral, cell-based as well as molecular therapies. PMID:17925889

Thirion, Christian; Lochmüller, Hanns

2007-01-01

181

Photoacoustic imaging and temperature measurement for photothermal cancer therapy  

PubMed Central

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

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

2009-01-01

182

Current Prospects and Challenges for Epilepsy Gene Therapy  

PubMed Central

This review addresses the state of gene therapy research for the treatment of epilepsy. Preclinical studies have demonstrated the anti-seizure efficacy of viral vector-based gene transfer through the use of a variety of strategies – from modulating classic neurotransmitter systems to targeting or overexpressing of neuropeptide receptors in seizure-specific brain regions. While these studies provide substantive proof of principle for viral vector gene therapy, future studies must address the challenges of vector immunity, cellular specificity and effective global delivery. As these issues are resolved, viral vector gene therapy should significantly impact the treatment of intractable epilepsy.

Weinberg, Marc S.; McCown, Thomas J.

2011-01-01

183

Radiolabeled regulatory peptides for imaging and therapy  

PubMed Central

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

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

2010-01-01

184

Gene therapy and gastrointestinal cancer: concepts and clinical facts  

Microsoft Academic Search

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

Martin Hauses; Hans K. Schackert

1999-01-01

185

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

PubMed Central

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.

Buckland, Karen F.; Bobby Gaspar, H.

2014-01-01

186

Translational Approaches towards Cancer Gene Therapy: Hurdles and Hopes  

PubMed Central

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.

Barar, Jaleh; Omidi, Yadollah

2012-01-01

187

Quantitative Imaging for Evaluation of Response to Cancer Therapy  

Microsoft Academic Search

Advances in molecular medicine offer the potential to move cancer therapy beyond traditional cytotoxic treatments to safer and more effective targeted therapies based on molecular characteristics of a patient's tumor. Within this context, the role of quantitative imaging as an in vivo biomarker has received considerable attention as a means to predict and measure the response to therapy. For example,

Laurence P. Clarke; Barbara S. Croft; Robert Nordstrom; Huiming Zhang; Gary Kelloff; J. Tatum

188

The status of gene therapy for brain tumors  

PubMed Central

The advent of gene therapy in the early 1990’s raised expectations for brain tumor therapies; however, whereas clinical trials in patients with malignant gliomas provided evidence of safety, therapeutic benefit was not convincing. These early forays resembled the historical introductions of other therapies that seemed promising, only to fail in human trials. Nevertheless, re-study in the laboratory and retesting in iterative laboratory–clinic processes enabled therapies with strong biological rationales to ultimately show evidence of success in humans and become accepted. Examples, such as organ transplantation, monoclonal antibody therapy and antiangiogenic therapy, provide solace that a strategy’s initial lack of success in humans provides an opportunity for its further refinement in the laboratory and development of solutions that will translate into patient success stories. The authors herein summarize results from clinical trials of gene therapy for malignant gliomas, and discuss the influence of these results on present thought in preclinical research.

Chiocca, E Antonio

2010-01-01

189

Gene Therapy for Heart Failure: Where Do We Stand?  

PubMed Central

Advances in understanding of the molecular basis of myocardial dysfunction, together with the development of increasingly efficient gene transfer technology, has placed heart failure within reach of gene-based therapy. Multiple components of cardiac contractility, including the Beta-adrenergic system, the calcium channel cycling pathway, and cytokine mediated cell proliferation, have been identified as appropriate targets for gene therapy. The development of efficient and safe vectors such as adeno-associated viruses and polymer nanoparticles has provided an opportunity for clinical application for gene therapy. The recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) has the potential to open a new era for gene therapy in the treatment of heart failure.

Naim, Charbel; Yerevanian, Armen; Hajjar, Roger J.

2013-01-01

190

Novel therapies for the treatment of cystic fibrosis: new developments in gene and stem cell therapy.  

PubMed

Cystic fibrosis (CF) was one of the first target diseases for lung gene therapy. Studies of lung gene transfer for CF have provided many insights into the necessary components of successful gene therapy for lung diseases. Many advancements have been achieved with promising results in vitro and in small animal models. However, studies in primate models and patients have been discouraging despite a large number of clinical trials. This reflects a number of obstacles to successful, sustained, and repeatable gene transfer in the lung. Cell-based therapy with embryonic stem cells and adult stem cells (bone marrow or cord blood), have been investigated recently and may provide a viable therapeutic approach in the future. In this article, the authors review CF pathophysiology with a focus on specific targets in the lung epithelium for gene transfer and summarize the current status and future directions of gene- and cell-based therapies. PMID:17467554

Sueblinvong, Viranuj; Suratt, Benjamin T; Weiss, Daniel J

2007-06-01

191

Vector-mediated cancer gene therapy: an overview.  

PubMed

In recent years there has been a dramatic increase in developing gene therapy approaches for the treatment of cancer. The two events that have permitted the formulation of concept of cancer gene therapy are the new understanding of the molecular mechanisms underlying oncogenesis, and the development of the DNA-delivery vehicles or vectors. Many approaches to cancer gene therapy have been proposed, and several viral and non-viral vectors have been utilized. The purpose of this review article is to describe the various strategies of cancer gene therapy (transfer of tumor suppressor genes, suicide genes-enzyme/pro-drug approach, inhibition of dominant oncogenes, immunomodulation approaches, expression of molecules that affect angiogenesis, tumor invasion and metastasis, chemosensitization and radiosensitization approaches, and chemoprotection of stem cells). The chapter also reviews the commonly used vectors (retroviral vectors, adenoviral vectors, adeno-associated viral vectors, pox viruses, herpes simplex viruses, HIV- vectors, non-viral vectors and targetable vectors) for cancer gene therapy. Some of the important issues in cancer gene therapy, and the potential future directions are also being discussed. PMID:15908802

Seth, Prem

2005-05-01

192

Gene therapy to the kidney using viral vectors  

PubMed Central

Many pediatric diseases have reached a therapeutic plateau using currently available surgical and pharmacological approaches. Gene therapy has emerged as an exciting new technology to manipulate cells in the mammalian system, and in some cases, this method has achieved amazing therapeutic benefits. Compared to other organs, such as the brain, liver and lung, methods to genetically modify renal cells have received relatively little attention. The current review will discuss the challenges and important developments regarding gene therapy to the kidney, and relate the recent successes and failures to the future potential of gene therapy as a treatment modality in the context of pediatric disease.

Akbulut, Talha; Park, Frank

2009-01-01

193

Identification of Hematopoietic Stem Cell Engraftment Genes in Gene Therapy Studies  

PubMed Central

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.

Powers, John M; Trobridge, Grant D

2013-01-01

194

Deciphering Development: Quantifying Gene Expression through Imaging  

NSDL National Science Digital Library

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.

Melissa Lee Philips (;)

2007-08-01

195

Stem Cell Gene Therapy for Fanconi Anemia: Report from the 1st International Fanconi Anemia Gene Therapy Working Group Meeting  

PubMed Central

Survival rates after allogeneic hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) have increased dramatically since 2000. However, the use of autologous stem cell gene therapy, whereby the patient's own blood stem cells are modified to express the wild-type gene product, could potentially avoid the early and late complications of allogeneic HCT. Over the last decades, gene therapy has experienced a high degree of optimism interrupted by periods of diminished expectation. Optimism stems from recent examples of successful gene correction in several congenital immunodeficiencies, whereas diminished expectations come from the realization that gene therapy will not be free of side effects. The goal of the 1st International Fanconi Anemia Gene Therapy Working Group Meeting was to determine the optimal strategy for moving stem cell gene therapy into clinical trials for individuals with FA. To this end, key investigators examined vector design, transduction method, criteria for large-scale clinical-grade vector manufacture, hematopoietic cell preparation, and eligibility criteria for FA patients most likely to benefit. The report summarizes the roadmap for the development of gene therapy for FA.

Tolar, Jakub; Adair, Jennifer E; Antoniou, Michael; Bartholomae, Cynthia C; Becker, Pamela S; Blazar, Bruce R; Bueren, Juan; Carroll, Thomas; Cavazzana-Calvo, Marina; Clapp, D Wade; Dalgleish, Robert; Galy, Anne; Gaspar, H Bobby; Hanenberg, Helmut; Von Kalle, Christof; Kiem, Hans-Peter; Lindeman, Dirk; Naldini, Luigi; Navarro, Susana; Renella, Raffaele; Rio, Paula; Sevilla, Julian; Schmidt, Manfred; Verhoeyen, Els; Wagner, John E; Williams, David A; Thrasher, Adrian J

2011-01-01

196

Infection of cultured striatal neurons with a defective HSV-1 vector: implications for gene therapy.  

PubMed Central

Several neurological diseases which affect the corpus striatum are candidates for gene therapy. We have developed a defective Herpes Simplex Virus (HSV-1) vector system to introduce genes into postmitotic cells, such as neurons. The prototype vector, pHSVlac, contains a transcription unit which places the E. coli Lac Z gene under the control of the HSV-1 immediate early (IE) 4/5 promoter, a constitutive promoter. We now demonstrate that a HSV-1 vector can deliver a gene into striatal neurons. Infection of cultured rat striatal neurons with pHSVlac virus resulted in stable expression of beta-galactosidase for at least two weeks, without cell death. The potential to replace the Lac Z gene with other genes of interest, such as the gene responsible for Huntington's Disease, once it is isolated, may lead to insights about the pathogenesis of this genetic neurodegenerative disease, and may provide a method for performing gene therapy on this disease. Similarly, introduction of the tyrosine hydroxylase gene, which encodes the rate-limiting enzyme in the conversion of tyrosine to dopamine, into striatal neurons might provide a novel gene therapy approach towards treating Parkinson's Disease. Images

Freese, A; Geller, A

1991-01-01

197

Molecular Genetic and Gene Therapy Studies of the Musculoskeletal System.  

National Technical Information Service (NTIS)

The proposed research projects focuses on bone health, including relevance to the musculoskeletal system in battlefield performance and in battlefield injury. We have utilized state-of-the-art molecular genetic and gene therapy technologies to address fun...

S. Mohan

2007-01-01

198

Molecular imaging in stem cell therapy for spinal cord injury.  

PubMed

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

Song, Fahuan; Tian, Mei; Zhang, Hong

2014-01-01

199

Gene transfer to the lung: lessons learned from more than 2 decades of CF gene therapy.  

PubMed

Gene therapy is currently being developed for a wide range of acute and chronic lung diseases. The target cells, and to a degree the extra and intra-cellular barriers, are disease-specific and over the past decade the gene therapy community has recognized that no one vector is good for all applications, but that the gene transfer agent (GTA) has to be carefully matched to the specific disease target. Gene therapy is particularly attractive for diseases that currently do not have satisfactory treatment options and probably easier for monogenic disorders than for complex diseases. Cystic fibrosis (CF) fulfils these criteria and is, therefore, a good candidate for gene therapy-based treatment. This review will focus on CF as an example for lung gene therapy, but lessons learned may be applicable to other target diseases. PMID:19138713

Griesenbach, Uta; Alton, Eric W F W

2009-02-27

200

Clinical development of gene therapy for colorectal cancer.  

PubMed

Colorectal cancer (CRC) is the second most common type of malignancy in Western nations. Improvements in surgical and radiotherapeutic techniques and the increased availability of new cytotoxic drugs have improved outcome, but 50% of patients still die from recurrent or metastatic disease. Several features of its natural history render CRC a good candidate for gene therapy. Techniques include gene replacement, virus-directed enzyme-prodrug therapy, immune manipulation and virotherapy, all of which have entered clinical trials. PMID:12894249

Kerr, David

2003-08-01

201

Gene therapy for the fetus: is there a future?  

PubMed

Gene therapy uses the intracellular delivery of genetic material for the treatment of disease. A wide range of diseases - including cancer, vascular and neurodegenerative disorders and inherited genetic diseases - are being considered as targets for this therapy in adults. There are particular reasons why fetal application might prove better than application in the adult for treatment, or even prevention of early-onset genetic disorders such as cystic fibrosis and Duchenne muscular dystrophy. Research shows that gene transfer to the developing fetus targets rapidly expanding populations of stem cells, which are inaccessible after birth, and indicates that the use of integrating vector systems results in permanent gene transfer. In animal models of congenital disease such as haemophilia, studies show that the functionally immature fetal immune system does not respond to the product of the introduced gene, and therefore immune tolerance can be induced. This means that treatment could be repeated after birth, if that was necessary to continue to correct the disease. For clinicians and parents, fetal gene therapy would give a third choice following prenatal diagnosis of inherited disease, where termination of pregnancy or acceptance of an affected child are currently the only options. Application of this therapy in the fetus must be safe, reliable and cost-effective. Recent developments in the understanding of genetic disease, vector design, and minimally invasive delivery techniques have brought fetal gene therapy closer to clinical practice. However more research needs to be done in before it can be introduced as a therapy. PMID:17900991

David, Anna L; Peebles, Donald

2008-02-01

202

Gene therapy: regulations, ethics and its practicalities in liver disease.  

PubMed

Gene therapy is a new and promising approach which opens a new door to the treatment of human diseases. By direct transfer of genetic materials to the target cells, it could exert functions on the level of genes and molecules. It is hoped to be widely used in the treatment of liver disease, especially hepatic tumors by using different vectors encoding the aim gene for anti-tumor activity by activating primary and adaptive immunity, inhibiting oncogene and angiogenesis. Despite the huge curative potential shown in animal models and some pilot clinical trials, gene therapy has been under fierce discussion since its birth in academia and the public domain because of its unexpected side effects and ethical problems. There are other challenges arising from the technique itself like vector design, administration route test and standard protocol exploration. How well we respond will decide the fate of gene therapy clinical medical practice. PMID:18416454

Jin, Xi; Yang, Yi-Da; Li, You-Ming

2008-04-21

203

Gene Therapy Progress and Prospects: cancer gene therapy using tumour suppressor genes  

Microsoft Academic Search

Targeting tumour suppressor gene pathways is an attractive therapeutic strategy in cancer. Since the first clinical trial took place in 1996, at least 20 other trials have investigated the possibility of restoring p53 function, either alone or in combination with chemotherapy, but with limited success. Other recent clinical trials have sought to harness abnormalities in the p53 pathway to permit

IA McNeish; SJ Bell; NR Lemoine

2004-01-01

204

Progress in gene therapy of dystrophic heart disease  

PubMed Central

The heart is frequently afflicted in muscular dystrophy. In severe cases, cardiac lesion may directly result in death. Over the years, pharmacological and/or surgical interventions have been the mainstay to alleviate cardiac symptoms in muscular dystrophy patients. Although these traditional modalities remain useful, the emerging field of gene therapy has now provided an unprecedented opportunity to transform our thinking/approach in the treatment of dystrophic heart disease. In fact, the premise is already in place for genetic correction. Gene mutations have been identified and animal models are available for several types of muscular dystrophy. Most importantly, innovative strategies have been developed to effectively deliver therapeutic genes to the heart. Dystrophin-deficient Duchenne cardiomyopathy is associated with Duchenne muscular dystrophy (DMD), the most common lethal muscular dystrophy. Considering its high incidence, there has been a considerable interest and significant input in the development of Duchenne cardiomyopathy gene therapy. Using Duchenne cardiomyopathy as an example, here we illustrate the struggles and successes experienced in the burgeoning field of dystrophic heart disease gene therapy. In light of abundant and highly promising data with the adeno-associated virus (AAV) vector, we have specially emphasized on AAV-mediated gene therapy. Besides DMD, we have also discussed gene therapy for treating cardiac diseases in other muscular dystrophies such as limb-girdle muscular dystrophy.

Lai, Y; Duan, D

2013-01-01

205

Gene therapy: light is finally in the tunnel.  

PubMed

After two decades of ups and downs, gene therapy has recently achieved a milestone in treating patients with Leber's congenital amaurosis (LCA). LCA is a group of inherited blinding diseases with retinal degeneration and severe vision loss in early infancy. Mutations in several genes, including RPE65, cause the disease. Using adeno-associated virus as a vector, three independent teams of investigators have recently shown that RPE65 can be delivered to retinal pigment epithelial cells of LCA patients by subretinal injections resulting in clinical benefits without side effects. However, considering the whole field of gene therapy, there are still major obstacles to clinical applications for other diseases. These obstacles include innate and immune barriers to vector delivery, toxicity of vectors and the lack of sustained therapeutic gene expression. Therefore, new strategies are needed to overcome these hurdles for achieving safe and effective gene therapy. In this article, we shall review the major advancements over the past two decades and, using lung gene therapy as an example, discuss the current obstacles and possible solutions to provide a roadmap for future gene therapy research. PMID:22231356

Cao, Huibi; Molday, Robert S; Hu, Jim

2011-12-01

206

Stem-Cell-Based Gene Therapy for HIV Infection  

PubMed Central

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.

Zhen, Anjie; Kitchen, Scott

2013-01-01

207

Gene therapy for the regeneration of bone  

Microsoft Academic Search

Gene transfer technologies offer the prospect of enhancing bone regeneration by delivering osteogenic gene products locally to osseous defects. In most cases the gene product will be a protein, which will be synthesized endogenously within and around the lesion in a sustained fashion. It will have undergone authentic post-translational processing and lack the alterations that occur when recombinant proteins are

Christopher Evans

2011-01-01

208

Molecular Genetic and Gene Therapy Studies of the Musculoskeletal System.  

National Technical Information Service (NTIS)

The primary goal of the proposed work is to apply several state of the art molecular genetic and gene therapy technologies to address fundamental questions in bone biology with a particular emphasis on attempting: l)to clarify gene functions of the those ...

D. J. Baylink S. Mohan

2004-01-01

209

Fetal and neonatal gene therapy: benefits and pitfalls  

Microsoft Academic Search

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

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

2004-01-01

210

Gene therapy in the treatment of intestinal inflammation  

Microsoft Academic Search

BackgroundLocal expression of anti-inflammatory or immunoregulatory genes may offer an alternative treatment of gastrointestinal inflammation.DiscussionWe review the basic requirements for gene therapy, the possible routes of delivery, and the different strategies for specific targeting focusing on gastrointestinal inflammation.

Catherine van Montfrans; Anje A. te Velde; Sander J. H. van Deventer; MariaSol Rodriguez Pena

2004-01-01

211

Computational Models of HIV1 Resistance to Gene Therapy Elucidate Therapy Design Principles  

Microsoft Academic Search

Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs, and can potentially control the virus while alleviating major limitations of current approaches. Yet, HIV-1's ability to rapidly acquire mutations and escape therapy presents a critical challenge to any novel treatment paradigm. Viral escape is thus a key consideration in the design of any gene-based technique. We develop a computational

Sharon Aviran; Priya S. Shah; David V. Schaffer; Adam P. Arkin

2010-01-01

212

Cognitive)ehavioral body image therapy for body dysmorphic disorder  

Microsoft Academic Search

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

James C. Rosen; Jeff Reiter; Pam Orosan

1995-01-01

213

PET Imaging of Response and Resistance to Cancer Therapy  

Microsoft Academic Search

As cancer treatment moves towards more targeted therapy, there is an increasing need for tools to guide therapy selection\\u000a and to evaluate response. Biochemical and molecular imaging can complement existing in vitro assay methods and is likely to\\u000a play a key role in early drug testing and development, as well as future clinical practice. Imaging is ideally suited to assessing

David A. Mankoff; Kenneth A. Krohn

214

Concept and organization of a clinical gene therapy lab.  

PubMed

Designing a dedicated clinical facility to meet the needs of existing and developing Gene Therapy Protocols presents a unique challenge. Here, we review some of the issues we faced and share some of our design concepts. An optimal Clinical Gene Therapy Lab must meet relevant regulatory guidelines, interface with other hospital labs as well as the clinic and patient care areas, be efficient and flexible in utilization of space, and have the potential to meet future needs without continual renovation. As clinical science expands to include more gene transfer approaches, specific laboratory areas for this type of work will become increasingly necessary. PMID:7593261

Kittler, E L; Quesenberry, P J

1995-08-01

215

Gene therapy of inherited skin adhesion disorders: a critical overview.  

PubMed

Gene therapy has the potential to treat devastating inherited diseases for which there is little hope of finding a conventional cure. These include lethal diseases, like immunodeficiencies or several metabolic disorders, or conditions associated with a relatively long life expectancy but poor quality of life and expensive and life-long symptomatic treatments, such as muscular dystrophy, cystic fibrosis and thalassaemia. Skin adhesion defects belong to both groups. For the nonlethal forms, gene therapy, or transplantation of cultured skin derived from genetically corrected epidermal stem cells, represents a very attractive therapeutic option, and potentially a definitive treatment. Recent advances in gene transfer and stem cell culture technology are making this option closer than ever. This paper critically reviews the progress and prospects of gene therapy for epidermolysis bullosa, and the technical and nontechnical factors currently limiting its development. PMID:19466960

De Luca, M; Pellegrini, G; Mavilio, F

2009-07-01

216

Gene therapy of skin adhesion disorders (mini review).  

PubMed

Gene therapy is a potential treatment for severe inherited disorders for which there is little hope of finding a conventional cure. These include lethal diseases like immunodeficiencies and metabolic disorders, and non lethal conditions associated to poor quality of life and life-long symptomatic treatments, like muscular dystrophy, cystic fibrosis or thalassemia. Skin adhesion defects belong to both groups. For the non-lethal forms, gene therapy, or transplantation of cultured skin derived from genetically corrected epidermal stem cells, represents a very attractive therapeutic option, and potentially a definitive treatment. Recent advances in gene transfer and stem cell culture technology are making this option closer than ever. This paper critically reviews the progress and prospects of gene therapy for skin adhesion defects, and the factors currently limiting its development. PMID:22250710

Cavazza, Alessia; Mavilio, Fulvio

2012-08-01

217

Advances in gene therapy technologies to treat retinitis pigmentosa  

PubMed Central

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.

Petrs-Silva, Hilda; Linden, Rafael

2014-01-01

218

Recent Advances in Gene Therapy for Severe Congenital Immunodeficiency Diseases  

PubMed Central

Purpose of Review To discuss new data on safety and efficacy of the ongoing gene therapy trials for primary immune deficiencies, the first reports of new trials and the preclinical developments that are likely to be translated to the clinic in the near future. Recent findings Both clinical successes and severe adverse events continue to be reported in trials of gammaretroviral gene therapy for SCID-X1, ADA-SCID and CGD. Insertion site analyses of recently reported trials in all of these diseases have discovered preferential insertion in the 5’ ends of genes, including potentially dangerous genes such as proto-oncogenes, and signal transduction and proliferation genes. Preclinical work in rodent and canine models has tested novel vectors, including lentiviruses and foamy viruses. Summary Gene therapy for the most common forms of SCID can lead to immune reconstitution in most patients, although a minority of patients has derived minimal clinical benefit and some have suffered severe adverse events, including death. Ongoing pre-clinical work attempts to address the latter shortcomings. In the meantime, in the presence of a careful risk-benefit assessment, gene therapy remains an appropriate subject of clinical investigation.

Sokolic, Robert; Kesserwan, Chimene; Candotti, Fabio

2009-01-01

219

The challenge of liposomes in gene therapy  

Microsoft Academic Search

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

Francis Martin; Teni Boulikas

1998-01-01

220

Gene therapy for the treatment of cystic fibrosis.  

PubMed

Gene therapy is being developed as a novel treatment for cystic fibrosis (CF), a condition that has hitherto been widely-researched yet for which no treatment exists that halts the progression of lung disease. Gene therapy involves the transfer of correct copies of cystic fibrosis transmembrane conductance regulator (CFTR) DNA to the epithelial cells in the airways. The cloning of the CFTR gene in 1989 led to proof-of-principle studies of CFTR gene transfer in vitro and in animal models. The earliest clinical trials in CF patients were conducted in 1993 and used viral and non-viral gene transfer agents in both the nasal and bronchial airway epithelium. To date, studies have focused largely on molecular or bioelectric (chloride secretion) outcome measures, many demonstrating evidence of CFTR expression, but few have attempted to achieve clinical efficacy. As CF is a lifelong disease, turnover of the airway epithelium necessitates repeat administration. To date, this has been difficult to achieve with viral gene transfer agents due to host recognition leading to loss of expression. The UK Cystic Fibrosis Gene Therapy Consortium (Imperial College London, University of Edinburgh and University of Oxford) is currently working on a large and ambitious program to establish the clinical benefits of CF gene therapy. Wave 1, which has reached the clinic, uses a non-viral vector. A single-dose safety trial is nearing completion and a multi-dose clinical trial is shortly due to start; this will be powered for clinically-relevant changes. Wave 2, more futuristically, will look at the potential of lentiviruses, which have long-lasting expression. This review will summarize the current status of translational research in CF gene therapy. PMID:23776378

Burney, Tabinda J; Davies, Jane C

2012-01-01

221

Nuclear imaging in cardiac cell therapy  

Microsoft Academic Search

Cardiac stem cell therapy is an innovative and promising therapeutic approach for heart failure. However, despite an increasing\\u000a body of existing experimental and human data, it still presents a substantial challenge for basic scientists and clinical\\u000a researchers. Several issues concerning biologic mechanisms of therapy remain to be answered, and unequivocal proof of clinical\\u000a efficacy is needed. The variety of different

Frank M. Bengel

2006-01-01

222

Image-Guided Photodynamic Cancer Therapy  

Microsoft Academic Search

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

Zheng-Rong Lu; Anagha Vaidya

223

Imaging of complications of oncological therapy in the gastrointestinal system  

PubMed Central

Abstract Treatment of cancer involves a multidisciplinary approach consisting of surgery, chemotherapy, molecular targeted therapy and radiation therapy. These therapies work on the tumor cells to result in cell stasis or cell death. The same mechanism can result in toxicity to the normal gastrointestinal tract. Radiation therapy can cause acute and chronic injury. The chronic injury results from involvement of the vascular supply of the gastrointestinal tract and by causing fibrosis. The purpose of this article is to describe the imaging of complications resulting from oncologic treatment in the gastrointestinal system.

Viswanathan, Chitra; Bhosale, Priya; Moorthy Ganeshan, Dhakshin; Truong, Myelene T.; Silverman, Paul

2012-01-01

224

In Vivo Optical Imaging of Molecular Responses to Photodynamic Therapy  

Microsoft Academic Search

Photodynamic therapy activates a variety of molecular responses, which are considered important for long-term tumor control. Using recently developed antibody labeling technique that enables high resolution, high contrast imaging of cell populations in vivo, we demonstrate the ability to visualize these responses using confocal fluorescence imaging in superficial tumors.

Soumya Mitra; Thomas H. Foster

225

Stem cells' guided gene therapy of cancer: New frontier in personalized and targeted therapy  

PubMed Central

Introduction Diagnosis and therapy of cancer remain to be the greatest challenges for all physicians working in clinical oncology and molecular medicine. The statistics speak for themselves with the grim reports of 1,638,910 men and women diagnosed with cancer and nearly 577,190 patients passed away due to cancer in the USA in 2012. For practicing clinicians, who treat patients suffering from advanced cancers with contemporary systemic therapies, the main challenge is to attain therapeutic efficacy, while minimizing side effects. Unfortunately, all contemporary systemic therapies cause side effects. In treated patients, these side effects may range from nausea to damaged tissues. In cancer survivors, the iatrogenic outcomes of systemic therapies may include genomic mutations and their consequences. Therefore, there is an urgent need for personalized and targeted therapies. Recently, we reviewed the current status of suicide gene therapy for cancer. Herein, we discuss the novel strategy: genetically engineered stem cells’ guided gene therapy. Review of therapeutic strategies in preclinical and clinical trials Stem cells have the unique potential for self renewal and differentiation. This potential is the primary reason for introducing them into medicine to regenerate injured or degenerated organs, as well as to rejuvenate aging tissues. Recent advances in genetic engineering and stem cell research have created the foundations for genetic engineering of stem cells as the vectors for delivery of therapeutic transgenes. Specifically in oncology, the stem cells are genetically engineered to deliver the cell suicide inducing genes selectively to the cancer cells only. Expression of the transgenes kills the cancer cells, while leaving healthy cells unaffected. Herein, we present various strategies to bioengineer suicide inducing genes and stem cell vectors. Moreover, we review results of the main preclinical studies and clinical trials. However, the main risk for therapeutic use of stem cells is their cancerous transformation. Therefore, we discuss various strategies to safeguard stem cell guided gene therapy against iatrogenic cancerogenesis. Perspectives Defining cancer biomarkers to facilitate early diagnosis, elucidating cancer genomics and proteomics with modern tools of next generation sequencing, and analyzing patients’ gene expression profiles provide essential data to elucidate molecular dynamics of cancer and to consider them for crafting pharmacogenomics-based personalized therapies. Streamlining of these data into genetic engineering of stem cells facilitates their use as the vectors delivering therapeutic genes into specific cancer cells. In this realm, stem cells guided gene therapy becomes a promising new frontier in personalized and targeted therapy of cancer.

Mavroudi, Maria; Zarogoulidis, Paul; Porpodis, Konstantinos; Kioumis, Ioannis; Lampaki, Sofia; Yarmus, Lonny; Malecki, Raf; Zarogoulidis, Konstantinos; Malecki, Marek

2014-01-01

226

Gene therapy for Parkinson's disease: progress and challenges.  

PubMed

Therapy for Parkinson's disease (PD), a common neurological disorder characterized by pathological degeneration of the nigrostriatal dopaminergic system, remains unsatisfactory. Gene therapy is considered one of the most promising approaches to developing a novel effective treatment for PD. Among the numerous candidate genes that have been tested as therapeutic agents, those encoding tyrosine hydroxylase, guanosine triphosphate cyclohydrolase I and aromatic L-amino acid decarboxylase all boost dopamine production, while glial cell line-derived neurotrophic factor promotes the survival of dopaminergic neurons and is generally believed to possess the greatest potential for successful restoration of the dopaminergic system. The genes encoding vesicular monoamine transporter-2 and glutamic acid decarboxylase have also produced therapeutic effects in animal models of PD. Both viral and non-viral vectors, each with its particular advantages and disadvantages, have been used to deliver these genes into the brain. Whether or not regulatable expression systems are essential to successful gene therapy for PD remains a critical issue in the clinical application of this emerging treatment. Here we review the current status of gene therapy for PD, including the application of control systems for transgene expression in the brain. PMID:15638712

Chen, Qin; He, Yi; Yang, Keyi

2005-02-01

227

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

PubMed Central

Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs, and can potentially control the virus while alleviating major limitations of current approaches. Yet, HIV-1's ability to rapidly acquire mutations and escape therapy presents a critical challenge to any novel treatment paradigm. Viral escape is thus a key consideration in the design of any gene-based technique. We develop a computational model of HIV's evolutionary dynamics in vivo in the presence of a genetic therapy to explore the impact of therapy parameters and strategies on the development of resistance. Our model is generic and captures the properties of a broad class of gene-based agents that inhibit early stages of the viral life cycle. We highlight the differences in viral resistance dynamics between gene and standard antiretroviral therapies, and identify key factors that impact long-term viral suppression. In particular, we underscore the importance of mutationally-induced viral fitness losses in cells that are not genetically modified, as these can severely constrain the replication of resistant virus. We also propose and investigate a novel treatment strategy that leverages upon gene therapy's unique capacity to deliver different genes to distinct cell populations, and we find that such a strategy can dramatically improve efficacy when used judiciously within a certain parametric regime. Finally, we revisit a previously-suggested idea of improving clinical outcomes by boosting the proliferation of the genetically-modified cells, but we find that such an approach has mixed effects on resistance dynamics. Our results provide insights into the short- and long-term effects of gene therapy and the role of its key properties in the evolution of resistance, which can serve as guidelines for the choice and optimization of effective therapeutic agents.

Aviran, Sharon; Shah, Priya S.; Schaffer, David V.; Arkin, Adam P.

2010-01-01

228

Gene Therapy and Children (For Parents)  

MedlinePLUS

... have completed the initial work of sequencing and mapping virtually all of the 25,000 genes in ... symptoms appear. Scientists hope that the human genome mapping will help lead to cures for many diseases ...

229

Viroreplicative Gene Therapy Targeted to Prostate Cancer.  

National Technical Information Service (NTIS)

Replication-competent retrovirus (RCR) vectors can propagate specifically within actively dividing cancer cells and achieve highly efficient and tumor-selective gene delivery. To improve their tumor-specificity and safety profile, we have developed RCR ve...

N. Kasahara

2010-01-01

230

State-of-the-art 2003 on PKU gene therapy  

PubMed Central

Phenylketonuria (or PKU) is a well-known and widespread genetic disease for which many countries perform newborn screening, and life-long dietary restriction is still the ultimate and effective therapy. However, the diet is complicated, unpalatable, and expensive. The long-term effects of diet discontinuation in adults, except for the serious adverse effects of maternal hyperphenylalaninemia upon the developing fetus, have not been systematically studied, but congnitive decline and neurologic abnormalities have been anecdotally reported. Thus, alternative approaches for PKU therapy, including gene therapy, must be further explored. Here we summarize past present nonviral and viral gene transfer approaches, both in vitro studies and preclinical animal trials, to delivering the PAH gene into liver or other organs as potential alternatives to life-long phenylalanine-restricted dietary theraphy.

Ding, Zhaobing; Harding, Cary O.; Thony, Beat

2009-01-01

231

Adeno-associated virus for cystic fibrosis gene therapy.  

PubMed

Gene therapy is an alternative treatment for genetic lung disease, especially monogenic disorders such as cystic fibrosis. Cystic fibrosis is a severe autosomal recessive disease affecting one in 2500 live births in the white population, caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR). The disease is classically characterized by pancreatic enzyme insufficiency, an increased concentration of chloride in sweat, and varying severity of chronic obstructive lung disease. Currently, the greatest challenge for gene therapy is finding an ideal vector to deliver the transgene (CFTR) to the affected organ (lung). Adeno-associated virus is the most promising viral vector system for the treatment of respiratory disease because it has natural tropism for airway epithelial cells and does not cause any human disease. This review focuses on the basic properties of adeno-associated virus and its use as a vector for cystic fibrosis gene therapy. PMID:21952739

Martini, S V; Rocco, P R M; Morales, M M

2011-11-01

232

GENE THERAPY FOR THE TREATMENT OF PITUITARY TUMORS  

PubMed Central

Pituitary adenomas constitute the most frequent neuroendocrine pathology in humans. Current therapies include surgery, radiotherapy and pharmacological approaches. Although useful, none of them offers a permanent cure. Current research efforts to implement gene therapy in pituitary tumors include the treatment of experimental adenomas with adenoviral vector-mediated transfer of the suicide gene for 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. Also, regulatable adenoviral vector systems are being assessed in gene therapy approaches for experimental pituitary tumors. Although the efficiency and safety of current viral vectors must be optimized before clinical use, they remain as highly promising therapeutic tools.

Rodriguez, Silvia S.; Castro, Maria G.; Brown, Oscar A.; Goya, Rodolfo G.; Console, Gloria M.

2010-01-01

233

Phase contrast portal imaging for image-guided microbeam radiation therapy  

NASA Astrophysics Data System (ADS)

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

Umetani, Keiji; Kondoh, Takeshi

2014-03-01

234

Image-guided thermal therapy of uterine fibroids  

PubMed Central

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.

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

2009-01-01

235

Optical Bioluminescence and Positron Emission Tomography Imaging of a Novel Fusion Reporter Gene in Tumor Xenografts of Living Mice  

Microsoft Academic Search

Noninvasive imaging of reporter gene expression using various imaging modalities is playing an increasingly important role in defining molecular events in the field of cancer biology, cell biology, and gene therapy. In this study, a novel reporter vector was constructed encoding a fusion protein comprised of a mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39tk )( tk), a positron

Pritha Ray; Anna M. Wu; Sanjiv S. Gambhir

2003-01-01

236

Choice of surrogate and physiological markers for prenatal gene therapy.  

PubMed

Surrogate genetically encoded markers have been utilized in order to analyze gene transfer efficacy, location, and persistence. These marker genes have greatly accelerated the development of gene transfer vectors for the ultimate application of gene therapy using therapeutic genes. They have also been used in many other applications, such as gene marking in order to study developmental cell lineages, to track cell migration, and to study tumor growth and metastasis. This chapter aims to describe the analysis of several commonly used marker genes: green fluorescent protein (GFP), ?-galactosidase, firefly luciferase, human factor IX, and alkaline phosphatase. The merits and disadvantages of each are briefly discussed. In addition a few short examples are provided for continual and endpoint analysis in different disease models including hemophilia, cystic fibrosis, ornithine transcarbamylase deficiency and Gaucher disease. PMID:22648777

Delhove, Juliette M K M; Rahim, Ahad A; McKay, Tristan R; Waddington, Simon N; Buckley, Suzanne M K

2012-01-01

237

Viral gene therapy strategies: from basic science to clinical application.  

PubMed

A major impediment to the successful application of gene therapy for the treatment of a range of diseases is not a paucity of therapeutic genes, but the lack of an efficient non-toxic gene delivery system. Having evolved to deliver their genes to target cells, viruses are currently the most effective means of gene delivery and can be manipulated to express therapeutic genes or to replicate specifically in certain cells. Gene therapy is being developed for a range of diseases including inherited monogenic disorders and cardiovascular disease, but it is in the treatment of cancer that this approach has been most evident, resulting in the recent licensing of a gene therapy for the routine treatment of head and neck cancer in China. A variety of virus vectors have been employed to deliver genes to cells to provide either transient (eg adenovirus, vaccinia virus) or permanent (eg retrovirus, adeno-associated virus) transgene expression and each approach has its own advantages and disadvantages. Paramount is the safety of these virus vectors and a greater understanding of the virus-host interaction is key to optimizing the use of these vectors for routine clinical use. Recent developments in the modification of the virus coat allow more targeted approaches and herald the advent of systemic delivery of therapeutic viruses. In the context of cancer, the ability of attenuated viruses to replicate specifically in tumour cells has already yielded some impressive results in clinical trials and bodes well for the future of this approach, particularly when combined with more traditional anti-cancer therapies. PMID:16362990

Young, Lawrence S; Searle, Peter F; Onion, David; Mautner, Vivien

2006-01-01

238

Gene- and Viral-Based Therapies for Brain Tumors  

PubMed Central

Summary Advances in understanding and controlling genes and their expression have set the stage to alter genetic material to fight or prevent disease with brain tumors being among one of the first human malignancies to be targeted by gene therapy. All proteins are coded for by DNA and most neoplastic diseases ultimately result from the expression or lack thereof with one or more proteins (e.g., coded by oncogenes or tumor suppressor genes, respectively). In theory, therefore, diseases could be treated by expression of the appropriate protein in the affected cells. Gene therapy is an experimental treatment that involves introducing genetic material (DNA or RNA) into cells, and it has made important advances in the past decade. Within this short time span, it has moved from the conceptual laboratory research stage to clinical translational trials for brain tumors. The most efficient approaches for gene delivery are based on viral vectors, which have been proven relatively safe in the CNS, despite occasional cases of morbidity and death in non-neurosurgical trials. However, the human response to various viral vectors can not be predicted in a reliable manner from animal experimentation, nor can size, consistency, and extent of experimental brain tumors in mouse models reflect the large, necrotic, infiltrative nature of malignant gliomas. Furthermore, the problem of delivering genetic vectors into solid brain tumors and the efficiency in situ gene transfer remains one of the most significant hurdles in gene therapy.

Asadi-Moghaddam, Kaveh; Chiocca, E. Antonio

2011-01-01

239

Combined suicide and cytokine gene therapy for peritoneal carcinomatosis  

PubMed Central

BACKGROUND—Gene therapy is a novel approach for the treatment of cancers, and tumours disseminated in the peritoneal cavity are suitable for in situ delivery of a therapeutic gene.?AIMS—The efficacy of a therapy combining a suicide gene (herpes simplex virus type I thymidine kinase (HSV-TK)) and cytokine genes was investigated in a model of peritoneal carcinomatosis induced by colon carcinoma cells in syngeneic rats.?MATERIAL AND METHODS—Pre-established macroscopic tumours in BDIX rats were treated by intraperitoneal injections of retrovirus producing cells (FLYA13 TK, FLYA13 granulocyte macrophage-colony stimulating factor (GM-CSF), FLYA13 interleukin 12 (IL-12)) and ganciclovir (GCV).?RESULTS—TK/GCV treated animals showed a slight increase in survival time (72 days) compared with the control group (63 days) while the association of cytokine and TK/GCV gene therapy resulted in significantly improved survival, with a large proportion of animals remaining tumour free on day 480 (60% and 40% for TK/GCV/GM-CSF and TK/GCV/IL-12 treated animals, respectively). Histological analysis of treated animals showed that the remaining tumour nodes were infiltrated by mononuclear cells but no major differences were observed between the various treatments. Immunohistochemical analysis revealed that lymphoid CD4+ and CD8+ T cells as well as macrophages accumulated outside untreated tumour nodes while CD8+ and CD25+ activated T cells and macrophages heavily infiltrated the tumours after the different treatments.?CONCLUSIONS—Our data indicate that combined suicide and cytokine gene therapy is a powerful approach for the treatment of macroscopic peritoneal carcinomatosis.???Keywords: gene therapy; thymidine kinase; interleukin 12; granulocyte macrophage-colony stimulating factor; peritoneal carcinomatosis

Lechanteur, C; Delvenne, P; Princen, F; Lopez, M; Fillet, G; Gielen, J; Merville, M; Bours, V

2000-01-01

240

Current status of gene therapy for brain tumors  

PubMed Central

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.

MURPHY, ANDREA M.; RABKIN, SAMUEL D.

2013-01-01

241

Gene therapy for neurodegenerative diseases based on lentiviral vectors.  

PubMed

Gene therapy approaches to treat inherited and acquired disorders offer many unique advantages over conventional therapeutic approaches. For neurodegenerative diseases, gene therapy is particularly attractive due to the restricted bioavailability of conventional therapeutic substances to the affected structures of the brain and progressive nature of these diseases. With the development of lentiviral vector systems, many issues have been addressed and new delivery routes to the nervous system have been identified. Lentiviral vectors can efficiently deliver genes to postmitotic neuronal cell types offering long-term expression, can be generated in high titers, and do not give immunological complications. Various animal studies have demonstrated the effectiveness of these vectors to deliver therapeutic genes into the nervous system, as well as to model human diseases. This chapter will describe the basic features of lentiviral vectors, the progress, and their applications as a therapeutic strategy to treat diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, Parkinson's disease, and Huntington's disease. PMID:19660657

Nanou, Aikaterini; Azzouz, Mimoun

2009-01-01

242

Non-viral vectors for gene-based therapy.  

PubMed

Gene-based therapy is the intentional modulation of gene expression in specific cells to treat pathological conditions. This modulation is accomplished by introducing exogenous nucleic acids such as DNA, mRNA, small interfering RNA (siRNA), microRNA (miRNA) or antisense oligonucleotides. Given the large size and the negative charge of these macromolecules, their delivery is typically mediated by carriers or vectors. In this Review, we introduce the biological barriers to gene delivery in vivo and discuss recent advances in material sciences, nanotechnology and nucleic acid chemistry that have yielded promising non-viral delivery systems, some of which are currently undergoing testing in clinical trials. The diversity of these systems highlights the recent progress of gene-based therapy using non-viral approaches. PMID:25022906

Yin, Hao; Kanasty, Rosemary L; Eltoukhy, Ahmed A; Vegas, Arturo J; Dorkin, J Robert; Anderson, Daniel G

2014-08-01

243

Gene targeting: Roadmap to future therapies  

Microsoft Academic Search

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

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

2004-01-01

244

Gene-directed enzyme prodrug therapy: a current assessment.  

PubMed

Gene-directed enzyme prodrug therapy involves tumor-specific delivery of a gene encoding a drug-metabolizing enzyme allowing metabolism of a non-toxic prodrug to a toxic species directly within tumor cells. This review covers the wide range of enzyme-prodrug combinations currently under preclinical and clinical investigation. Issues of tumor specificity and enhanced cytotoxicity through bystander effects will be discussed. PMID:15468601

McKeown, Stephanie R; Ward, Claire; Robson, Tracy

2004-08-01

245

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

PubMed

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

Qasim, Waseem; Gennery, Andrew R

2014-06-01

246

Neural Stem Cell-based Gene Therapy for Brain Tumors  

Microsoft Academic Search

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

Seung U. Kim

2011-01-01

247

New strategy for monitoring targeted therapy: molecular imaging  

PubMed Central

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.

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

2013-01-01

248

A preclinical approach for gene therapy of ?-thalassemia  

PubMed Central

Lentiviral-mediated ?-globin gene transfer successfully treated ?-thalassemic mice. Based on this result, clinical trials were initiated. To date, however, no study has investigated the efficacy of gene therapy in relation to the nature of the different ?-globin mutations found in patients. Most mutations can be classified as ?0 or ?+, based on the amount of ?-globin protein produced. Therefore, we propose that a screening in vitro is necessary to verify the efficacy of gene transfer prior to treatment of individual patients. We used a two-phase liquid culture system to expand and differentiate erythroid progenitor cells (ErPCs) transduced with lentiviral vectors. We propose the use of this system to test the efficiency of lentiviral vectors carrying the human ?-globin gene, to correct the phenotype of ErPCs from patients preparing for gene therapy. This new approach might have profound implications for designing gene therapy and for understanding the genotype/phenotype variability observed in Cooley’s anemia patients.

Breda, Laura; Kleinert, Dorothy A.; Casu, Carla; Casula, Laura; Cartegni, Luca; Fibach, Eitan; Mancini, Irene; Giardina, Patricia J.; Gambari, Roberto; Rivella, Stefano

2011-01-01

249

Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapy.  

PubMed

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

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; Wissinger, Bernd; Jacobson, Samuel G

2013-12-01

250

Design of clinical trials of gene therapy in Parkinson disease.  

PubMed

No current therapy for Parkinson disease has been shown to slow or reverse the progressive course of the disease. As a departure from traditional treatments, gene therapy approaches provide a new hope for realizing this long-sought goal; but before they can be widely employed for use in patients, they must first be submitted to the rigorous safety and efficacy standards of the clinical trial. Some of the challenges of gene therapy clinical trial design are similar to those in studies of conventional pharmacological agents and include addressing the heterogeneity of the disease, the need for clinical and surrogate endpoints, and the issue of distinguishing "symptomatic" from "neuroprotective" effects. Gene therapy trials also raise the issues of the risks of viral therapy, issues of dose-response, the need for sham surgery, and the long duration of risks and benefits. We conclude that the most feasible designs are for those treatments that are expected to produce a rapid improvement in directly observable symptoms. Trials of agents which are expected to produce only a slowing of progression and not a reversal of the disease course are likely to take much longer and will require the development of methods to assess quality of life and other non-motor aspects of the disease. PMID:17920590

Lewis, Travis B; Standaert, David G

2008-01-01

251

Integration of genomics, proteomics, and imaging for cardiac stem cell therapy  

Microsoft Academic Search

Cardiac stem cell therapy is beginning to mature as a valid treatment for heart disease. As more clinical trials utilizing\\u000a stem cells emerge, it is imperative to establish the mechanisms by which stem cells confer benefit in cardiac diseases. In\\u000a this paper, we review three methods—molecular cellular imaging, gene expression profiling, and proteomic analysis—that can\\u000a be integrated to provide further

Hyung J. Chun; Kitch O. Wilson; Mei Huang; Joseph C. Wu

2007-01-01

252

Gene therapy of experimental brain tumors using neural progenitor cells  

Microsoft Academic Search

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

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

2000-01-01

253

The Current Status of Gene Therapy in Autologous Transplantation  

Microsoft Academic Search

Autologous hematopoietic cells have been used as targets of gene transfer, with applications in inherited disorders, cell therapy, and acquired immunodeficiency. The types of cells include hematopoietic progenitor cells, lymphocytes, and mesenchymal stem cells. The inherited disorders thus far approached in clinical trials include severe combined immunodeficiency, common variable ?-chain immunodeficiency, chronic granulomatous disease, and Gaucher disease. Preclinical studies are

Pamela S. Becker

2005-01-01

254

Enhancement of radiotherapy by hyperthermia-regulated gene therapy  

Microsoft Academic Search

Purpose: Interleukin 12 (IL-12) has shown strong antitumoral effects in numerous pre-clinical studies and appears to act synergistically with radiation in murine tumors. The major impediment to its clinical use has been its systemic toxicity. While using intratumorally injected viral gene therapy vectors encoding IL-12 reduces systemic side effects substantially, elevated systemic transgene levels are still observed because adenovirus can

Frank Lohr; Kang Hu; Qian Huang; Li Zhang; Thaddeus V Samulski; Mark W Dewhirst; Chuan-Yuan Li

2000-01-01

255

Future of Cell and Gene Therapies for Parkinson's Disease  

PubMed Central

The experimental field of restorative neurology continues to advance with implantation of cells or transfer of genes to treat patients with neurological disease. Both strategies have generated a consensus that demonstrates their capacity for structural and molecular brain modification in the adult brain. However, both approaches have yet to successfully address the complexities to make such novel therapeutic modalities work in the clinic. Prior experimental cell transplantation to patients with PD utilized dissected pieces of fetal midbrain tissue, containing mixtures of cells and neuronal types, as donor cells. Stem cell and progenitor cell biology provide new opportunities for selection and development of large batches of specific therapeutic cells. This may allow for cell composition analysis and dosing to optimize the benefit to an individual patient. The biotechnology used for cell and gene therapy for treatment of neurological disease may eventually be as advanced as today’s pharmaceutical drug-related design processes. Current gene therapy phase 1 safety trials for PD include the delivery of a growth factor (neurturin via the glial cell line–derived neurotrophic factor receptor) and a transmitter enzyme (glutamic acid decarboxylase and aromatic acid decarboxylase). Many new insights from cell biological and molecular studies provide opportunities to selectively express or suppress factors relevant to neuroprotection and improved function of neurons involved in PD. Future gene and cell therapies are likely to coexist with classic pharmacological therapies because their use can be tailored to individual patients’ underlying disease process and need for neuroprotective or restorative interventions.

Isacson, Ole; Kordower, Jeffrey H.

2014-01-01

256

Cell and gene therapy using mesenchymal stem cells (MSCs)  

Microsoft Academic Search

Mesenchymal stem cells (MSCs) are considered to be a promising platform for cell and gene therapy for a variety of diseases. First, in the field of hematopoietic stem cell transplantation, there are two applications of MSCs: 1) the improvement of stem cell engrafting and the acceleration of hematopoietic reconstitution based on the hematopoiesis-supporting ability; and 2) the treatment of severe

Keiya Ozawa; Kazuya Sato; Iekuni Oh; Katsutoshi Ozaki; Ryosuke Uchibori; Yoko Obara; Yuji Kikuchi; Takayuki Ito; Takashi Okada; Masashi Urabe; Hiroaki Mizukami; Akihiro Kume

2008-01-01

257

Targeting a Novel Vector for Breast Cancer Gene Therapy.  

National Technical Information Service (NTIS)

We are testing the hypothesis that a model parasite gene therapy vector can be genetically altered to safely, specifically and effectively target breast cancer cells in vitro and in vivo. The primary purpose and scope of this IDEA award project is to expe...

D. J. Bzik

2002-01-01

258

RNA interference based gene therapy for neurological disease  

Microsoft Academic Search

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

Aarti Jagannath; Matthew Wood

2007-01-01

259

T Cell Gene Therapy to Eradicate Disseminated Breast Cancers.  

National Technical Information Service (NTIS)

There is no cure for metastatic breast cancer, which kills 40,000 American women (and 500 men) each year: all presently available treatments are palliative. Gene therapy techniques are used to introduce chimeric immunoglobulin-T cell receptors (IgTCR) int...

R. P. Junghans

2012-01-01

260

Immune parameters affecting adenoviral vector gene therapy in the brain  

Microsoft Academic Search

Gene therapy utilizing replication deficient adenoviral vectors represents a potentially promising approach to the treatment of brain tumors. Limited duration of systemic transgene expression and inefficient transduction following repeat systemic vector administration secondary to an effective anti-vector immune response limits the potential application of first generation adenoviral vectors. Whether host immune responses will significantly limit the use of these vectors

Michael J Parr; Patrick Y Wen; Meike Schaub; Samia J Khoury; Mohamed H Sayegh; Howard A Fine

1998-01-01

261

Gene therapy and transplantation in CNS repair: The visual system  

Microsoft Academic Search

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

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

2006-01-01

262

Gene therapy rescues cone function in congenital achromatopsia  

PubMed Central

The successful restoration of visual function with recombinant adeno-associated virus (rAAV)-mediated gene replacement therapy in animals and humans with an inherited disease of the retinal pigment epithelium has ushered in a new era of retinal therapeutics. For many retinal disorders, however, targeting of therapeutic vectors to mutant rods and/or cones will be required. In this study, the primary cone photoreceptor disorder achromatopsia served as the ideal translational model to develop gene therapy directed to cone photoreceptors. We demonstrate that rAAV-mediated gene replacement therapy with different forms of the human red cone opsin promoter led to the restoration of cone function and day vision in two canine models of CNGB3 achromatopsia, a neuronal channelopathy that is the most common form of achromatopsia in man. The robustness and stability of the observed treatment effect was mutation independent, but promoter and age dependent. Subretinal administration of rAAV5–hCNGB3 with a long version of the red cone opsin promoter in younger animals led to a stable therapeutic effect for at least 33 months. Our results hold promise for future clinical trials of cone-directed gene therapy in achromatopsia and other cone-specific disorders.

Komaromy, Andras M.; Alexander, John J.; Rowlan, Jessica S.; Garcia, Monique M.; Chiodo, Vince A.; Kaya, Asli; Tanaka, Jacqueline C.; Acland, Gregory M.; Hauswirth, William W.; Aguirre, Gustavo D.

2010-01-01

263

Gene Therapy for Muscular Dystrophy: Lessons Learned and Path Forward  

PubMed Central

Our Translational Gene Therapy Center has used small molecules for exon skipping and mutation suppression and gene transfer to replace or provide surrogate genes as tools for molecular-based approaches for the treatment of muscular dystrophies. Exon skipping is targeted at the pre-mRNA level allowing one or more exons to be omitted to restore the reading frame. In Duchenne Muscular Dystrophy (DMD), clinical trials have been performed with two different oligomers, a 2?O-methyl-ribo-oligonucleoside-phosphorothioate (2?OMe) and a phosphorodiamidate morpholino (PMO). Both have demonstrated early evidence of efficacy. A second molecular approach involves suppression of stop codons to promote readthrough of the DMD gene. We have been able to establish proof of principle for mutation suppression using the aminoglycoside, gentamicin. A safer, orally administered, alternative agent referred to as Ataluren (PTC124) has been used in clinical trials and is currently under consideration for approval by the FDA. Using a gene therapy approach, we have completed two trials and have initiated a third. For DMD, we used a mini-dystrophin transferred in adeno-associated virus (AAV). In this trial an immune response was seen directed against transgene product, a quite unexpected outcome that will help guide further studies. For limb girdle muscular dystrophy 2D (alpha-sarcoglycan deficiency), the transgene was again transferred using AAV but in this study, a muscle specific creatine kinase promoter controlled gene expression that persisted for six months. A third gene therapy trial has been initiated with transfer of the follistatin gene in AAV directly to the quadriceps muscle. Two diseases with selective quadriceps muscle weakness are undergoing gene transfer including sporadic inclusion body myositis (sIBM) and Becker muscular dystrophy (BMD). Increasing the size and strength of the muscle is the goal of this study. Most importantly, no adverse events have been encountered in any of these clinical trials.

Mendell, Jerry R.; Rodino-Klapac, Louise; Sahenk, Zarife; Malik, Vinod; Kaspar, Brian K.; Walker, Christopher M.; Clark, K. Reed

2012-01-01

264

Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy  

PubMed Central

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.

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

2012-01-01

265

Imaging Stem Cell Therapy for the Treatment of Peripheral Arterial Disease  

PubMed Central

Arteriosclerotic cardiovascular diseases are among the leading causes of morbidity and mortality worldwide. Therapeutic angiogenesis aims to treat ischemic myocardial and peripheral tissues by delivery of recombinant proteins, genes, or cells to promote neoangiogenesis. Concerns regarding the safety, side effects, and efficacy of protein and gene transfer studies have led to the development of cell-based therapies as alternative approaches to induce vascular regeneration and to improve function of damaged tissue. Cell-based therapies may be improved by the application of imaging technologies that allow investigators to track the location, engraftment, and survival of the administered cell population. The past decade of investigations has produced promising clinical data regarding cell therapy, but design of trials and evaluation of treatments stand to be improved by emerging insight from imaging studies. Here, we provide an overview of pre-clinical and clinical experience using cell-based therapies to promote vascular regeneration in the treatment of peripheral arterial disease. We also review four major imaging modalities and underscore the importance of in vivo analysis of cell fate for a full understanding of functional outcomes.

Ransohoff, Julia D.; Wu, Joseph C.

2013-01-01

266

RNA based gene therapy for dominantly inherited diseases.  

PubMed

There are numerous examples in the literature of gene therapy applications for recessive disorders. There are precious few instances, however, of studies conducted to treat dominantly inherited pathologies. The reasons are simple: there are fewer cases of dominantly inherited diseases on one hand, but mostly it is far easier to correct recessive mutations than dominant ones. Typically recessive mutations cause a loss of (or reduced) gene function which can be compensated for by introduction of a replacement allele into the cell. In contrast, dominant negative mutations not only display impaired function, but also exhibit a novel one that is pathologic to the cell. Treating these conditions by gene therapy implies silencing the dominant allele without altering the expression of the wild-type gene. We describe here different strategies aimed at silencing dominant mutations through mRNA destruction and provide examples of their application to known autosomal dominant diseases. An overview of the most common molecular tools (antisense DNA and RNA, ribozymes and RNA interference) suitable to utilize these strategies is also presented and we discuss the relevant aspects involved in the choice of a particular approach in a gene therapy experiment. PMID:16475951

Pelletier, Richard; Caron, Solenne O P; Puymirat, Jack

2006-02-01

267

Current progress on gene therapy for primary immunodeficiencies.  

PubMed

Primary immunodeficiencies have played a major role in the development of gene therapy for monogenic diseases of the bone marrow. The last decade has seen convincing evidence of long-term disease correction as a result of ex vivo viral vector-mediated gene transfer into autologous haematopoietic stem cells. The success of these early studies has been balanced by the development of vector-related insertional mutagenic events. More recently the use of alternative vector designs with self-inactivating designs, which have an improved safety profile has led to the initiation of a wave of new studies that are showing early signs of efficacy. The ongoing development of safer vector platforms and gene-correction technologies together with improvements in cell-transduction techniques and optimised conditioning regimes is likely to make gene therapy amenable for a greater number of PIDs. If long-term efficacy and safety are shown, gene therapy will become a standard treatment option for specific forms of PID. PMID:23719067

Zhang, L; Thrasher, A J; Gaspar, H B

2013-10-01

268

Zinc Finger Nucleases: Tailor-made for Gene Therapy  

PubMed Central

Genome editing with the use of zinc finger nucleases has been successfully applied to variety of a eukaryotic cells. Furthermore, the proof of concept for this approach has been extended to diverse animal models from Drosophila to mice. Engineered zinc finger nucleases are able to target specifically and manipulate disease-causing genes through site-specific double strand DNA breaks followed by non-homologous end joining or homologous recombination mechanisms. Consequently, this technology has considerable flexibility that can result in either a gain or loss of function of the targeted gene. In addition to this flexibility, gene therapy by zinc finger nucleases may enable persistent long term gene modification without continuous transfection- a potential advantage over RNA interference or direct gene inhibitors. With systemic viral delivery systems, this gene-editing approach corrected the mutant factor IX in models of mouse hemophilia. Moreover, phase I clinical trials have been initiated with zinc finger nucleases in patients with glioblastoma and HIV. Thus, this emerging field has significant promise as a therapeutic strategy for human genetic diseases, infectious diseases and oncology. In this article, we will review recent advances and potential risks in zinc finger nuclease gene therapy.

Chou, S.-T.; Leng, Qixin; Mixson, A. J.

2012-01-01

269

Gene Therapy in Parkinson's Disease: Rationale and Current Status  

PubMed Central

Neurodegenerative diseases pose a unique treatment challenge to clinicians due to the slow progression of disease, the profound neuron loss prior to clinical symptoms and the paucity of early diagnostic biomarkers and restorative therapies. Treatment options are further constrained by the post-mitotic nature of CNS neurons and restricted ability of these cells to regenerate. Lastly, because the blood brain barrier impedes peripheral access to the brain there are inherent limitations with respect to treatment especially protein and peptide-based therapeutics. Due to these intrinsic constraints, researchers are continuing to expand a therapeutic platform based on the delivery of genes engineered for efficient CNS expression. Gene therapeutic approaches were first tested almost 20 years ago and continue to evolve as a viable treatment for CNS neurodegenerative disorders. In this review we consider the current advances in human gene therapy for one common neurodegenerative disorder, Parkinson’s disease (PD).

Feng, Li Rebekah; Maguire-Zeiss, Kathleen A.

2010-01-01

270

Lentivirus-mediated gene transfer to the respiratory epithelium: a promising approach to gene therapy of cystic fibrosis  

Microsoft Academic Search

Gene therapy of cystic fibrosis (CF) lung disease needs highly efficient delivery and long-lasting complementation of the CFTR (cystic fibrosis transmembrane conductance regulator) gene into the respiratory epithelium. The development of lentiviral vectors has been a recent advance in the field of gene transfer and therapy. These integrating vectors appear to be promising vehicles for gene delivery into respiratory epithelial

E Copreni; M Penzo; S Carrabino; M Conese

2004-01-01

271

Dual-mode transducers for ultrasound imaging and thermal therapy.  

PubMed

Medical imaging is a vital component of high intensity focused ultrasound (HIFU) therapy, which is gaining clinical acceptance for tissue ablation and cancer therapy. Imaging is necessary to plan and guide the application of therapeutic ultrasound, and to monitor the effects it induces in tissue. Because they can transmit high intensity continuous wave ultrasound for treatment and pulsed ultrasound for imaging, dual-mode transducers aim to improve the guidance and monitoring stages. Their primary advantage is implicit registration between the imaging and treatment axes, and so they can help ensure before treatment that the therapeutic beam is correctly aligned with the planned treatment volume. During treatment, imaging signals can be processed in real-time to assess acoustic properties of the tissue that are related to thermal ablation. Piezocomposite materials are favorable for dual-mode transducers because of their improved bandwidth, which in turn improves imaging performance while maintaining high efficiency for treatment. Here we present our experiences with three dual-mode transducers for interstitial applications. The first was an 11-MHz monoelement designed for use in the bile duct. It had a 25x7.5 mm(2) aperture that was cylindrically focused to 10mm. The applicator motion was step-wise rotational for imaging and therapy over a 360 degrees, or smaller, sector. The second transducer had 5-elements, each measuring 3.0x3.8 mm(2) for a total aperture of 3.0x20 mm(2). It operated at 5.6 MHz, was cylindrically focused to 14 mm, and was integrated with a servo-controlled oscillating probe designed for sector imaging and directive therapy in the liver. The last transducer was a 5-MHz, 64-element linear array designed for beam-formed imaging and therapy. The aperture was 3.0x18 mm(2) with a pitch of 0.280 mm. Characterization results included conversion efficiencies above 50%, pulse-echo bandwidths above 50%, surface intensities up to 30 W/cm(2), and axial imaging resolutions to 0.2 mm. The second transducer was evaluated in vivo using porcine liver, where coagulation necrosis was induced up to a depth of 20 mm in 120 s. B-mode and M-mode images displayed a hypoechoic region that agreed well with lesion depth observed by gross histology. These feasibility studies demonstrate that the dual-mode transducers had imaging performance that was sufficient to aid the guidance and monitoring of treatment, and could sustain high intensities to induce coagulation necrosis in vivo. PMID:19758673

Owen, N R; Chapelon, J Y; Bouchoux, G; Berriet, R; Fleury, G; Lafon, C

2010-02-01

272

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

PubMed

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 degrees 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

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

2009-01-27

273

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

Microsoft Academic Search

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

Wilfried Weber; Martin Fussenegger

2002-01-01

274

Chemotherapeutic agents potentiate adenoviral gene therapy for pancreatic cancer.  

PubMed

Adenovirus-mediated gene therapy combined with chemotherapeutic agents is expected to represent a new approach for treating pancreatic cancer. However, there have been no reports of definitive effects of chemotherapeutic agents on adenovirus-mediated gene therapies. In the present study, we investigated the effects of chemotherapeutic agents on the transduction efficiency of an adenovirus-based gene therapy. Adenovirus (Ad-NK4) expressing NK4, which acts as a hepatocyte growth factor antagonist, was used as a representative gene therapy. Pancreatic cancer cells infected with Ad-NK4 were treated with chemotherapeutic agents (5-fluorouracil [5FU], cisplatin or etoposide), and the NK4 levels in their culture media were measured. To examine the effects of chemotherapeutic agents in vivo, Ad-NK4 was administered to subcutaneous tumors in mice after treatment with the agents, and the tumor NK4 levels were measured. The NK4 levels in culture media from cells treated with 5FU, cisplatin and etoposide were 5.2-fold (P = 0.026), 6-fold (P < 0.001) and 4.3-fold (P < 0.001) higher than those of untreated cells, respectively. The chemotherapeutic agents also increased Ad-NK4 uptake. The NK4 levels in tumors treated with 5FU, cisplatin and etoposide were 5.4-fold (P = 0.006), 11.8-fold (P < 0.001) and 4.9-fold (P = 0.017) higher than those in untreated tumors, respectively. The present findings suggest that chemotherapeutic agents significantly improve the efficiency of adenovirus-mediated gene transfer in pancreatic cancer. Furthermore, they will contribute to decreases in the adenovirus doses required for gene transfer, thereby controlling the side-effects of adenovirus infection in normal tissues. PMID:19302285

Egami, Takuya; Ohuchida, Kenoki; Miyoshi, Kei; Mizumoto, Kazuhiro; Onimaru, Manabu; Toma, Hiroki; Sato, Norihiro; Matsumoto, Kunio; Tanaka, Masao

2009-04-01

275

Gene therapy progress and prospects: Ultrasound for gene transfer  

Microsoft Academic Search

Ultrasound exposure (USE) in the presence of microbubbles (MCB) (e.g. contrast agents used to enhance ultrasound imaging) increases plasmid transfection efficiency in vitro by several orders of magnitude. Formation of short-lived pores in the plasma membrane (‘sonoporation’), up to 100 nm in effective diameter lasting a few seconds, is implicated as the dominant mechanism, associated with acoustic cavitation. Ultrasound enhanced

C M H Newman; T Bettinger; CMH Newman

2007-01-01

276

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

PubMed

Multiple endocrine neoplasia type 1 (MEN1) is characterized by the combined occurrence of pituitary, pancreatic, and parathyroid tumors showing loss of heterozygosity in the putative tumor suppressor gene MEN1. This gene encodes the protein menin, the overexpression of which inhibits cell proliferation in vitro. In this study, we conducted a preclinical evaluation of MEN1 gene therapy in pituitary tumors of Men1(+/-) mice, using a recombinant nonreplicating adenoviral serotype 5 vector that contained the murine Men1 cDNA under control of a cytomegalovirus promoter (Men1.rAd5). Pituitary tumors in 55 Men1(+/-) female mice received a transauricular intratumoral injection of Men1.rAd5 or control treatments, followed by 5-bromo-2-deoxyuridine (BrdUrd) in drinking water for four weeks before magnetic resonance imaging (MRI) and immunohistochemical analysis. Immediate procedure-related and 4-week mortalities were similar in all groups, indicating that the adenoviral gene therapy was not associated with a higher mortality. Menin expression was higher in the Men1.rAd5-treated mice when compared with other groups. Daily proliferation rates assessed by BrdUrd incorporation were reduced significantly in Men1.rAd5-injected tumors relative to control-treated tumors. In contrast, apoptotic rates, immune T-cell response, and tumor volumes remained similar in all groups. Our findings establish that MEN1 gene replacement therapy can generate menin expression in pituitary tumors, and significantly reduce tumor cell proliferation. PMID:22915754

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

2012-10-01

277

Estimating gene signals from noisy microarray images.  

PubMed

In oligonucleotide microarray experiments, noise is a challenging problem, as biologists now are studying their organisms not in isolation but in the context of a natural environment. In low photomultiplier tube (PMT) voltage images, weak gene signals and their interactions with the background fluorescence noise are most problematic. In addition, nonspecific sequences bind to array spots intermittently causing inaccurate measurements. Conventional techniques cannot precisely separate the foreground and the background signals. In this paper, we propose analytically based estimation technique. We assume a priori spot-shape information using a circular outer periphery with an elliptical center hole. We assume Gaussian statistics for modeling both the foreground and background signals. The mean of the foreground signal quantifies the weak gene signal corresponding to the spot, and the variance gives the measure of the undesired binding that causes fluctuation in the measurement. We propose a foreground-signal and shape-estimation algorithm using the Gibbs sampling method. We compare our developed algorithm with the existing Mann-Whitney (MW)- and expectation maximization (EM)/iterated conditional modes (ICM)-based methods. Our method outperforms the existing methods with considerably smaller mean-square error (MSE) for all signal-to-noise ratios (SNRs) in computer-generated images and gives better qualitative results in low-SNR real-data images. Our method is computationally relatively slow because of its inherent sampling operation and hence only applicable to very noisy-spot images. In a realistic example using our method, we show that the gene-signal fluctuations on the estimated foreground are better observed for the input noisy images with relatively higher undesired bindings. PMID:18556262

Sarder, P; Nehorai, A; Davis, P H; Stanley, S L

2008-06-01

278

Imaging and interventional therapy for varicoceles.  

PubMed

Varicocele is a common treatable cause of testicular pain, male infertility, and Leydig cell dysfunction. Scrotal ultrasonography has become the modality of choice in the diagnosis and post-treatment follow-up of varicocele. Visualization of dilated veins and reflux into the pampiniform plexus enables accurate diagnosis. Although the pathophysiology of varicocele in testicular dysfunction remains unclear, numerous studies have established significant improvement in the seminal parameters and pregnancy rates after varicocele repair. Interventional therapy is a minimally invasive effective treatment option for primary and salvage varicocele repair. This review discusses sonographic criteria used in the pre- and post-procedural evaluation of varicocele and various interventional techniques for varicocele treatment. PMID:24522291

Kwak, No; Siegel, David

2014-04-01

279

Gene therapy of the rheumatic diseases: 1998 to 2008  

PubMed Central

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.

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

2009-01-01

280

Intricacies for posttranslational tumor-targeted cytokine gene therapy.  

PubMed

The safest and most effective cytokine therapies require the favorable accumulation of the cytokine in the tumor environment. While direct treatment into the neoplasm is ideal, systemic tumor-targeted therapies will be more feasible. Electroporation-mediated transfection of cytokine plasmid DNA including a tumor-targeting peptide-encoding sequence is one method for obtaining a tumor-targeted cytokine produced by the tumor-bearing patient's tissues. Here, the impact on efficacy of the location of targeting peptide, choice of targeting peptide, tumor histotype, and cytokine utilization are studied in multiple syngeneic murine tumor models. Within the same tumor model, the location of the targeting peptide could either improve or reduce the antitumor effect of interleukin (IL)12 gene treatments, yet in other tumor models the tumor-targeted IL12 plasmid DNAs were equally effective regardless of the peptide location. Similarly, the same targeting peptide that enhances IL12 therapies in one model fails to improve the effect of either IL15 or PF4 for inhibiting tumor growth in the same model. These interesting and sometimes contrasting results highlight both the efficacy and personalization of tumor-targeted cytokine gene therapies while exposing important aspects of these same therapies which must be considered before progressing into approved treatment options. PMID:24369443

Cutrera, Jeffry; Dibra, Denada; Satelli, Arun; Xia, Xuexing; Li, Shulin

2013-01-01

281

SMaRT technology enables gene expression repair in skin gene therapy.  

PubMed

In this issue, Wally et al. (2008) report successful gene expression repair by spliceosome-mediated RNA trans-splicing (SMaRT), a novel achievement in molecular medicine. In their model, SMaRT was able to replace a mutation of the plectin gene in epidermolysis bullosa simplex with muscular dystrophy. This approach is particularly attractive for skin gene therapy of dominant-negative mutations present in a number of blistering genodermatoses. PMID:18268535

Hengge, Ulrich R

2008-03-01

282

Method to directly radiolabel antibodies for diagnostic imaging and therapy  

SciTech Connect

This patent describes a method for directly labeling proteins with radionuclides for use in diagnostic imaging and therapy. It comprises: the steps of incubating a protein-containing solution with a solution of sodium ascorbate; adding a required quantity of reduced radionuclide to the incubated protein-containing solution and incubating.

Thakur, M.L.

1991-04-30

283

Physics in Modern Medicine: Applications in Imaging, Surgery, and Therapy  

NSDL National Science Digital Library

This is the website for a course on medical technologies and the physical principles behind them for non-scientists. Topics covered include laparoscopic and laser surgery, photodynamic therapy, and a range of imaging techniques. Included on this page is the course syllabus and a list of internet resources that will be useful to help students research projects.

Kane, Suzanne A.

2009-10-26

284

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

PubMed Central

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

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

2006-01-01

285

Cellular unfolded protein response against viruses used in gene therapy.  

PubMed

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

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

2014-01-01

286

Bacteriophages and medical oncology: targeted gene therapy of cancer.  

PubMed

Targeted gene therapy of cancer is of paramount importance in medical oncology. Bacteriophages, viruses that specifically infect bacterial cells, offer a variety of potential applications in biomedicine. Their genetic flexibility to go under a variety of surface modifications serves as a basis for phage display methodology. These surface manipulations allow bacteriophages to be exploited for targeted delivery of therapeutic genes. Moreover, the excellent safety profile of these viruses paves the way for their potential use as cancer gene therapy platforms. The merge of phage display and combinatorial technology has led to the emergence of phage libraries turning phage display into a high throughput technology. Random peptide libraries, as one of the most frequently used phage libraries, provide a rich source of clinically useful peptide ligands. Peptides are known as a promising category of pharmaceutical agents in medical oncology that present advantages such as inexpensive synthesis, efficient tissue penetration and the lack of immunogenicity. Phage peptide libraries can be screened, through biopanning, against various targets including cancer cells and tissues that results in obtaining cancer-homing ligands. Cancer-specific peptides isolated from phage libraries show huge promise to be utilized for targeting of various gene therapy vectors towards malignant cells. Beyond doubt, bacteriophages will play a more impressive role in the future of medical oncology. PMID:25012686

Bakhshinejad, Babak; Karimi, Marzieh; Sadeghizadeh, Majid

2014-08-01

287

Cellular unfolded protein response against viruses used in gene therapy  

PubMed Central

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.

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

2014-01-01

288

Gene therapy for PIDs: Progress, pitfalls and prospects  

PubMed Central

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.

Mukherjee, Sayandip; Thrasher, Adrian J.

2013-01-01

289

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

PubMed

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

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

2014-09-01

290

Functional Magnetic Nanoparticles for Non-Viral Gene Delivery and MR Imaging.  

PubMed

Gene therapy is becoming a promising strategy to treat various kinds of genetic and acquired diseases. However, the development of safe, efficient, and targetable gene delivery systems remains a major challenge in gene therapy. The unique material characteristics of magnetic nanoparticles (MNPs), including high surface area, facile surface modification, controllable size, and excellent magnetic properties, make them promising candidates for gene delivery. The engineered MNPs with modifiable functional surfaces and bioactive cores can result in several advantageous diagnostic and therapeutic properties including enhanced magnetic resonance imaging (MRI) signal intensity, long permeation and retention in the circulatory system, specific delivery of therapeutic genes to target sites. In this review, the updated research on the preparation and surface modification of MNPs for gene delivery is summarized. PMID:24065595

Xing, Ruijun; Liu, Gang; Zhu, Jinghan; Hou, Yanglong; Chen, Xiaoyuan

2014-06-01

291

Gene mutations and molecularly targeted therapies in acute myeloid leukemia  

PubMed Central

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.

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

2013-01-01

292

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

SciTech Connect

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.

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

293

The role of HSV amplicon vectors in cancer gene therapy Review Article  

Microsoft Academic Search

Summary Recent progress in tumor biology, virology and immunology has led to new approaches to the gene therapy for cancer. Herpes Simplex Virus (HSV) based vectors are attractive vectors for gene therapy use due to a number of favorable biologic features. Several characteristics render HSV suitable for gene therapy, including high transduction efficiency, ability to transduce non-dividing cells, high packaging

Kutubuddin Mahmood; Khaled Tolba; Howard J. Federoff

294

International Society for Cell and Gene Therapy of Cancer: 2005 meeting in Shenzhen, China  

Microsoft Academic Search

The 2005 International Society for Cell and Gene Therapy of Cancer (ISCGT) Congress was held in Shenzhen, China (www.iscgtchina2005.com) from December 9th–11th 2005. Here, we describe a representation of the most seminal presentations providing an overview of the progress in the field of cancer gene therapy including the successful introduction of the first approved gene therapy drug.

B A Guinn; J S Norris; F Farzaneh; A B Deisseroth

2007-01-01

295

Dual imaging-guided photothermal/photodynamic therapy using micelles.  

PubMed

We report a type of photosensitizer (PS)-loaded micelles integrating cyanine dye as potential theranostic micelles for precise anatomical tumor localization via dual photoacoustic (PA)/near-infrared fluorescent (NIRF) imaging modalities, and simultaneously superior cancer therapy via sequential synergistic photothermal therapy (PTT)/photodynamic therapy (PDT). The micelles exhibit enhanced photostability, cell internalization and tumor accumulation. The dual NIRF/PA imaging modalities of the micelles cause the high imaging contrast and spatial resolution of tumors, which provide precise anatomical localization of the tumor and its inner vasculature for guiding PTT/PDT treatments. Moreover, the micelles can generate severe photothermal damage on cancer cells and destabilization of the lysosomes upon PTT photoirradiation, which subsequently facilitate synergistic photodynamic injury via PS under PDT treatment. The sequential treatments of PTT/PDT trigger the enhanced cytoplasmic delivery of PS, which contributes to the synergistic anticancer efficacy of PS. Our strategy provides a dual-modal cancer imaging with high imaging contrast and spatial resolution, and subsequent therapeutic synergy of PTT/PDT for potential multimodal theranostic application. PMID:24613048

Guo, Miao; Mao, Huajian; Li, Yanli; Zhu, Aijun; He, Hui; Yang, Hong; Wang, Yangyun; Tian, Xin; Ge, Cuicui; Peng, Qiaoli; Wang, Xiaoyong; Yang, Xiangliang; Chen, Xiaoyuan; Liu, Gang; Chen, Huabing

2014-05-01

296

Compact Gamma-Ray Imager for In-Vivo Gene Imaging  

SciTech Connect

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.

Greenwald, A. C.

2000-06-01

297

Long-term effects of hepatocyte growth factor gene therapy in rat myocardial infarct model.  

PubMed

We investigated the long-term effects of human hepatocyte growth factor (HGF) gene therapy in a rat myocardial infarct model. Treatment adenovirus coexpressing the HGF therapeutic gene and the human sodium/iodide symporter (NIS) reporter gene or control adenovirus expressing the NIS gene alone were injected directly into the infarct border zone immediately after permanent coronary ligation in rats (n=6 each). A uniform disease state was confirmed in the acute phase in terms of impaired left ventricular (LV) function by cine magnetic resonance imaging (MRI), large infarct extent by (99m)Tc-tetrofosmin single-photon emission computed tomography (SPECT) and successful gene transfer and expression by (99m)TcO(4)(-) SPECT. After a 10-week follow-up, repeated cine MRI demonstrated no significant difference in the LV ejection fraction between the time points or groups, but a significantly increased end-diastolic volume from the acute to the chronic phase without a significant difference between the groups. Capillary density was significantly higher in the treatment group, whereas arteriole density remained unchanged. Two-photon excitation fluorescence microscopy revealed extremely thin capillaries (2-5??m), and their irregular networks increased in the infarct border zone of the treated myocardium. Our results indicated that single HGF gene therapy alone induced an immature and irregular microvasculature. PMID:21918549

Jin, Y-N; Inubushi, M; Masamoto, K; Odaka, K; Aoki, I; Tsuji, A B; Sagara, M; Koizumi, M; Saga, T

2012-08-01

298

Arthritis Gene Therapy and its Tortuous Path into the Clinic  

PubMed Central

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.

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

2013-01-01

299

Transductional targeting of adenovirus vectors for gene therapy  

PubMed Central

Cancer gene therapy approaches will derive considerable benefit from adenovirus (Ad) vectors capable of self-directed localization to neoplastic disease or immunomodulatory targets in vivo. The ablation of native Ad tropism coupled with active targeting modalities has demonstrated that innate gene delivery efficiency may be retained while circumventing Ad dependence on its primary cellular receptor, the coxsackie and Ad receptor. Herein, we describe advances in Ad targeting that are predicated on a fundamental understanding of vector/cell interplay. Further, we propose strategies by which existing paradigms, such as nanotechnology, may be combined with Ad vectors to form advanced delivery vehicles with multiple functions.

Glasgow, JN; Everts, M; Curiel, DT

2007-01-01

300

Gene and stem cell therapy of the hair follicle.  

PubMed

The hair follicle is a highly complex appendage of the skin containing a multiplicity of cell types. The follicle undergoes constant cycling through the life of the organism including growth and resorption with growth dependent on specific stem cells. The targeting of the follicle by genes and stem cells to change its properties, in particular, the nature of the hair shaft is discussed. Hair follicle delivery systems are described such as liposomes and viral vectors for gene therapy. The nature of the hair follicle stem cells is discussed, in particular, its pluripotency. PMID:15502205

Hoffman, Robert M

2005-01-01

301

Engineering adeno-associated viruses for clinical gene therapy.  

PubMed

Clinical gene therapy has been increasingly successful owing both to an enhanced molecular understanding of human disease and to progressively improving gene delivery technologies. Among these technologies, delivery vectors based on adeno-associated viruses (AAVs) have emerged as safe and effective and, in one recent case, have led 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

Kotterman, Melissa A; Schaffer, David V

2014-07-01

302

GENE AND CELL-MEDIATED THERAPIES FOR MUSCULAR DYSTROPHY  

PubMed Central

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.

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

2014-01-01

303

Consideration of gene therapy for paediatric neurotransmitter diseases.  

PubMed

The paediatric neurotransmitter diseases (PNDs) are a group of inborn errors of metabolism characterized by abnormalities of neurotransmitter synthesis or metabolism. Although some children may react favourably to neurotransmitter augmentation treatment, optimal response is not universal and other modes of treatment should be sought. The genes involved in many of the currently known monoamine PNDs have been utilized in pre-clinical and in phase I clinical trials in Parkinson disease (PD) and the basic principles could be applied to the therapy of PNDs with some modifications regarding the targeting and distribution of vectors. However, issues that go beyond neurotransmitter replacement are important considerations in PD and even more so in PNDs. Understanding the pathophysiology of PNDs including abnormal development resulting from the neurotransmitter deficiency will be critical for rational therapeutic approaches. Better animal models of PNDs are necessary to test gene therapy before clinical trials can be attempted. PMID:19259783

Rotstein, Michael; Kang, Un Jung

2009-06-01

304

Prevention of peritoneal adhesions: A promising role for gene therapy  

PubMed Central

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.

Atta, Hussein M

2011-01-01

305

Prospects for the gene therapy of spinal muscular atrophy.  

PubMed

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by a deficiency of functional SMN protein because of mutations in SMN1. A decrease in SMN activity results in motor neuron cell loss in the spinal cord, leading to a weakness of the proximal muscles responsible for crawling, walking, head/neck control and swallowing as well as the involuntary muscles that control breathing and coughing. Thus, patients present with pulmonary manifestations, paralysis and a shortened lifespan. Gene therapy is emerging as a promising therapeutic strategy for SMA given that the molecular basis for this monogenic disorder is well established. Recent advances and findings from preclinical studies in animal models provide optimism that gene therapy might be an effective therapeutic strategy for treating SMA. PMID:21334976

Passini, Marco A; Cheng, Seng H

2011-05-01

306

Image guidance for focal therapy of prostate cancer.  

PubMed

Focal therapy is an appealing strategy for any tumor and in time may prove to be a valuable treatment option for low-risk, carefully selected prostate cancer (PCa) patients. In an era where active surveillance is now considered a viable option for low-risk PCa patients, it is conceivable that organ-sparing treatments could also become an established option. The aim of focal therapy is to achieve long-term cancer control with minimal morbidity yet without the side effects of radical therapy. Although lacking in evidence, it remains intuitive that if we treat the smallest possible region of the prostate where to ensure cancer control by ablation (laser, cryotherapy or another ablative source), then there is less potential for untoward side effects. Thus, we believe the ultimate goal in focal therapy is to target specifically the cancerous site while ablating it and the smallest zone of normal prostate tissue around it to obtain cancer control. To achieve this goal, one is dependent on high-quality imaging to: locate the cancerous lesion and have it assist in guiding the ablative modality toward the lesion; monitor the ablation in real time; accurately assess the extent and totality of the ablation post-treatment and finally be used to follow-up and monitor the prostate in search of a recurrence of cancer in the treated area or the development ion new zones. This review seeks to discuss such issues focusing on imaging modalities as they relate to focal therapy of PCa. PMID:20963422

Lindner, U; Lawrentschuk, N; Trachtenberg, J

2010-12-01

307

Gene Therapy Used for Adipose Stem Cell Engineering  

Microsoft Academic Search

\\u000a The fundamental principal of gene therapy is the transfer of genetic material into individuals for therapeutic purposes by\\u000a altering cellular function or structure at the molecular level. The genetic alteration ultimately leads to the production\\u000a of a therapeutic protein that is secreted into the surrounding tissue milieu, is expressed on the cell surface or acts as\\u000a a signaling molecule to

Ulrich R. Goessler

308

Characterization of folate-chitosan-DNA nanoparticles for gene therapy  

Microsoft Academic Search

Gene therapy using polymers such as chitosan shows good biocompatibility, but low transfection efficiency. The mechanism of folic acid (FA) uptake by cells to promote targeting and internalization could improve transfection rates. The objective of this study was to synthesize and characterize FA-chitosan-DNA nanoparticles and evaluate their cytotoxicity in vitro. Chitosan-DNA and FA-Chitosan-DNA nanoparticles were prepared using reductive amidation and

Sania Mansouri; Yan Cuie; Francoise Winnik; Qin Shi; Patrick Lavigne; Mohamed Benderdour; Eric Beaumont; Julio C. Fernandes

2006-01-01

309

Gene Therapy and Virotherapy: Novel Therapeutic Approaches for Brain Tumors  

PubMed Central

Glioblastoma multiforme (GBM) is a deadly primary brain tumor in adults, with a median survival of ~12–18 months post-diagnosis. Despite recent advances in conventional therapeutic approaches, only modest improvements in median survival have been achieved; GBM usually recurs within 12 months post-resection, with poor prognosis. Thus, novel therapeutic strategies to target and kill GBM cells are desperately needed. Our group and others are pursuing virotherapy and gene therapy strategies for the treatment of GBM. In this review, we will discuss various virotherapy and gene therapy approaches for GBM currently under preclinical and clinical evaluation including direct or conditional cytotoxic, and/or immunostimulatory approaches. We also discuss cutting-edge technologies for drug/gene delivery and targeting brain tumors, including the use of stem cells as delivery platforms, the use of targeted immunotoxins, and the therapeutic potential of using GBM microvesicles to deliver therapeutic siRNAs or virotherapies. Finally, various animal models available to test novel GBM therapies are discussed.

Kroeger, Kurt M.; Ghulam Muhammad, A.K.M.; Baker, Gregory J.; Assi, Hikmat; Wibowo, Mia K.; Xiong, Weidong; Yagiz, Kader; Candolfi, Marianela; Lowenstein, Pedro R.; Castro, Maria G.

2010-01-01

310

Neurotrophic gene polymorphisms and response to psychological therapy.  

PubMed

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

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

311

Neurotrophic gene polymorphisms and response to psychological therapy  

PubMed Central

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.

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

312

Towards more successful gene therapy clinical trials for ?-thalassemia.  

PubMed

?-thalassemias constitute hereditary blood disorders characterized by reduced or absence of ?-globin synthesis resulting in mild to severe anemia, depending on the genotype. More than 200 mutations in the ?-globin gene are responsible for their specific features leading to a very heterogeneous phenotype. Current therapies for ?-thalassemia include blood transfusions, usually along with iron chelation and in selected cases with bone marrow transplantation (BMT) of HLA-matched hematopoietic stem cells (HSCs). However, these approaches are limited by factors, such as iron overload and donor availability, respectively. Since 2000, when globin lentiviral vectors (LVs) were first successfully tested for transfer efficiency of the therapeutic transgene, which led to disease amelioration in murine models, attention was drawn towards the improvement of such vectors for ?-thalassemia gene therapy. Constantly improving vector design and efficient HSC manipulation led recently to the first successful clinical trial in France, which further proved that this genetic approach can be curative. Furthermore, improved new efficient vectors and methods to safely monitor integration sites and therapeutic transgene position effects, promise a new era for ?-thalassemia gene therapy, with more and safer clinical trials yet to come. PMID:23865429

Drakopoulou, E; Papanikolaou, E; Georgomanoli, M; Anagnou, N P

2013-09-01

313

FGF-4 gene therapy GENERX--Collateral Therapeutics.  

PubMed

Collateral Therapeutics and Schering AG in Germany are developing a gene therapy product, GENERX for coronary artery disease. Based on the terms of the agreement, Schering or its affliates will be responsible for conducting and financing phase II/III clinical trials which are currently underway in the US and Europe. In particular, Berlex Labs (the US subsidiary of Schering AG), is involved in developing the gene therapy in the US. GENERX is an angiogenic gene therapy which triggers the production of a protein that stimulates new blood vessel growth providing an alternative route for blood to bypass clogged and blocked arteries in the heart. GENERX involves a one-time, non-surgical delivery of an adenovirus vector containing the human fibroblast growth factor-4 (FGF-4) into coronary arteries via a standard catheter. The FGF-4 gene was licensed from New York University. Collateral Therapeutics has been granted a US patent for "gene transfer-mediated angiogenesis therapy" for the nonsurgical administration of angiogenic genes for coronary and peripheral vascular disease. The patented technology has been licensed from the University of California. Collateral and Berlex have initiated pivotal phase IIb/III trials with GENERX in the US and Europe. The US-based study will evaluate the safety and efficacy of GENERX in patients with stable exertional angina due to coronary artery disease. The European-based study will evaluate patients with advanced coronary artery disease who are not considered candidates for interventions such as angioplasty and bypass surgery and/or patients who are unlikely to have positive outcomes from such interventions. Both studies, of a multicentre, randomised, double-blind and placebo-controlled design, will evaluate 2 dose levels of GENERX which will be non-surgically administered to the heart via intracoronary infusion through a standard cardiac catheter. Collateral also plans to develop a non-surgical gene therapy product using the FGF-4 gene for the treatment of patients with heart failure. In a blinded placebo-controlled study in a pig model of pacing-induced heart failure, intracoronary delivery of human FGF-4 expressed in an adenovirus vector showed significant improvement in regional cardiac function and a reduction in the size of the heart over a 3-week study period. If these results translated favourably to humans, FGF-4 gene therapy may be a therapeutic option for patients with dilated heart failure. Collateral Therapeutics has also announced a research collaboration with Targeted Genetics on the use of viral vectors to deliver therapeutic genes in cardiovascular disease. Under the terms of the agreement, Targeted Genetics and Collateral Therapeutics each have the option to collaborate further to use Targeted Genetics' recombinant adeno-associated viral vector to treat congestive heart failure. In such an event, Targeted Genetics would be responsible for constructing and manufacturing the vector, and Collateral Therapeutics will fund the costs of future collaboration. Either party may terminate this agreement at any time upon 30 days prior written notice. PMID:11909005

2002-01-01

314

Leber Hereditary Optic Neuropathy Gene Therapy Clinical Trial Recruitment  

PubMed Central

Objective To describe the patient profiles of the Leber hereditary optic neuropathy (LHON) Gene Therapy Clinical Trial, year 1. This study aims to identify and characterize affected patients and carriers with the G11778A mutation in mitochondrial DNA for planned gene therapy that will use “allotopic expression” by delivering a normal nuclear-encoded ND4 gene into the nuclei of retinal ganglion cells via an adeno-associated virus vector injected into the vitreous. Methods Patients with LHON with visual loss as well as asymptomatic maternally related family members were molecularly screened for ND1, ND4, and ND6 mutations in mitochondrial DNA commonly associated with LHON. All patients and maternal relatives also underwent complete neuro-ophthalmic examination, automated visual field testing, pattern electroretinogram (PERG), and OCT3. Results Twenty-five subjects with LHON and 21 carriers positive for the G11778A mitochondrial DNA mutation were recruited. Three additional mutations in the ND4 gene, G11719A, G11947A, or G11914A, were detected. Mean retinal nerve fiber layer (RNFL) thickness was 78.3 ?m up to 32 months after visual loss. It was 63.5 ?m for all affected patients and 100.7 ?m for carriers (P<.01). Mean PERG amplitude was lower in affected patients (40% of normal) than in carriers (94% of normal) (P<.01). Four carriers with PERG amplitudes less than 75% of normal had Early Treatment Diabetic Retinopathy Study acuity more than 20/25, mean defect more than ?2 dB, and average RNFL thickness more than 80 ?m. Conclusions Potential candidates for future gene therapy may include affected patients, as late as 32 months after loss of vision, with mildly reduced RNFL thickness or carriers with low PERG amplitudes and normal RNFL thickness, if the PERG amplitude is a predictor of conversion to LHON in these carriers.

Lam, Byron L.; Feuer, William J.; Abukhalil, Fawzi; Porciatti, Vittorio; Hauswirth, William W.; Guy, John

2011-01-01

315

Taking the good out of the bad: lentiviral-based gene therapy of the hemoglobinopathies  

Microsoft Academic Search

Sickle cell disease and ?-thalassemia are excellent candidates for gene therapy since transfer of a single gene into hematopoietic stem cells should theoretically elicit a therapeutic response. Initial attempts at gene therapy of these hemoglobinopathies have proved unsuccessful due to limitations of available gene transfer vectors. With the extensive research on human immunodeficiency virus-1 due to the acquired immune deficiency

Peter B. Stathopulos

2003-01-01

316

A microarray gene analysis of peripheral whole blood in normal adult male rats after long-term GH gene therapy  

Microsoft Academic Search

The main aims of this study were to determine the effects of GH gene abuse\\/misuse in normal animals and to discover genes\\u000a that could be used as candidate biomarkers for the detection of GH gene therapy abuse\\/misuse in humans. We determined the\\u000a global gene expression profile of peripheral whole blood from normal adult male rats after long-term GH gene therapy

Ying Qin; Ya-Ping Tian

2010-01-01

317

Construction of an MUC1 promoter driven, conditionally replicating adenovirus that expresses the sodium iodide symporter for gene therapy of breast cancer  

Microsoft Academic Search

INTRODUCTION: The sodium iodide symporter (NIS) directs the uptake and concentration of iodide in thyroid cells. This in turn allows radioiodine imaging and therapy for thyroid cancer. To extend the use of NIS-mediated radioiodine therapy to other types of cancer, we successfully transferred and expressed the sodium-iodide symporter (NIS) gene in prostate, colon, and breast cancer cells both in vivo

Miguel A Trujillo; Michael J Oneal; Julia Davydova; Elizabeth Bergert; Masato Yamamoto; John C Morris

2009-01-01

318

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

PubMed

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

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

2013-01-01

319

Pleiotrophin Gene Therapy for Peripheral Ischemia: Evaluation of Full-Length and Truncated Gene Variants  

PubMed Central

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

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

2013-01-01

320

In vivo visualization of gene expression using magnetic resonance imaging  

Microsoft Academic Search

High-resolution in vivo imaging of gene expression is not possible in opaque animals by existing techniques. Here we present a new approach for obtaining such images by magnetic resonance imaging (MRI) using an MRI contrast agent that can indicate reporter gene expression in living animals. We have prepared MRI contrast agents in which the access of water to the first

Angelique Y. Louie; Martina M. Hüber; Eric T. Ahrens; Ute Rothbächer; Rex Moats; Russell E. Jacobs; Scott E. Fraser; Thomas J. Meade

2000-01-01

321

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

PubMed

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

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

2014-01-01

322

Targeted Imaging and Therapy of Brain Cancer using Theranostic Nanoparticles  

PubMed Central

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.

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

2012-01-01

323

Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy  

PubMed Central

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.

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

2008-01-01

324

Immunological Monitoring to Rationally Guide AAV Gene Therapy.  

PubMed

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

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

2013-01-01

325

A Novel Linear Accelerator For Image Guided Radiation Therapy  

NASA Astrophysics Data System (ADS)

RadiaBeam is developing a novel linear accelerator which produces both kilovoltage (~100 keV) X-rays for imaging, and megavoltage (6 to 20 MeV) X-rays for therapy. We call this system the DEXITron: Dual Energy X-ray source for Imaging and Therapy. The Dexitron is enabled by an innovation in the electromagnetic design of the linac, which allows the output energy to be rapidly switched from high energy to low energy. In brief, the method involves switching the phase of the radiofrequency (RF) power by 180 degrees at some point in the linac such that, after that point, the linac decelerates the beam, rather than accelerating it. The Dexitron will have comparable cost to other linacs, and avoids the problems associated with current IGRT equipment.

Ding, Xiaodong; Boucher, Salime

2011-06-01

326

Functionalized Gold Nanorods for Tumor Imaging and Targeted Therapy  

PubMed Central

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.

Gui, Chen; Cui, Da-xiang

2012-01-01

327

344. Application of a suicide Gene to X-SCID Gene Therapy  

Microsoft Academic Search

X-linked severe combined immunodeficiency (X-SCID) is a fatal disease characterized by the absence of humoral and cellular immunity due to mutations in the gene encoding the common gamma (?c) chain. X-SCID is a good candidate for the somatic gene therapy because T and NK cells will develop once the ?c chain is introduced into patients' CD34 positive cells in vitro.

Toru Uchiyama; Satoru Kumaki; Masahumi Onodera; Du Wei; Looi Chung Yeng; Yoichi Sasahara; Sigeru Tsuchiya

2005-01-01

328

Improved Cancer Therapy and Molecular Imaging with Multivalent, Multispecific Antibodies  

PubMed Central

Summation Antibodies are highly versatile proteins with the ability to be used to target diverse compounds, such as radionuclides for imaging and therapy, or drugs and toxins for therapy, but also can be used unconjugated to elicit therapeutically beneficial responses, usually with minimal toxicity. This update describes a new procedure for forming multivalent and/or multispecific proteins, known as the dock-and-lock (DNL) technique. Developed as a procedure for preparing bispecific antibodies capable of binding divalently to a tumor antigen and monovalently to a radiolabeled hapten-peptide for pretargeted imaging and therapy, this methodology has the flexibility to create a number of other biologic agents of therapeutic interest. A variety of constructs, based on anti-CD20 and CD22 antibodies, have been made, with results showing that multispecific antibodies have very different properties from the respective parental monospecific antibodies. The technique is not restricted to antibody combination, but other biologics, such as interferon-?2b, have been prepared. These types of constructs not only allow small biologics to be sustained in the blood longer, but also to be selectively targeted. Thus, DNL technology is a highly flexible platform that can be used to prepare many different types of agents that could further improve cancer detection and therapy.

Rossi, Edmund A.; Chang, Chien-Hsing; Goldenberg, David M.

2010-01-01

329

Gene therapy for diabetes mellitus in rats by hepatic expression of insulin.  

PubMed Central

Type 1 diabetes mellitus is caused by severe insulin deficiency secondary to the autoimmune destruction of pancreatic beta cells. Patients need to be controlled by periodic insulin injections to prevent the development of ketoacidosis, which can be fatal. Sustained, low-level expression of the rat insulin 1 gene from the liver of severely diabetic rats was achieved by in vivo administration of a recombinant retroviral vector. Ketoacidosis was prevented and the treated animals exhibited normoglycemia during a 24-hr fast, with no evidence of hypoglycemia. Histopathological examination of the liver in the treated animals showed no apparent abnormalities. Thus, the liver is an excellent target organ for ectopic expression of the insulin gene as a potential treatment modality for type 1 diabetes mellitus by gene therapy. Images Fig. 3

Kolodka, T M; Finegold, M; Moss, L; Woo, S L

1995-01-01

330

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

PubMed Central

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

2012-01-01

331

Introduction to the background, principles, and state of the art in suicide gene therapy  

Microsoft Academic Search

Gene therapy is defined as a technology that aims to modify the genetic component of cells to gain therapeutic benefits. Suicide\\u000a gene therapy (or gene-directed enzyme prodrug therapy [GDEPT]) is a two-step treatment for cancer (especially, solid tumors).\\u000a In the first step, a gene for a foreign enzyme is delivered to the tumor by a vector. Following the expression of

Ion Niculescu-Duvaz; Caroline J. Springer

2005-01-01

332

Potential of gene therapy for Parkinson's disease: neurobiologic issues and new developments in gene transfer methodologies.  

PubMed

Gene transfer techniques have been explored as therapeutic modalities and neurobiologic tools to understand the role of various genes in animal models of Parkinson's disease. The gene for tyrosine hydroxylase, the rate-limiting step of dopamine synthesis, has been transferred into animal models by viral vectors or by implantable cells that have been modified by retrovirus vectors. The role of additional genes such as GTP cyclohydrolase 1 and aromatic L-amino acid decarboxylase in optimal delivery of dopamine in animal models is reviewed. Gene therapy also allows goals beyond replacement of dopamine. Neurotrophic factors such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor can be introduced to promote sprouting of neurites and protect the dopaminergic neurons from degeneration. Genes involved in apoptosis, free radical scavenger pathway, or other cell death mechanism could also be used to prevent the degeneration of the neurons. Current technology of gene therapy is limited in its long-term expression and ability to regulate the gene expression. However, recent developments provide better understanding of these limitations and suggest potential solutions to these technical hurdles. PMID:9613721

Kang, U J

1998-01-01

333

Ribozyme gene therapy for autosomal dominant retinal disease.  

PubMed

Gene delivery to cells of the retina, particularly to photoreceptor cells, has broad potential both for answering basic questions of retinal biology and for more applied therapeutic purposes. The use of ribozymes as therapy for autosomal dominant retinal diseases is a promising technique, and the theoretical and practical basis for their use is discussed. The process involves designing and testing ribozymes first in vitro and then in animal models of retinal disease. Viral vectors based on the nonpathogenic human adeno-associated virus, when coupled with the strong, rod photoreceptor specific opsin promoter, offer an efficient and nontoxic way to deliver and express ribozymes in photoreceptor cells for long time periods of time. Effective ribozyme-mediated therapy also demands careful in vitro analysis of a ribozyme's ability to efficiently and specifically distinguish between mutant and wild type RNAs. Finally, effective demonstration of therapy in an animal model requires careful analysis of any rescue effect in the retina using multiple criteria, including biochemical, structural and physiological assays. For this purpose, ribozyme therapy in a transgenic rat model of retinitis pigmentosa containing a dominant rod opsin mutation (proline-to-histidine change at position 23) is discussed in detail. PMID:10834402

Hauswirth, W W; LaVail, M M; Flannery, J G; Lewin, A S

2000-02-01

334

Regulatable Gene Expression Systems for Gene Therapy Applications: Progress and Future Challenges  

PubMed Central

Gene therapy aims to revert diseased phenotypes by the use of both viral and nonviral gene delivery systems. Substantial progress has been made in making gene transfer vehicles more efficient, less toxic, and nonimmunogenic and in allowing long-term transgene expression. One of the key issues in successfully implementing gene therapies in the clinical setting is to be able to regulate gene expression very tightly and consistently as and when it is needed. The regulation ought to be achievable using a compound that should be nontoxic, be able to penetrate into the desired target tissue or organ, and have a half-life of a few hours (as opposed to minutes or days) so that when withdrawn or added (depending on the regulatable system used) gene expression can be turned “on” or “off” quickly and effectively. Also, the genetic switches employed should ideally be nonimmunogenic in the host. The ability to switch transgenes on and off would be of paramount importance not only when the therapy is no longer needed, but also in the case of the development of adverse side effects to the therapy. Many regulatable systems are currently under development and some, i.e., the tetracycline-dependent transcriptional switch, have been used successfully for in vivo preclinical applications. Despite this, there are no examples of switches that have been employed in a human clinical trial. In this review, we aim to highlight the main regulatable systems currently under development, the gene transfer systems employed for their expression, and also the preclinical models in which they have been used successfully. We also discuss the substantial challenges that still remain before these regulatable switches can be employed in the clinical setting.

Goverdhana, S.; Puntel, M.; Xiong, W.; Zirger, J. M.; Barcia, C.; Curtin, J. F.; Soffer, E. B.; Mondkar, S.; King, G. D.; Hu, J.; Sciascia, S. A.; Candolfi, M.; Greengold, D. S.; Lowenstein, P. R.; Castro, M. G.

2009-01-01

335

Achromatopsia as a potential candidate for gene therapy.  

PubMed

Achromatopsia is an autosomal recessive retinal disease involving loss of cone function that afflicts approximately 1 in 30,000 individuals. Patients with achromatopsia usually have visual acuities lower than 20/200 because of the central vision loss, photophobia, complete color blindness and reduced cone-mediated electroretinographic (ERG) amplitudes. Mutations in three genes have been found to be the primary causes of achromatopsia, including CNGB3 (beta subunit of the cone cyclic nucleotide-gated cation channel), CNGA3 (alpha subunit of the cone cyclic nucleotide-gated cation channel), and GNAT2 (cone specific alpha subunit of transducin). Naturally occurring mouse models with mutations in Cnga3 (cpfl5 mice) and Gnat2 (cpfl3 mice) were discovered at The Jackson Laboratory. A natural occurring canine model with CNGB3 mutations has also been found. These animal models have many of the central phenotypic features of the corresponding human diseases. Using adeno-associated virus (AAV)-mediated gene therapy, we and others show that cone function can be restored in all three models. These data suggest that human achromatopsia may be a good candidate for corrective gene therapy. PMID:20238068

Pang, Ji-Jing; Alexander, John; Lei, Bo; Deng, Wentao; Zhang, Keqing; Li, Qiuhong; Chang, Bo; Hauswirth, William W

2010-01-01

336

Prospects for retinal cone-targeted gene therapy.  

PubMed

Gene therapy strategies that target therapeutic genes to retinal cones are a worthy goal both because cone photoreceptor diseases are severely vision limiting and because many retinal diseases that do not affect cones directly eventually lead to cone loss, the reason for eventual blindness. Human achromatopsia is a genetic disease of cones that renders them nonfunctional but otherwise intact. Thus, animal models of achromatopsia were used in conjunction with adeno-associated virus (AAV) vectors whose serotype efficiently transduces cones and with a promoter that limits transgene expression to cones. In the Gnat2(cpfl3) mouse model of one genetic form of human achromatopsia, we were able to demonstrate recovery of normal cone function and visual acuity after a single subretinal treatment of vector that supplied wild-type Gnat2 protein to cones. This validates the overall strategy of targeting cones using recombinant viral vectors and justifies a more complete examination of animal models of cone disease as a prelude to considering a clinical gene therapy trial. PMID:18596991

Alexander, John J; Hauswirth, William W

2008-06-01

337

T cell receptor gene therapy for autoimmune diseases.  

PubMed

The current quality of autoimmune disease treatments is not satisfactory in regard to efficacy and safety. Antigen-specific immunotherapy is a future therapy that could achieve maximal efficacy with minimal adverse effects. T cells are essential components in antigen-specific immunity. However, we do not have a sufficient strategy for manipulating antigen-specific T cells. We propose that T cell receptor (TCR) gene transfer is a hopeful approach for antigen-specific immunotherapy. We confirmed the efficacy of TCR gene therapy in animal models of systemic autoimmune disease and arthritis. In lupus-prone NZB/W F1 mice, nucleosome-specific TCR and CTLA4Ig transduced cells suppressed autoantibody production and nephritis development. In the therapeutic experiment of collagen-induced arthritis (CIA), arthritis-related TCRs were isolated from single T cells accumulating in the arthritis site. Arthritis-related TCR and TNFRIg transduced cells or TCR and Foxp3 transduced cells suppressed arthritis progression and bone destruction. Therefore, engineered antigen-specific cells manipulated to express appropriate functional genes could be applied to specific immunotherapy. PMID:17911437

Fujio, Keishi; Okamura, Tomohisa; Okamoto, Akiko; Yamamoto, Kazuhiko

2007-09-01

338

Time-Lapse Imaging of Neuroblastoma Cells to Determine Cell Fate upon Gene Knockdown  

PubMed Central

Neuroblastoma is the most common extra-cranial solid tumor of early childhood. Standard therapies are not effective in case of poor prognosis and chemotherapy resistance. To improve drug therapy, it is imperative to discover new targets that play a substantial role in tumorigenesis of neuroblastoma. The mitotic machinery is an attractive target for therapeutic interventions and inhibitors can be developed to target mitotic entry, spindle apparatus, spindle activation checkpoint, and mitotic exit. We present an elaborate analysis pipeline to determine cancer specific therapeutic targets by first performing a focused gene expression analysis to select genes followed by a gene knockdown screening assay of live cells. We interrogated gene expression studies of neuroblastoma tumors and selected 240 genes relevant for tumorigenesis and cell cycle. With these genes we performed time-lapse screening of gene knockdowns in neuroblastoma cells. We classified cellular phenotypes and used the temporal context of the perturbation effect to determine the sequence of events, particularly the mitotic entry preceding cell death. Based upon this phenotype kinetics from the gene knockdown screening, we inferred dynamic gene functions in mitosis and cell proliferation. We identified six genes (DLGAP5, DSCC1, SMO, SNRPD1, SSBP1, and UBE2C) with a vital role in mitosis and these are promising therapeutic targets for neuroblastoma. Images and movies of every time point of all screened genes are available at https://ichip.bioquant.uni-heidelberg.de.

Batra, Richa; Harder, Nathalie; Gogolin, Sina; Diessl, Nicolle; Soons, Zita; Jager-Schmidt, Christina; Lawerenz, Christian; Eils, Roland; Rohr, Karl; Westermann, Frank; Konig, Rainer

2012-01-01

339

Time-lapse imaging of neuroblastoma cells to determine cell fate upon gene knockdown.  

PubMed

Neuroblastoma is the most common extra-cranial solid tumor of early childhood. Standard therapies are not effective in case of poor prognosis and chemotherapy resistance. To improve drug therapy, it is imperative to discover new targets that play a substantial role in tumorigenesis of neuroblastoma. The mitotic machinery is an attractive target for therapeutic interventions and inhibitors can be developed to target mitotic entry, spindle apparatus, spindle activation checkpoint, and mitotic exit. We present an elaborate analysis pipeline to determine cancer specific therapeutic targets by first performing a focused gene expression analysis to select genes followed by a gene knockdown screening assay of live cells. We interrogated gene expression studies of neuroblastoma tumors and selected 240 genes relevant for tumorigenesis and cell cycle. With these genes we performed time-lapse screening of gene knockdowns in neuroblastoma cells. We classified cellular phenotypes and used the temporal context of the perturbation effect to determine the sequence of events, particularly the mitotic entry preceding cell death. Based upon this phenotype kinetics from the gene knockdown screening, we inferred dynamic gene functions in mitosis and cell proliferation. We identified six genes (DLGAP5, DSCC1, SMO, SNRPD1, SSBP1, and UBE2C) with a vital role in mitosis and these are promising therapeutic targets for neuroblastoma. Images and movies of every time point of all screened genes are available at https://ichip.bioquant.uni-heidelberg.de. PMID:23251412

Batra, Richa; Harder, Nathalie; Gogolin, Sina; Diessl, Nicolle; Soons, Zita; Jäger-Schmidt, Christina; Lawerenz, Christian; Eils, Roland; Rohr, Karl; Westermann, Frank; König, Rainer

2012-01-01

340

Suicide Gene Therapy With Adenoviral Delivery of HSV-tK Gene for Patients With Local Recurrence of Prostate Cancer After Hormonal Therapy  

Microsoft Academic Search

We conducted a Phase I study of in situ herpes simplex virus thymidine kinase (HSV-tk) plus ganciclovir (GCV) gene therapy, which was approved by the Japanese government as the first prostate cancer gene therapy trial. Major inclusion criteria were local recurrence of prostate cancer after hormonal therapy and no metastasis. Adv.HSV-tk was injected directly into the prostate in escalating doses

Yasutomo Nasu; Takashi Saika; Shin Ebara; Nobuyuki Kusaka; Haruki Kaku; Fernando Abarzua; Daisuke Manabe; Timothy C Thompson; Hiromi Kumon

2007-01-01

341

Gene Regulation Systems for Gene Therapy Applications in the Central Nervous System  

PubMed Central

Substantial progress has been made in the development of novel gene therapy strategies for central nervous system (CNS) disorders in recent years. However, unregulated transgene expression is a significant issue limiting human applications due to the potential side effects from excessive levels of transgenic protein that indiscriminately affect both diseased and nondiseased cells. Gene regulation systems are a tool by which tight tissue-specific and temporal regulation of transgene expression may be achieved. This review covers the features of ideal regulatory systems and summarises the mechanics of current exogenous and endogenous gene regulation systems and their utility in the CNS.

Naidoo, Jerusha; Young, Deborah

2012-01-01

342

Targeted therapies in renal cell cancer: recent developments in imaging  

PubMed Central

Targeted therapy has significantly improved the perspectives of patients with metastatic renal cell cancer (mRCC). Frequently, these new molecules cause disease stabilization rather than substantial tumor regression. As treatment options expand with the growing number of targeted agents, there is an increasing need for surrogate markers to early assess tumor response. Here, we review the currently available imaging techniques and response evaluation criteria for the assessment of tumor response in mRCC patients. For computed tomography (CT), different criteria are discussed including the Response Evaluation Criteria in Solid Tumors (RECIST), the Choi criteria, the modified Choi criteria, and the size and attenuation CT (SACT) criteria. Functional imaging modalities are discussed, such as dynamic contrast-enhanced CT (DCE-CT), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), dynamic contrast-enhanced ultrasonography (DCE-US), and positron emission tomography (PET).

Meijerink, Martijn R.; van den Eertwegh, Alfons J. M.; Boven, Epie

2010-01-01

343

Image correlation techniques in radiation therapy treatment planning.  

PubMed

A technique to spatially correlate multi-modality or serial imaging studies of the head is described. Surface fitting of a well defined structure in different imaging studies is used to determine the optimal three dimensional transformation between the coordinate systems. The transformation is then used to map volumes of interest between studies or to reslice the studies along comparable planes. The approach is feasible in the presence of variations in slice thickness, pixel size, imaging plane, or head position, and for correlations between different modalities. Correlations have been performed between serial CT, CT/MRI, and PET/CT/MRI studies. Phantom studies and clinical cases are presented. Accuracy is typically on the order of the sum of the pixel sizes between studies. Applications in radiation therapy treatment planning are described. PMID:2785845

Chen, G T; Pelizzari, C A

1989-01-01

344

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

PubMed Central

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

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

2013-01-01

345

Diffusion Imaging for Therapy Response Assessment of Brain Tumor  

PubMed Central

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.

Chenevert, Thomas L.; Ross, Brian D.

2014-01-01

346

Tissue-Engineered Skeletal Muscle Organoids for Reversible Gene Therapy  

NASA Technical Reports Server (NTRS)

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.

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

1996-01-01

347

Tissue-Engineered Skeletal Muscle Organoids for Reversible Gene Therapy  

NASA Technical Reports Server (NTRS)

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.

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

1996-01-01

348

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

PubMed Central

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

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

2010-01-01

349

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

PubMed Central

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.

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

350

Critical issues in gene therapy for neurologic disease.  

PubMed

Gene therapy for the nervous system is a newly emerging field with special issues related to modes of delivery, potential toxicity, and realistic expectations for treatment of this vital and highly complex tissue. This review focuses on the potential for gene delivery to the brain, as well as possible risks and benefits of these procedures. This includes discussion of appropriate vectors, such as adeno-associated virus, lentivirus, gutless adenovirus, and herpes simplex virus hybrid amplicons, and cell vehicles, such as neuroprogenitor cells. Routes of delivery for focal and global diseases are enumerated, including use of migratory cells, facilitation of vascular delivery across the blood-brain barrier, cerebrospinal fluid delivery, and convection injection. Attention is given to examples of diseases falling into different etiologic types: metabolic deficiency states, including Canavan disease and lysosomal storage disorders; and degenerative conditions, including Parkinson's disease and other neurodegenerative conditions. PMID:11916483

Hsich, Gary; Sena-Esteves, Miguel; Breakefield, Xandra O

2002-03-20

351

Toward Gene Therapy for Cystic Fibrosis Using a Lentivirus Pseudotyped With Sendai Virus Envelopes  

Microsoft Academic Search

Gene therapy for cystic fibrosis (CF) is making encouraging progress into clinical trials. However, further improvements in transduction efficiency are desired. To develop a novel gene transfer vector that is improved and truly effective for CF gene therapy, a simian immunodeficiency virus (SIV) was pseudotyped with envelope proteins from Sendai virus (SeV), which is known to efficiently transduce unconditioned airway

Katsuyuki Mitomo; Uta Griesenbach; Makoto Inoue; Lucinda Somerton; Cuixiang Meng; Eiji Akiba; Toshiaki Tabata; Yasuji Ueda; Gad M Frankel; Raymond Farley; Charanjit Singh; Mario Chan; Felix Munkonge; Andrea Brum; Stefania Xenariou; Sara Escudero-Garcia; Mamoru Hasegawa; Eric WFW Alton

2010-01-01

352

Delivery systems intended for in vivo gene therapy of cancer: targeting and replication competent viral vectors  

Microsoft Academic Search

Cancer gene therapy represents one of the most rapidly evolving areas in pre-clinical and clinical cancer research. Application of gene transfer techniques in clinical trials has made increasingly obvious that several issues will need to be addressed prior to meaningful incorporation of gene therapy in the care of cancer patients. Two of the most important problems to overcome are lack

Evanthia Galanis; Richard Vile; Stephen J Russell

2001-01-01

353

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

NSDL National Science Digital Library

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.

2008-03-26

354

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

PubMed Central

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.

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

2012-01-01

355

Suicidal gene therapy in the effective control of primary human hepatocellular carcinoma as monitored by noninvasive bioimaging.  

PubMed

Hepatocellular carcinoma (HCC) is usually refractory to the available treatments. For cancer gene therapy purposes, real-time imaging of therapeutic gene expression is of great importance because there are multiple factors that modulate the therapeutic gene expression in a complex tumor microenvironment. As a consequence, multiple doses of therapeutic viral vectors may be required for improved efficacy. In the present study, the luciferase reporter gene and the yeast cytosine deaminase (yCD) genes were bicistronically expressed using the foot-and-mouth disease virus 2A peptide under the regulation of the cytomegalovirus (CMV) promoter. The effectiveness of the yCD/5-FC (5-fluorocytosine) killing efficacy mediated by the herpes simplex virus type 1 (HSV-1) amplicon viral vector was shown using HCC and non-HCC cell lines in vitro. In addition, in vivo experiment also showed tumor regression of a primary HCC 26-1004 tumor xenograft in tumor expressing high levels of the yCD gene (as determined by noninvasive imaging) after intratumoral injection of 1.5 × 10(6)?TU HGCX-L2C HSV-1 amplicon viral vector and 5-FC administration. The HSV-1 amplicon viral vector coupled with the yCD/5-FC prodrug activated suicide gene could potentially be of use in clinical gene therapy for HCC. PMID:21918545

Sia, K C; Huynh, H; Chinnasamy, N; Hui, K M; Lam, P Y P

2012-05-01

356

Animal models for prenatal gene therapy: rodent models for prenatal gene therapy.  

PubMed

Fetal gene transfer has been studied in various animal models, including rabbits, guinea pigs, cats, dogs, and nonhuman primate; however, the most common model is the rodent, particularly the mouse. There are numerous advantages to mouse models, including a short gestation time of around 20 days, large litter size usually of more than six pups, ease of colony maintenance due to the small physical size, and the relatively low expense of doing so. Moreover, the mouse genome is well defined, there are many transgenic models particularly of human monogenetic disorders, and mouse-specific biological reagents are readily available. One criticism has been that it is difficult to perform procedures on the fetal mouse with suitable accuracy. Over the past decade, accumulation of technical expertise and development of technology such as high-frequency ultrasound have permitted accurate vector delivery to organs and tissues. Here, we describe our experiences of gene transfer to the fetal mouse with and without ultrasound guidance from mid to late gestation. Depending upon the vector type, the route of delivery and the age of the fetus, specific or widespread gene transfer can be achieved, making fetal mice excellent models for exploratory biodistribution studies. PMID:22648774

Roybal, Jessica L; Endo, Masayuki; Buckley, Suzanne M K; Herbert, Bronwen R; Waddington, Simon N; Flake, Alan W

2012-01-01

357

Imaging approaches for the study of cell based cardiac therapies  

PubMed Central

Despite promising preclinical data, the treatment of cardiovascular diseases using embryonic, bone-marrow-derived, and skeletal myoblast stem cells has not yet come to fruition within mainstream clinical practice. Major obstacles in cardiac stem cell investigations include the ability to monitor cell engraftment and survival following implantation within the myocardium. Several cellular imaging modalities, including reporter gene and MRI-based tracking approaches, have emerged that provide the means to identify, localize and monitor stem cells longitudinally in vivo following implantation. This Review will examine the various cardiac cellular tracking modalities, including the combinatorial use of several probes in multimodality imaging, with a focus on data from the last five years.

Lau, Joe F.; Anderson, Stasia A.; Adler, Eric; Frank, Joseph A.

2009-01-01

358

Combined anti-tumor necrosis factor-? therapy and DMARD therapy in rheumatoid arthritis patients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone  

PubMed Central

Periodic assessment of gene expression for diagnosis and monitoring in rheumatoid arthritis (RA) may provide a readily available and useful method to detect subclinical disease progression and follow responses to therapy with disease modifying anti-rheumatic agents (DMARDs) or anti-TNF-? therapy. We used quantitative real-time PCR to compare peripheral blood gene expression profiles in active (“unstable”) RA patients on DMARDs, stable RA patients on DMARDs, and stable RA patients treated with a combination of a disease-modifying anti-rheumatoid drug (DMARD) and an anti-TNF-? agent (infliximab or etanercept) to healthy human controls. The expression of 48 inflammatory genes were compared between healthy controls (N = 122), unstable DMARD patients (N = 18), stable DMARD patients (N = 26), and stable patients on combination therapy (N = 20). Expression of 13 genes was very low or undetectable in all study groups. Compared to healthy controls, patients with unstable RA on DMARDs exhibited increased expression of 25 genes, stable DMARD patients exhibited increased expression of 14 genes and decreased expression of five genes, and combined therapy patients exhibited increased expression of six genes and decreased expression of 10 genes. These findings demonstrate that active RA is associated with increased expression of circulating inflammatory markers whereas increases in inflammatory gene expression are diminished in patients with stable disease on either DMARD or anti-TNF-? therapy. Furthermore, combination DMARD and anti-TNF-? therapy is associated with greater reductions in circulating inflammatory gene expression compared to DMARD therapy alone. These results suggest that assessment of peripheral blood gene expression may prove useful to monitor disease progression and response to therapy.

Edwards, Carl K.; Green, Julie S.; Volk, Hans-Dieter; Schiff, Michael; Kotzin, Brian L.; Mitsuya, Hiroaki; Kawaguchi, Tatsuya; Sakata, Ken-Mei; Cheronis, John; Trollinger, David; Bankaitis-Davis, Danute; Dinarello, Charles A.; Norris, David A.; Bevilacqua, Michael P.; Fujita, Mayumi; Burmester, Gerd-Rudiger

2012-01-01

359

Optimization of image-guided targeting in renal focal therapy.  

PubMed

Focal renal therapy for small renal masses (T(1a) or T(1b)) has been used as primary treatment for patients with comorbidities who are considered poor candidates for surgical resection. With a continuing effort toward optimization of minimally invasive nephron-sparing modalities, the effort to expand the patient pool will continue. As long-term results of renal ablative therapies become available and the safety, precision, and efficacy become well established, renal ablation may be used with increasing frequency for a wider group of patients. When this happens, high-quality imaging for localization and targeting of these renal lesions will become the central core of the treatment, with emphasis on superior results, accurate positioning of the probe, precise localization of the tumor, and real-time intraoperative monitoring of outcomes. PMID:20477541

Leveillee, Raymond J; Ramanathan, Rajan

2010-05-01

360

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

PubMed Central

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.

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

2010-01-01

361

N3-substituted thymidine bioconjugates for cancer therapy and imaging  

PubMed Central

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.

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

2013-01-01

362

Alkylphosphocholine analogs for broad-spectrum cancer imaging and therapy.  

PubMed

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 ((124)I) or molecular radiotherapeutic ((131)I) agent. CLR1404 analogs displayed prolonged tumor-selective retention in 55 in vivo rodent and human cancer and cancer stem cell models. (131)I-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 (124)I-CLR1404 or (131)I-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 (124)I-CLR1404 tumor imaging for planning (131)I-CLR1404 therapy. PMID:24920661

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

2014-06-11

363

Clinical development of gene therapy needs a tailored approach: a regulatory perspective from the European Union.  

PubMed

Gene therapy is a rapidly evolving field that needs an integrated approach, as acknowledged in the concept article on the revision of the guideline on gene transfer medicinal products. The first gene therapy application for marketing authorization was approved in the International Conference on Harmonisation (ICH) region in 2012, the product being Alipogene tiparvovec. The regulatory process for this product has been commented on extensively, highlighting the challenges posed by such a novel technology. Here, as current or previous members of the Committee for Advanced Therapies, we share our perspectives and views on gene therapy as a treatment modality based on current common understanding and regulatory experience of gene therapy products in the European Union to date. It is our view that a tailored approach is needed for a given gene therapy product in order to achieve successful marketing authorization. PMID:24649836

Narayanan, Gopalan; Cossu, Giulio; Galli, Maria Cristina; Flory, Egbert; Ovelgonne, Hans; Salmikangas, Paula; Schneider, Christian K; Trouvin, Jean-Hugues

2014-03-01

364

The Use of Medical Images in Planning and Delivery of Radiation Therapy  

Microsoft Academic Search

The authors provide a survey of how images are used in radiation therapy to improve the precision of radiation therapy plans, and delivery of radiation treatment. In contrast to diagnostic radiology, where the focus is on interpretation of the images to decide if disease is present, radiation therapy quantifies the extent of the region to be treated, and relates it

Ira J Kalet; Mary M Austin-Seymour

1997-01-01

365

Harnessing autophagy for cell fate control gene therapy  

PubMed Central

We hypothesized that rapamycin, through induction of autophagy and promotion of an antiapoptotic phenotype, would permit lentiviral (LV)-based transgene delivery to human T-Rapa cells, which are being tested in phase II clinical trials in the setting of allogeneic hematopoietic cell transplantation. Manufactured T-Rapa cells were exposed to supernatant enriched for a LV vector encoding a fusion protein consisting of truncated CD19 (for cell surface marking) and DTYMK/TMPK?, which provides “cell-fate control” due to its ability to phosphorylate (activate) AZT prodrug. LV-transduction in rapamycin-treated T-Rapa cells: (1) resulted in mitochondrial autophagy and a resultant antiapoptotic phenotype, which was reversed by the autophagy inhibitor 3-MA; (2) yielded changes in MAP1LC3B and SQSTM1 expression, which were reversed by 3-MA; and (3) increased T-Rapa cell expression of the CD19-DTYMK? fusion protein, despite their reduced proliferative status. Importantly, although the transgene-expressing T-Rapa cells expressed an antiapoptotic phenotype, they were highly susceptible to cell death via AZT exposure both in vitro and in vivo (in a human-into-mouse xenogeneic transplantation model). Therefore, rapamycin induction of T cell autophagy can be used for gene therapy applications, including the CD19-DTYMK? cell-fate control axis to improve the safety of T cell immuno-gene therapy.

Felizardo, Tania C.; Foley, Jason; Steed, Kevin; Dropulic, Boro; Amarnath, Shoba; Medin, Jeffrey A.; Fowler, Daniel H.

2013-01-01

366

Physiologic and metabolic safety of butyrylcholinesterase gene therapy in mice.  

PubMed

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 40mg/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

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

2014-07-16

367

Imaging gene delivery in a mouse model of congenital neuronal ceroid lipofuscinosis  

PubMed Central

Adeno-associated virus (AAV) mediated gene replacement for lysosomal disorders have been spurred by the ability of some serotypes to efficiently transduce neurons in the brain and by the ability of lysosomal enzymes to cross-correct among cells. Here, we explored enzyme replacement therapy in a knock-out mouse model of congenital neuronal ceroid lipofuscinosis (NCL), the most severe of the NCLs in humans. The missing protease in this disorder, cathepsin D (CathD) has high levels in the central nervous system (CNS). This enzyme has the potential advantage for assessing experimental therapy in that it can be imaged using a near-infrared fluorescence (NIRF) probe activated by CathD. Injections of an AAV2/rh8 vector encoding mouse cathepsin D (mCathD) into both cerebral ventricles and peritoneum of newborn knock-out mice resulted in a significant increase in lifespan. Successful delivery of active CathD by the AAV2/rh8-mCathD vector was verified by NIRF imaging of mouse embryonic fibroblasts (MEFs) from knock-out mice in culture, as well as by ex vivo NIRF imaging of brain and liver after gene transfer. These studies support the potential effectiveness and imaging evaluation of enzyme replacement therapy to the brain and other organs in CathD null mice via AAV-mediated gene delivery in neonatal animals.

Pike, Lisa S.; Tannous, Bakhos A.; Deliolanis, Nikolaos C.; Hsich, Gary; Morse, Danielle; Tung, Ching-Hsuan; Sena-Esteves, Miguel; Breakefield, Xandra O.

2011-01-01

368

Radiation Therapy Alone for Imaging-Defined Meningiomas  

SciTech Connect

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

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

2010-01-15

369

Advancing Translational Research Through the NHLBI Gene Therapy Resource Program (GTRP)  

PubMed Central

Abstract Translational research is a lengthy, complex, and necessary endeavor in order to bring basic science discoveries to clinical fruition. The NIH offers several programs to support translational research including an important resource established specifically for gene therapy researchers—the National Heart, Lung, and Blood Institute (NHLBI) Gene Therapy Resource Program (GTRP). This paper reviews the core components of the GTRP and describes how the GTRP provides researchers with resources that are critical to advancing investigational gene therapy products into clinical testing.

Benson, Janet; Cornetta, Kenneth; Diggins, Margaret; Johnston, Julie C.; Sepelak, Susan; Wang, Gensheng; Wilson, James M.; Wright, J. Fraser; Skarlatos, Sonia I.

2013-01-01

370

The Attitude of Oncology Physicians and Nurses to the Acceptance of New Drugs for Gene Therapy  

Microsoft Academic Search

With the efficacy of gene therapy verified in phase III trials, cancer patients will consider whether to accept gene therapy\\u000a sooner or later. The purpose of this study is to investigate the attitudes of oncology physicians and nurses regarding effective\\u000a gene therapy. A questionnaire was administered to 368 oncology physicians and nurses. A total of 328 valid questionnaires\\u000a were returned

Zi-ming Liu; Chang Liu; Jun-ying Li; Chun-hua Yu; Yu Jiang

2011-01-01

371

Micro-PET/CT Monitoring of Herpes Thymidine Kinase Suicide Gene Therapy in a Prostate Cancer Xenograft: The Advantage of a Cell-specific Transcriptional Targeting Approach  

PubMed Central

Cancer gene therapy based on tissue-restricted expression of cytotoxic gene should achieve superior therapeutic index over an unrestricted method. This study compared the therapeutic effects of a highly augmented, prostate-specific gene expression method to a strong constitutive promoter-driven approach. Molecular imaging was coupled to gene therapy to ascertain real-time therapeutic activity. The imaging reporter gene (luciferase) and the cytotoxic gene (herpes simplex thymidine kinase) were delivered by adenoviral vectors injected directly into human prostate tumors grafted in SCID mice. Serial bioluminescence imaging, positron emission tomography, and computed tomography revealed restriction of gene expression to the tumors when prostate-specific vector was employed. In contrast, administration of constitutive active vector resulted in strong signals in the liver. Liver serology, tissue histology, and frail condition of animals confirmed liver toxicity suffered by the constitutive active cohorts, whereas the prostate-targeted group was unaffected. The extent of tumor killing was analyzed by apoptotic staining and human prostate marker (prostate-specific antigen). Overall, the augmented prostate-specific expression system was superior to the constitutive approach in safeguarding against systemic toxicity, while achieving effective tumor killing. Integrating noninvasive imaging into cytotoxic gene therapy will provide a useful strategy to monitor gene expression and therapeutic efficacy in future clinical protocols.

Johnson, Mai; Sato, Makoto; Burton, Jeremy; Gambhir, Sanjiv S.; Carey, Michael; Wu, Lily

2010-01-01

372

Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo.  

PubMed Central

The therapeutic efficacy of adenovirus-mediated herpes simplex virus thymidine kinase (HSV-tk) gene transduction of rat C6 glioma cells followed by ganciclovir (GCV) administration was studied in tumors generated in the brains of nude mice. C6 glioma cells were efficiently transduced in vitro by a replicative-defective recombinant adenovirus carrying the HSV-tk gene (ADV/RSV-tk) that rendered them sensitive to GCV in a dose-dependent manner. Tumors were generated by stereotaxic intracerebral injection of 1 x 10(4) C6 cells in nude mice. After 8 days of tumor growth, 3 x 10(8) ADV/RSV-tk viral particles were injected into the tumors and the mice subsequently were treated with GCV for 6 days. Tumor size in untreated and treated animals was compared 20 days after tumor implantation. The mean cross-sectional area of the tumors in the treated animals was 23-fold smaller than in control animals and the tumor volume was reduced by > 500-fold. These results demonstrate that the recombinant adenoviral vector can function as an efficient gene delivery vehicle for the treatment of gliomas by in vivo gene therapy. Images

Chen, S H; Shine, H D; Goodman, J C; Grossman, R G; Woo, S L

1994-01-01

373

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

PubMed Central

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 on monogenic diseases, we discuss the problem of insertional oncogenesis and identify areas for future research, such as developing more quantitative assays for risk and efficacy, and ways of minimizing the genotoxic effects of gene therapy protocols, which will be important if gene therapy is to fulfill its conceptual promise.

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

2006-01-01

374

Gene therapy: the role of cytoskeleton in gene transfer studies based on biology and mathematics.  

PubMed

Gene therapy is a promising approach for treating a wide range of human pathologies such as genetic disorders as well as diseases acquired over time. Viral and non-viral vectors are used to convey sequences of genes that can be expressed for therapeutic purposes. Plasmid DNA is receiving considerable attention for intramuscular gene transfer due to its safety, simplicity and low cost of production. Nevertheless, strategies to improve DNA uptake into the nucleus of cells for its expression are required. Cytoskeleton plays an important role in the intracellular trafficking. The mechanism regulating this process must be elucidated. Here, we propose a new methodological approach based on the coupling of biology assays and predictive mathematical models, in order to clarify the mechanism of the DNA uptake and its expression into the cells. Once these processes are better clarified, we will be able to propose more efficient therapeutic gene transfer protocols for the treatment of human patients. PMID:24606116

Notarangelo, Maria G; Natalini, Roberto; Signori, Emanuela

2014-01-01

375

Perfluorocarbon nanoparticles for physiological and molecular imaging and therapy.  

PubMed

Herein, we review the use of non-nephrotoxic perfluorocarbon nanoparticles (PFC NPs) for noninvasive detection and therapy of kidney diseases, and we provide a synopsis of other related literature pertinent to their anticipated clinical application. Recent reports indicate that PFC NPs allow for quantitative mapping of kidney perfusion and oxygenation after ischemia-reperfusion injury with the use of a novel multinuclear (1)H/(19)F magnetic resonance imaging approach. Furthermore, when conjugated with targeting ligands, the functionalized PFC NPs offer unique and quantitative capabilities for imaging inflammation in the kidney of atherosclerotic ApoE-null mice. In addition, PFC NPs can facilitate drug delivery for treatment of inflammation, thrombosis, and angiogenesis in selected conditions that are comorbidities for kidney failure. The excellent safety profile of PFC NPs 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

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

2013-11-01

376

Gene Transfer in Human Vestibular Epithelia and the Prospects for Inner Ear Gene Therapy  

PubMed Central

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

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

2009-01-01

377

Photoacoustic imaging of lacZ gene expression in vivo  

Microsoft Academic Search

In the postgenomic era, imaging techniques are playing an important role in visualizing gene expression in vivo. This work represents the first demonstration of pho- toacoustic tomography PAT for reporter gene imaging. Rats inoculated with 9L\\/lacZ gliosarcoma tumor cells are imaged with PAT before and after injection of X-gal, a colorimetric assay for the lacZ-encoded enzyme -galactosidase. Using far-red optical

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

2007-01-01

378

Non-invasive genetic imaging for molecular and cell therapies of cancer  

Microsoft Academic Search

Gene therapy is a very attractive strategy in experimental cancer therapy. Ideally, the approach aims to deliver therapeutic\\u000a genes selectively to cancer cells. However, progress in the improvement of gene therapy formulations has been hampered by\\u000a difficulties in measuring transgene delivery and in quantifying transgene expression in vivo. In clinical trials, endpoints rely almost exclusively on the analysis of biopsies,

C. Belmar; P.-W. So; G. Vassaux; V. Moleiro-SanEmeterio; P. Martín-Duque

2007-01-01

379

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

NASA Astrophysics Data System (ADS)

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

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

2010-04-01

380

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

PubMed Central

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

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

2011-01-01

381

Photodynamic therapy mediated induction of early response genes.  

PubMed

Photodynamic therapy (PDT) generates reactive oxygen species which initiate the cytotoxic events of this tumor treatment. We demonstrate that PDT mediated oxidative stress induced a transient increase in the early response genes c-fos, c-jun, c-myc, and egr-1 in murine radiation-induced fibrosarcoma cells. Incubation of exponentially growing cells with porphyrin based photosensitizers in the dark also induced an increase in mRNA levels of early response genes. However, the xanthine photosensitizer, rose bengal, produced increased c-fos mRNA levels only following light treatment. Nuclear runoff experiments confirmed that the induction of c-fos mRNA is controlled in part at the level of transcription. Likewise, a chloramphenicol acetyltransferase reporter construct containing the major c-fos transcriptional response elements was inducible by porphyrin and PDT. Signal transduction pathways associated with PDT mediated c-fos activation were examined by treating cells with protein kinase inhibitors. Staurosporine and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine inhibited PDT mediated c-fos activation while N-(2-guanidinoethyl)-5-isoquinoline-sulfonamide had no effect. In addition, quinacrine, which can inhibit phospholipase activity, blocked PDT induced c-fos mRNA expression. These results suggest that photosensitizer mediated oxidative stress acts through protein kinase-mediated signal transduction pathway(s) to activate early response genes. PMID:8118827

Luna, M C; Wong, S; Gomer, C J

1994-03-01

382

A triple suicide gene strategy that improves therapeutic effects and incorporates multi-modality molecular imaging for monitoring gene-functions  

PubMed Central

Gene-directed enzyme prodrug therapy (GDEPT), or suicide gene therapy, has shown promise in clinical trials. In this preclinical study using stable cell lines and xenograft tumor models, we show that a triple-suicide-gene GDEPT approach produce enhanced therapeutic efficacy over previous methods. Importantly all the three genes (thymidine kinase, cytosine deaminase, and uracil phosphoribosyltransferase) function simultaneously as effectors for GDEPT and markers for multimodality molecular imaging (MMI), using positron-emission-tomography (PET), magnetic resonance-spectroscopy (MRS), and optical (fluorescent and bioluminescent) techniques. It was demonstrated that MMI can evaluate the distribution and function/activity of the triple-suicide-gene. The concomitant expression of these genes significantly enhances prodrug cytotoxicity and radiosensitivity in vitro and in vivo.

Xing, Ligang; Sun, Xiaorong; Deng, Xuelong; Kotedia, Khushali; Zanzonico, Pat B.; Ackerstaff, Ellen; Koutcher, Jason A.; Ling, C. Clifton; Li, Gloria C.

2013-01-01

383

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

NASA Astrophysics Data System (ADS)

In this paper, we present and validate a framework, based on deformable image registration, for automatic processing of serial three-dimensional CT images used in image-guided radiation therapy. A major assumption in deformable image registration has been that, if two images are being registered, every point of one image corresponds appropriately to some point in the other. For intra-treatment images of the prostate, however, this assumption is violated by the variable presence of bowel gas. The framework presented here explicitly extends previous deformable image registration algorithms to accommodate such regions in the image for which no correspondence exists. We show how to use our registration technique as a tool for organ segmentation, and present a statistical analysis of this segmentation method, validating it by comparison with multiple human raters. We also show how the deformable registration technique can be used to determine the dosimetric effect of a given plan in the presence of non-rigid tissue motion. In addition to dose accumulation, we describe a method for estimating the biological effects of tissue motion using a linear-quadratic model. This work is described in the context of a prostate treatment protocol, but it is of general applicability.

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

2005-12-01

384

Imaging dose management using multi-resolution in CT-guided radiation therapy  

Microsoft Academic Search

In image-guided radiation therapy, megavoltage computerized tomography (MVCT) delivers higher dose to the patient for lower image quality than diagnostic kilovoltage CT (kVCT). One way to reduce the mean imaging dose is to reduce the imaging volume, which is often sufficient for registration and dosimetry purposes. The filtered back projection using truncated data causes artefacts that degrade the image quality.

Ke Sheng; Robert Jeraj; Rick Shaw; Thomas R. Mackie; Bhudatt R. Paliwal

2005-01-01

385

Toward a gene therapy for neurological and somatic MPSIIIA  

PubMed Central

Mucopolysaccharidosis Type IIIA (MPSIIIA) represents an unmet medical need. MPSIIIA shares with many other lysosomal storage disorders (LSD) the characteristic of being a severe neurodegenerative disease accompanied by mild somatic involvement. Thus, the main target organ for the development of new treatments is the central nervous system (CNS), but overall clinical efficacy would be greatly enhanced by simultaneous correction of peripheral disease. We have recently developed a novel treatment for MPSIIIA based on the delivery to the cerebrospinal fluid of serotype 9 adeno-associated virus (AAV9)-derived vectors. This gene therapy strategy corrected both CNS and somatic pathology in animal models through widespread transduction of CNS, peripheral nervous system (PNS), and liver. The work set the grounds for the clinical translation of the approach to treat MPSIIIA in humans. Here we discuss some important considerations that further support the applicability of this treatment to MPSIIIA and other LSD with CNS and somatic involvement.

Haurigot, Virginia; Bosch, Fatima

2013-01-01

386

Gene therapy of gliomas: receptor and transcriptional targeting.  

PubMed

Through incremental increases in the overall therapeutic ratio of combined modality regimens, each addition of unique selective toxicity to a tumor moves one step closer to a cure. The primary advantage of adding gene therapy strategies to current oncologic regimens is the ability to design multiple levels of unique biologic selectivity into vectors using recombinant technology. This article presents an overview of current and potential methods for designing vectors targeted to high grade gliomas through selective cell entry or transcriptional regulation. Cell entry based methodologies are founded on increasing relative uptake of the vector through the chemical or recombinant addition of epitopes which bind to receptors selectively expressed on target cells. Transcriptional targeting utilizes promoter and enhancer systems which have potential for selectively activating transcription for transgene expression or vector propagation in target cells. PMID:9858886

Spear, M A

1998-01-01

387

Generation of Transgenic Mice Using Lentiviral Vectors: A Novel Preclinical Assessment of Lentiviral Vectors for Gene Therapy  

Microsoft Academic Search

Lentiviral vectors have become attractive delivery vehicles for gene therapy investigators. Specifically, the ability of lentiviral vectors to integrate into nondividing cells and provide stable and long-term gene expression in vivo is a desirable attribute of gene therapy approaches. We report here a simple method for generating transgenic mice using lentiviral vectors, which could be useful models for gene therapy.

Masahito Ikawa; Nobushige Tanaka; Winston W.-Y. Kao; Inder M. Verma

2003-01-01

388

Challenges in Image-Guided Therapy System Design  

PubMed Central

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

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

2013-01-01

389

A tumor targeted gene vector modified with G250 monoclonal antibody for gene therapy.  

PubMed

G250 is a tumor associated antigen that is found on > 90% of renal cell carcinoma (RCC). In order to develop a highly targeting gene vector for RCC gene therapy, G250 monoclonal antibody was prepared, purified and characterized. The antibody was chemically bound to Polyethylenimine (PEI) to form the IgG-PEI conjugate. The conjugate is capable of forming DNA complexes in the size of nano meters and with a narrow size distribution. The targeting effect and transfection efficiency were tested on five cell lines, ketr 3, Hela, ACHN, HepG2, and smooth muscle cells. The transfection was quantitatively determined by fluorescence activated cell sorting (FACS) and luciferase assay. The FACS results show that for G250 positive cells ketr 3 and Hela, the transfection efficiency of IgG-PEI are 2-fold higher than that of PEI. But for G250 negative cells, antibody modification has no effect on transfection. The expression of luciferase in ketr 3 cells which is expressed as enzyme activity is 15-fold and 61-fold higher than that in ACHN and SMC, respectively. In the presence of free antibody, the targeting effect of IgG-PEI is impaired and the transfection efficiency is normalized. It indicates that G250 antibody is an ideal targeting ligand for delivery of genes into RCC. Application of this IgG-PEI conjugate in RCC gene therapy will be of great interest. PMID:18316136

Duan, Yajun; Zheng, Junnian; Han, Sufang; Wu, Yi; Wang, Yanming; Li, Deguan; Kong, Deling; Yu, Yaoting

2008-04-21

390

Therapeutic Challenges to Retinitis Pigmentosa: From Neuroprotection to Gene Therapy  

PubMed Central

Syndromic retinitis pigmentosa (RP) is the result of several mutations expressed in rod photoreceptors, over 40 of which have so far been identified. Enormous efforts are being made to relate the advances in unraveling the patho-physiological mechanisms to therapeutic approaches in animal models, and eventually in clinical trials on humans. This review summarizes briefly the current clinical management of RP and focuses on the new exciting treatment possibilities. To date, there is no approved therapy able to stop the evolution of RP or restore vision. The current management includes an attempt at slowing down the degenerative process by vitamin supplementation, trying to treat ocular complications and to provide psychological support to blind patients. Novel therapeutic may be tailored dependant on the stage of the disease and can be divided in three groups. In the early stages, when there are surviving photoreceptors, the first approach would be to try to halt the degeneration by correction of the underlying biochemical abnormality in the visual cycle using gene therapy or pharmacological treatment. A second approach aims to cope with photoreceptor cell death using neurotrophic growth factors or anti-apoptotic factors, reducing the production of retino-toxic molecules, and limiting oxidative damage. In advanced stages, when there are few or no functional photoreceptors, strategies that may benefit include retinal transplantation, electronic retinal implants or a newly described optogenetic technique using a light-activated channel to genetically resensitize remnant cone-photoreceptor cells.

Sahni, Jayashree N; Angi, Martina; Irigoyen, Cristina; Semeraro, Francesco; Romano, Mario R; Parmeggiani, Francesco

2011-01-01

391

Combination Therapy and Noninvasive Imaging with a Dual Therapeutic Vector Expressing MDR1 Short Hairpin RNA and a Sodium Iodide Symporter  

Microsoft Academic Search

We investigated the feasibility of using combination gene therapy and noninvasive nuclear imaging after expression of the human sodium iodide symporter (hNIS) and inhibition of the multidrug resistance (MDR1) gene in colon cancer cells. Methods: HCT- 15 cells were stably transfected with a dual expression vector, in which the hNIS gene, driven by a constitutive cytomegalovirus promoter, has been coupled

Seung-Yoon Park; Wonjung Kwak; Narendra Tapha; Mi-Yeon Jung; Ju-Ock Nam; In-Seop So; So-Youn Kim; Jeongsoo Yoo; Jaetae Lee; In-San Kim

392

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

PubMed

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

Ozawa, Keiya

2014-03-01

393

Parameters Affecting Image-guided, Hydrodynamic Gene Delivery to Swine Liver  

PubMed Central

Development of a safe and effective method for gene delivery to hepatocytes is a critical step toward gene therapy for liver diseases. Here, we assessed the parameters for gene delivery to the livers of large animals (pigs, 40–65?kg) using an image-guided hydrodynamics-based procedure that involves image-guided catheter insertion into the lobular hepatic vein and hydrodynamic injection of reporter plasmids using a computer-controlled injector. We demonstrated that injection parameters (relative position of the catheter in the hepatic vasculature, intravascular pressure upon injection, and injection volume) are directly related to the safety and efficiency of the procedure. By optimizing these parameters, we explored for the first time, the advantage of the procedure for sequential injections to multiple lobes in human-sized pigs. The optimized procedure resulted in sustained expression of the human ?-1 antitrypsin gene in livers for more than 2 months after gene delivery. In addition, repeated hydrodynamic gene delivery was safely conducted and no adverse events were seen in the entire period of the study. Our results support the clinical applicability of the image-guided hydrodynamic gene delivery method for the treatment of liver diseases.

Kamimura, Kenya; Suda, Takeshi; Zhang, Guisheng; Aoyagi, Yutaka; Liu, Dexi

2013-01-01

394

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

Microsoft Academic Search

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

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

2006-01-01

395

[3] Stabilized plasmid-lipid particles: A systemic gene therapy vector  

Microsoft Academic Search

The ability of a systemically administered gene therapy vector to exhibit extended circulation lifetimes, accumulate at a distal tumor site, and enable transgene expression is unique to SPLP. The flexibility and low toxicity of SPLP as a platform technology for systemic gene therapy allows for further optimization of tumor transfection properties following systemic administration. For example, the PEG coating of

David B. Fenske; Ian MacLachlan; Pieter R. Cullis

2002-01-01

396

Targets for Gene Therapy of Parkinson's Disease: Growth Factors, Signal Transduction, and Promoters  

Microsoft Academic Search

Parkinson's disease gene therapy is in its infancy. All studies to date have been in experimental animals and there are no clinical protocols currently approved. Several non-human primate studies however, have been completed and preliminary data appear promising. When dealing with a complex acquired disorder of unknown etiology, gene therapy is likely to provide symptomatic and palliative relief at best

Paola Leone

1997-01-01

397

Scaffold-based articular cartilage repair - Future prospects wedding gene therapy and tissue engineering  

Microsoft Academic Search

Future prospects wedding gene therapy and tissue engineering. In this article, current clinical procedures for articular cartilage repair are reviewed in the context of the contributions that tissue engineering approaches can make in improving the outcome. Specific attention is directed toward the promising effects of growth factors and the potential advantages of employing gene therapy techniques in combination with three-dimensional

RAMILLE M. CAPITO; MYRON SPECTOR

2003-01-01

398

Oncogenesis Following Delivery of a Nonprimate Lentiviral Gene Therapy Vector to Fetal and Neonatal Mice  

Microsoft Academic Search

Gene therapy by use of integrating vectors carrying therapeutic transgene sequences offers the potential for a permanent cure of genetic diseases by stable vector insertion into the patients' chromosomes. However, three cases of T cell lymphoproliferative disease have been identified almost 3 years after retrovirus gene therapy for X-linked severe combined immune deficiency. In two of these cases vector insertion

Mike Themis; Simon N. Waddington; Manfred Schmidt; Christof von Kalle; Yoahe Wang; Faisal Al-Allaf; Lisa G. Gregory; Megha Nivsarkar; Matthew Themis; Maxine V. Holder; Suzanne M. K. Buckley; Niraja Dighe; Alaine T. Ruthe; Ajay Mistry; Brian Bigger; Ahad Rahim; Tuan H. Nguyen; Didier Trono; Adrian J. Thrasher; Charles Coutelle

2005-01-01

399

The 3rd International Meeting on Gene Therapy in Rheumatology and Orthopaedics  

Microsoft Academic Search

The 3rd International Meeting on Gene Therapy in Rheumatology and Orthopaedics was held in Boston, Massachusetts, USA in May 2004. Keystone lectures delivered by Drs Joseph Glorioso and Inder Verma provided comprehensive, up-to-date information on all major virus vectors. Other invited speakers covered the application of gene therapy to treatment of arthritis, including the latest clinical trial in rheumatoid arthritis,

Christopher H Evans; Steven C Ghivizzani; Elvire Gouze; John J Rediske; Edward M Schwarz; Paul D Robbins

2005-01-01

400

Gene therapy on renal-cell carcinoma: magic bullet or tragic insanity?  

Microsoft Academic Search

Correction of the aberrant genetic code as a means of rational therapy has been a challenge since the first discoveries of an abnormal genetic link to expression of certain disorders. Our growing understanding of the molecular basis of cancer has also led us into a new era in cancer therapy. The possibility of gene therapy represents one of the biggest

G. H. Mickisch

1995-01-01

401

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

PubMed

Gene therapy emerged as important approach in treatment for many inborn disorders caused by genetic defects, as well as other diseases. This manuscript focused on Adeno-associated virus (AAV) based gene therapy to eye diseases. The paper firstly introduced the AAV vectors and the techniques of eye delivery, then summarized some tested genes that were used in past treatment to retinal degeneration disorders. Finally the paper discussed the updated optogenetics and its roles in AAV based gene therapy for eye diseases. PMID:21344187

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

2011-05-01

402

Clinical Experience With Gene Therapy for the Treatment of Prostate Cancer  

PubMed Central

Localized prostate cancer can be treated effectively with radical prostatectomy or radiation therapy. The treatment options for metastatic prostate cancer are limited to hormonal therapy; hormone-refractory cancer is treated with taxane-based chemotherapy, which provides only a modest survival benefit. New treatments are needed. The gene for the initiation of prostate cancer has not been identified; however, gene therapy can involve tumor injection of a gene to kill cells, systemic gene delivery to target and kill metastases, or local gene expression intended to generate a systemic response. This review will provide an overview of the various strategies of cancer gene therapy, focusing on those that have gone to clinical trial, detailing clinical experience in prostate cancer patients.

Stanizzi, Matthew A; Hall, Simon J

2007-01-01

403

Enhanced thermal stability of silica-coated gold nanorods for photoacoustic imaging and image-guided therapy  

PubMed Central

Photothermal stability and, therefore, consistency of both optical absorption and photoacoustic response of the plasmonic nanoabsorbers is critical for successful photoacoustic image-guided photothermal therapy. In this study, silica-coated gold nanorods were developed as a multifunctional molecular imaging and therapeutic agent suitable for image-guided photothermal therapy. The optical properties and photothermal stability of silica-coated gold nanorods under intense irradiation with nanosecond laser pulses were investigated by UV-Vis spectroscopy and transmission electron microscopy. Silica-coated gold nanorods showed increased photothermal stability and retained their superior optical properties under much higher fluences. The changes in photoacoustic response of PEGylated and silica-coated nanorods under laser pulses of various fluences were compared. The silica-coated gold nanorods provide a stable photoacoustic signal, which implies better imaging capabilities and make silica-coated gold nanorods a promising imaging and therapeutic nano-agent for photoacoustic imaging and image-guided photothermal therapy.

Chen, Yun-Sheng; Frey, Wolfgang; Kim, Seungsoo; Homan, Kimberly; Kruizinga, Pieter; Sokolov, Konstantin; Emelianov, Stanislav

2010-01-01

404

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

Microsoft Academic Search

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

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

2007-01-01

405

Multifunctional magnetic nanoparticles for magnetic resonance image-guided photothermal therapy for cancer  

NASA Astrophysics Data System (ADS)

Key advances in multifunctional magnetic nanoparticles (MNPs) for magnetic resonance (MR) image-guided photothermal therapy of cancer are reviewed. We briefly outline the design and fabrication of such multifunctional MNPs. Bimodal image-guided photothermal therapies (MR/fluorescence and MR/ultrasound) are also discussed.

Yue, Xiu-Li; Ma, Fang; Dai, Zhi-Fei

2014-04-01

406

Diffusion-Weighted MR Imaging of Metastatic Disease of the Spine: Assessment of Response to Therapy  

Microsoft Academic Search

BACKGROUND AND PURPOSE: In cases of metastatic disease of the spine, monitoring the response to medical therapy with plain radiography, bone scanning, and conventional spin-echo sequence MR imaging is unsatisfactory because of the insensitivity or nonspecific findings of these imaging modalities. The purpose of this study was to investigate signal intensity changes of bone marrow after therapy by using diffusion-weighted

Woo Mok Byun; Yongmin Chang; Sang Jin Lee; Jurgen Finsterbusch; Jens Frahm

407

Kalman Filtered MR Temperature Imaging for Laser Induced Thermal Therapies  

PubMed Central

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

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

2013-01-01

408

Range of retinal diseases potentially treatable by AAV-vectored gene therapy.  

PubMed

Viable strategies for retinal gene therapy must be designed to cope with the genetic nature of the disease and/or the primary pathologic process responsible for retinal malfunction. For dominant gene defects the aim must be to destroy the presumably toxic gene product, for recessive gene defects the direct approach aims to provide a wild-type copy of the gene to the affected retinal cell type, and for diseases of either complex or unknown genetic origin, more general cell survival strategies that deal with preserving affected retinal cells are often the best and only option. Hence examples of each type of therapy will be briefly discussed in several animal models, including ribozyme therapy for autosomal dominant retinitis pigmentosa in the transgenic P23H opsin rat, beta-PDE gene augmentation therapy for autosomal recessive retinitis pigmentosa in the rd mouse, glial cell-derived neurotrophic factor (GDNF) gene therapy for autosomal dominant RP in the transgenic S334ter opsin rat and pigment epithelial cell-derived neurotrophic factor (PEDF) gene therapy for neovascular retinal disease in rodents. Each employs a recombinant AAV vectored passenger gene controlled by one of several promoters supporting either photoreceptor-specific expression or more general retinal cell expression depending on the therapeutic requirements. PMID:14750604

Hauswirth, William W; Li, Quihong; Raisler, Brian; Timmers, Adrian M; Berns, Kenneth I; Flannery, John G; LaVail, Matthew M; Lewin, Alfred S

2004-01-01

409

In Vivo Imaging of mdrla Gene Expression.  

National Technical Information Service (NTIS)

The authors' experience studying the MDR1 gene prompted them to initiate work on a novel animal model to study MDR1/mdr1 gene expression under a variety of normal and breast cancer-related physiological conditions. With the advent of new bioimaging techno...

T. W. Synold

2005-01-01

410

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

Microsoft Academic Search

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

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

1999-01-01