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1

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. PMID:12721514

2003-01-01

2

Viral imaging in gene therapy noninvasive demonstration of gene delivery and expression.  

PubMed

Gene therapy is a rapidly developing modality of treatment, with applications in acquired and inherited disorders. Gene delivery vehicles ("vectors") are the main impediment in the evolution of gene therapy into a clinically acceptable mainstream therapy. Vectors based on viral particles are the most commonly used vehicles to carry genes to the organs and tissues of interest. Despite initial promise and substantial progress in the development of experimental gene therapy protocols, human gene therapy still is based on technologies that so far do not allow for routine clinical use. Recent progress in viral vector production and better understanding of molecular aspects of vector delivery and targeting issues has created the need for imaging techniques that would be useful in addressing the problems and opportunities inherent in viral gene therapy development. Two integral components of gene therapy monitoring, the imaging of gene delivery and the imaging of resultant exogenous gene expression, are recognized. These molecular imaging components provide a realistic means for assessment of safety and efficacy of preclinical and clinical development of gene therapy. PMID:12687912

Schellingerhout, Dawid; Bogdanov, Alexei A

2002-11-01

3

Gene therapy review.  

PubMed

The use of genes to treat disease, more commonly known as gene therapy, is a valid and promising tool to manage and treat diseases that conventional drug therapies cannot cure. Gene therapy holds the potential to control a wide range of diseases, including cystic fibrosis, heart disease, diabetes, cancer, and blood diseases. This review assesses the current status of gene therapy, highlighting therapeutic methodologies and applications, terminology, and imaging strategies. This article presents an overview of roadblocks associated with each therapeutic methodology, along with some of the scientific, social, and ethical issues associated with gene therapy. PMID:25391667

Moss, Joseph Anthony

2014-11-01

4

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

5

Myocardial gene therapy  

Microsoft Academic Search

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

Jeffrey M. Isner

2002-01-01

6

Defining the success of cardiac gene therapy: how can nuclear imaging contribute?  

Microsoft Academic Search

Gene therapy is a promising modality for the treatment of various cardiovascular diseases such as ischaemia, heart failure, restenosis after revascularisation, hypertension and hyperlipidaemia. An increasing number of approaches are moving from experimental and preclinical validation to clinical application, and several multi-centre trials are currently underway. Despite the rapid progress in cardiac gene therapy, many basic tools and principles remain

Norbert Avril; Frank M. Bengel

2003-01-01

7

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

8

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. PMID:22263922

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

2012-01-01

9

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

Microsoft Academic Search

Develop a method to image gene expression that can be used to monitor successful gene transduction in patients. Currently there are no noninvasive ways to define the extent and spatial location of gene transduction or the level of gene expression in targeted organs or tumors. Wild-type RF2 s.c. tumors were produced by implantation of 10⁶ cells into both flanks of

J. Tjuvajev; R. Joshi; J. Kennedy

1996-01-01

10

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

11

Gene therapy progress and prospects: the eye  

Microsoft Academic Search

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

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

2006-01-01

12

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

PubMed Central

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

2013-01-01

13

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

PubMed Central

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

14

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. PMID:18176779

Traister, Russell S.

2008-01-01

15

Introduction to Gene Therapy  

Microsoft Academic Search

Gene therapy is broadly defined as the delivery or transferof genetic material to target cells for therapeutic purposes. Elucidation of the molecular bases of inherited diseases as\\u000a well as acquired diseases, such as cancer, allows for the possibility of therapeutic interventions at the molecular level.\\u000a The therapeutic benefits may be achieved by, interfering with gene function, restoring lost function, or

Ayman Al-Hendy; Salama A. Salama

16

Human gene therapy.  

PubMed

Human gene therapy is a procedure that is being used in an attempt to treat genetic and other diseases. Eleven clinical protocols are under way at the present time, each with scientific and clinical objectives. Human genetic engineering raises unique safety, social, and ethical concerns. PMID:1589762

Anderson, W F

1992-05-01

17

Bispecific Antibodies and Gene Therapy  

Microsoft Academic Search

\\u000a Gene therapy is the transfer of therapeutic genes, via gene transfer vectors, into patients for therapeutic purposes. Different\\u000a gene therapy strategies are being pursued, including long-term gene correction of monogenetic diseases, eradication of tumor\\u000a cells in cancer patients, or genetic vaccination for infectious diseases. Bispecific antibodies and gene therapy are connected\\u000a in two ways. First, bispecific antibodies are tools of

Dirk M. Nettelbeck

18

Radioprotective gene therapy.  

PubMed

Control of cancer by irradiation therapy alone or in conjunction with combination chemotherapy is often limited by organ specific toxicity. Ionizing irradiation toxicity is initiated by damage to normal tissue near the tumor target and within the transit volume of radiotherapy beams. Irradiation-induced cellular, tissue, and organ damage is mediated by acute effects, which can be dose limiting. A latent period follows recovery from the acute reaction, then chronic irradiation fibrosis (late effects) pose a second cause of organ failure. We have developed the technology for radioprotective gene therapy using the transgene for the antioxidant manganese superoxide dismutase, delivered to specific target organs (lung, esophagus, oral cavity, oropharynx, and bladder) using gene transfer vectors including plasmid/liposomes (PL) and adenovirus. Irradiation protection by MnSOD transgene overexpression at the cellular level has been demonstrated to be localized to the mitochondrial membrane. Using MnSOD transgene constructs lacking the mitochondrial localization leader sequence, and in other experiments attaching this localization signal to otherwise non-radioprotective cytoplasmic Cu/ZnSOD, mitochondrial localization has been demonstrated to be critical to protection. Organ specific injection of MnSOD-PL prior to irradiation demonstrates transgene expression for 48-72 hours, and an associated decrease in ionizing irradiation-induced expression of inflammatory cytokine mRNA and protein. Significant reduction of organ specific tissue injury has been demonstrated in several organ systems in rodent models. Application of MnSOD-PL gene therapy in the setting of fractionated chemo-radiotherapy is being tested in clinical trials for prevention of esophagitis during treatment of non-small cell carcinoma of the lung, and in prevention of mucositis during combination therapy of carcinomas of the head and neck. Encouraging results in pre-clinical models suggest that radioprotective gene therapy may facilitate dose escalation protocols to allow increases in the therapeutic ratio of cancer radiotherapy. PMID:12762478

Greenberger, J S; Epperly, M W; Gretton, J; Jefferson, M; Nie, S; Bernarding, M; Kagan, V; Guo, H L

2003-06-01

19

Gene therapy in pancreatic cancer  

PubMed Central

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

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

2014-01-01

20

Gene therapy in heart disease  

Microsoft Academic Search

Application of gene therapy to the field of cardiovascular disorders has been the subject of intensive work over the recent period. Gene therapy for cardiovascular disorders is now fast developing with most therapies being devoted to the consequences (ischemia) rather than the causes of atherosclerotic diseases. Recent human clinical trials have shown that injection of naked DNA encoding vascular endothelial

E Teiger; I Deprez; V Fataccioli; S Champagne; J. L Dubois-Randé; M Eloit; S Adnot

2001-01-01

21

Gene and Stem Cell Therapy  

Microsoft Academic Search

Gene and stem cell therapy are being developed as novel treatments for cystic fibrosis (CF). In gene therapy, the therapeutic nucleic acid is delivered to terminally differentiated epithelial cells in the airways. While technically less demanding, this approach has the drawback that therapy must be continually re-administered because of target cell turnover. Direct airway administration is also faced with powerful

A. Boyd

2006-01-01

22

nanosheets for gene therapy  

NASA Astrophysics Data System (ADS)

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

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

2014-10-01

23

Saporin suicide gene therapy.  

PubMed

New genes useful in suicide gene therapy are those encoding toxins such as plant ribosome-inactivating proteins (RIPs), which can irreversibly block protein synthesis, triggering apoptotic cell death. Plasmids expressing a cytosolic saporin (SAP) gene from common soapwort (Saponaria officinalis) are generated by placing the region encoding the mature plant toxin under the control of strong viral promoters and may be placed under tumor-specific promoters. The ability of the resulting constructs to inhibit protein synthesis is tested in cultured tumor cells co-transfected with a luciferase reporter gene. SAP expression driven by the cytomegalovirus (CMV) promoter (pCI-SAP) demonstrates that only 10 ng ofplasmid DNA per 1.6 x 10(4) B16 melanoma cells drastically reduces luciferase reporter activity to 18% of that in control cells (1). Direct intratumoral injections are performed in an aggressive melanoma model. B16 melanoma-bearing mice injected with pCI-SAP complexed with lipofectamine or N-(2,3-dioleoyloxy-1-propyl) trimethylammonium methyl sulfate (DOTAP) show a noteworthy attenuation in tumor growth, and this effect is significantly augmented by repeated administrations of the DNA complexes. Here, we describe in detail this cost-effective and safe suicide gene approach. PMID:19565907

Zarovni, Natasa; Vago, Riccardo; Fabbrini, Maria Serena

2009-01-01

24

Advances in Preclinical Investigation of Prostate Cancer Gene Therapy  

E-print Network

Advances in Preclinical Investigation of Prostate Cancer Gene Therapy Marxa L Figueiredo1 efforts in the last decade have shown that adenoviral vector-based gene therapy is a promising approach vectors, therapy coupled to reporter gene imaging, and com- bined treatment modalities. In fact, the early

Cai, Long

25

Gene Therapy and Cardiovascular Diseases  

Microsoft Academic Search

Gene therapy is a promising new field in modern medicine and holds great potential for the treatment of cardiovascular diseases.\\u000a This chapter will discuss the principles and methods of gene-based therapy and the use of gene transfer in research and in\\u000a treatment of cardiovascular diseases.

Yi Chu; Neal L. Weintraub; Donald D. Heistad

26

MRI-guided gene therapy Xiaoming Yanga  

E-print Network

, such as magnetic res- onance imaging (MRI), ultrasound, nuclear medicine, and optical imaging, have been appliedMinireview MRI-guided gene therapy Xiaoming Yanga , Ergin Atalara,b,* a Department of Radiology online 19 April 2006 Edited by Horst Feldmann Abstract MRI has the ability to generate high

Atalar, Ergin

27

Gene therapy in heart failure.  

PubMed

The treatment of heart failure (HF) may be entering a new era with clinical trials currently assessing the value of gene therapy as a novel therapeutic strategy. If these trials demonstrate efficacy then a new avenue of potential treatments could become available to the clinicians treating HF. In principle, gene therapy allows us to directly target the underlying molecular abnormalities seen in the failing myocyte. In this review we discuss the fundamentals of gene therapy and the challenges of delivering it to patients with HF. The molecular abnormalities underlying HF are discussed along with potential targets for gene therapy, focusing on SERCA2a. We discuss the laboratory and early clinical evidence for the benefit of SERCA2a gene therapy in HF. Finally, we discuss the ongoing clinical trials of SERCA2a gene therapy and possible future directions for this treatment. (Circ J 2014; 78: 2577-2587). PMID:25327883

Hayward, Carl; Patel, Hitesh; Lyon, Alexander

2014-10-24

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

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

E-print Network

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

Buschmann, Michael

30

Retinal dystrophies and gene therapy.  

PubMed

Retinal dystrophies are inherited disorders of photoreceptor and retinal pigment epithelial function that may result in severe visual impairment. Advances in molecular genetics have helped identify many of the gene defects responsible, and progress in gene transfer technology has enabled therapeutic strategies to be developed and applied. The first human clinical trials of gene therapy for RPE65 associated retinal dystrophy have shown promising initial results and have helped prepare the way for further trials of gene therapy for inherited retinal disorders. The results of these trials will provide further insight into the safety and efficacy of gene therapy for a range of currently untreatable and debilitating eye disorders. PMID:22080959

Sundaram, Venki; Moore, Anthony T; Ali, Robin R; Bainbridge, James W

2012-05-01

31

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

Microsoft Academic Search

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

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

2004-01-01

32

Systemic Gene Delivery for Muscle Gene Therapy  

Microsoft Academic Search

\\u000a The muscular dystrophies (MDs) are a heterogeneous group of monogenetic disorders that affect striated muscles, often throughout\\u000a the body. A promising approach to treating the MDs is to use gene therapy to replace, repair, or modify expression of the\\u000a mutant gene. Accomplishing such a goal requires that gene expression cassettes, which comprise a gene regulatory element driving\\u000a expression of an

Dilip Garikipati; Jeffrey S. Chamberlain

33

What is Gene Therapy? Rafael Yez  

E-print Network

What is Gene Therapy? Rafael Yáñez rafael.yanez@rhul.ac.uk Rare Disease Day @ Royal Holloway 28th therapy strategies: "random" integration transgene transgene * #12;Gene Therapy successes;Gene therapy strategies: episomal vectors transgene transgene * #12;DNA repair #12;Gene therapy

Royal Holloway, University of London

34

Nanoparticles for Retinal Gene Therapy  

PubMed Central

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

Conley, Shannon M.; Naash, Muna I.

2010-01-01

35

Gene Silencing Therapy Against Cancer  

Microsoft Academic Search

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

Chao-Zhong Song

36

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. PMID:16457646

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

2009-01-01

37

Gene Therapy in Heart Failure  

PubMed Central

With increasing knowledge of basic molecular mechanisms governing the development of heart failure (HF), the possibility of specifically targeting key pathological players is evolving. Technology allowing for efficient in vivo transduction of myocardial tissue with long-term expression of a transgene enables translation of basic mechanistic knowledge into potential gene therapy approaches. Gene therapy in HF is in its infancy clinically with the predominant amount of experience being from animal models. Nevertheless, this challenging and promising field is gaining momentum as recent preclinical studies in larger animals have been carried out and, importantly, there are 2 newly initiated phase I clinical trials for HF gene therapy. To put it simply, 2 parameters are needed for achieving success with HF gene therapy: (1) clearly identified detrimental/beneficial molecular targets; and (2) the means to manipulate these targets at a molecular level in a sufficient number of cardiac cells. However, several obstacles do exist on our way to efficient and safe gene transfer to human myocardium. Some of these obstacles are discussed in this review; however, it primarily focuses on the molecular target systems that have been subjected to intense investigation over the last decade in an attempt to make gene therapy for human HF a reality. PMID:18566312

Vinge, Leif Erik; Raake, Philip W.; Koch, Walter J.

2008-01-01

38

Gene therapy for Fabry disease.  

PubMed

Fabry disease is an X-linked metabolic disorder caused by a deficiency of alpha-galactosidase A (alpha-Gal A). Lack of this lysosomal hydrolase results in the accumulation of galactose-terminal glycosphingolipids in a number of tissues, including vascular endothelial cells. Premature death is predominantly associated with vascular conditions of the heart, kidneys and brain. Historically, treatment has largely been palliative. Alternative treatments for many lysosomal storage diseases have been developed, including allogeneic organ and bone marrow transplantation, enzyme replacement therapy, and gene therapy. Significant clinical risks still exist with allogeneic transplantations. Alpha-Gal A enzyme replacement therapy has been implemented in clinical trials. This approach has been effective but may have limitations for long-term systemic or cost-effective correction. As an alternative, gene therapy approaches, involving a variety of gene delivery systems, have been pursued for the amelioration of Fabry disease. Fabry disease is a compelling disorder for gene therapy, as target cells are readily accessible and relatively low levels of enzyme correction may suffice to reduce storage. Importantly, metabolic cooperativity effects are also manifested in Fabry disease, wherein corrected cells secrete alpha-Gal A that can correct bystander cells. In addition, a broad therapeutic window probably exists, and mouse models of Fabry disease have been generated to assist studies. As an example, in vitro and in vivo studies using alpha-Gal A-transduced haematopoietic cells from Fabry mice have demonstrated enzymatic correction of recipient cells and dissemination of alpha-Gal A upon transplantation, leading to reduced lipid storage in a number of clinically relevant organs. This corrective enzymatic effect has recently been shown to be even further enhanced upon pre-selection of therapeutically transduced cells prior to transplantation. This review will briefly detail current gene delivery methods and summarize results to date in the context of gene therapy for Fabry disease. PMID:11758676

Siatskas, C; Medin, J A

2001-01-01

39

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. PMID:15466989

Selkirk, S

2004-01-01

40

Gene therapy for retinal disease  

PubMed Central

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

McClements, Michelle E; MacLaren, Robert E

2013-01-01

41

Gene therapy for ischemic heart disease  

Microsoft Academic Search

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

Madhav Lavu; Susheel Gundewar; David J. Lefer

2011-01-01

42

Gene therapy for diabetes  

Microsoft Academic Search

\\u000a Diabetes mellitus is a devastating disease and the World Health Organization expects that the number of diabetic patients\\u000a will increase to 300 million by the year 2025. Intensive glycemic control with insulin therapy to both Type 1 and Type 2 diabetic\\u000a patients can reduce the risk of diabetic complications, but also increase the incidence of hypoglycemia. Many studies have\\u000a shown

Hirofumi Noguchi

43

Adenoviral vectors for gene therapy  

Microsoft Academic Search

Vectors based on human adenovirus serotypes 2 (Ad2) and 5 (Ad5) of species C possess a number of features that have favored\\u000a their widespread employment for gene delivery both in?vitro and in?vivo. However, the use of recombinant Ad2- and Ad5-based\\u000a vectors for gene therapy also suffers from a number of disadvantages. These vectors possess the tropism of the parental viruses,

Joanne T. Douglas

2007-01-01

44

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

45

ADENOVIRAL GENE THERAPY FOR OVARIAN CANCER  

E-print Network

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

Hemminki, Akseli

46

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. PMID:22691036

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

2012-01-01

47

Gene therapy for carcinoma of the breast  

PubMed Central

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

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

2007-01-01

48

Gene Therapy in the Cornea: 2005-present  

PubMed Central

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

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

2011-01-01

49

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. PMID:23021246

Kaliberov, Sergey A.; Buchsbaum, Donald J.

2013-01-01

50

Gene Therapy Targeting HIV Entry  

PubMed Central

Despite the unquestionable success of antiretroviral therapy (ART) in the treatment of HIV infection, the cost, need for daily adherence, and HIV-associated morbidities that persist despite ART all underscore the need to develop a cure for HIV. The cure achieved following an allogeneic hematopoietic stem cell transplant (HSCT) using HIV-resistant cells, and more recently, the report of short-term but sustained, ART-free control of HIV replication following allogeneic HSCT, using HIV susceptible cells, have served to both reignite interest in HIV cure research, and suggest potential mechanisms for a cure. In this review, we highlight some of the obstacles facing HIV cure research today, and explore the roles of gene therapy targeting HIV entry, and allogeneic stem cell transplantation in the development of strategies to cure HIV infection. PMID:24662607

Didigu, Chuka; Doms, Robert

2014-01-01

51

Molecular Imaging and Targeted Therapies  

PubMed Central

Targeted therapeutic and imaging agents are becoming more prevalent, and are used to treat increasingly smaller segments of the patient population. This has lead to dramatic increases in the costs for clinical trials. Biomarkers have great potential to reduce the numbers of patients needed to test novel targeted agents by predicting or identifying non-response early-on and thus enriching the clinical trial population with patients more likely to respond. Biomarkers are characteristics that are objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers can be used to predict response to specific therapies, predict response regardless of therapy, or to monitor response once a therapy has begun. In terms of drug development, predictive biomarkers have the greatest impact, as they can be used as inclusion criteria for patient segmentation. Prognostic markers are used routinely in clinical practice but do not provide direction for the use of targeted therapies. Imaging biomarkers have distinct advantages over those that require a biopsy sample in that they are “non-invasive” and can be monitored longitudinally at multiple time points in the same patient. This review will examine the role of functional and molecular imaging in predicting response to specific therapies; will explore the advantages and disadvantages of targeting intracellular or extracellular markers; and will discuss the attributes of useful targets and methods for target identification and validation. PMID:20399197

Morse, David L.; Gillies, Robert J.

2010-01-01

52

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

PubMed Central

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

Wirth, Thomas

2011-01-01

53

Imaging Gene Expression in Live Cells and Tissues  

PubMed Central

Monitoring gene expression is crucial for studying the responses of gene therapy and clarifying the function of certain genes in various environments. Molecular imaging is a powerful tool for noninvasive visualization of gene expression. This chapter will summarize the current status of fluorescence and bioluminescence imaging (BLI) of gene expression in live cells and tissues, and the emphasis will be mainly on the early studies that pioneered the field. First, we will describe fluorescence imaging of gene expression with a wide variety of fluorescent proteins. Next, we will discuss the strategies for BLI of gene expression. Besides incorporating the reporter gene into the host DNA, mRNA-based BLI of gene expression will also be briefly mentioned. Lastly, the construction of dual and triple fusion reporter genes will be presented. Since no single imaging modality is perfect and sufficient to obtain all of the necessary information for a given question, a combination of multiple molecular imaging modalities can offer synergistic advantages over any modality alone. Noninvasive optical imaging of gene expression has revolutionized biomedical research and the progress made over the last decade should allow molecular imaging to play a major role in the field of gene therapy. For basic and preclinical research, optical imaging is certainly indispensable for imaging gene expression. However, for clinical imaging of gene expression, positron emission tomography (PET) holds the greatest promise. PMID:21460057

Hong, Hao; Yang, Yunan; Cai, Weibo

2014-01-01

54

Gene Therapy for ALI/ARDS  

PubMed Central

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by acute respiratory failure and are associated with diverse disorders, such as pulmonary edema, pneumonia, sepsis, trauma, shock and lung contusion. Gene therapy is a potentially powerful approach to treat a variety of diseases related to ALI/ARDS. Numerous viral and non-viral methods for gene delivery to the lung have been developed, although pulmonary architecture and immune activation represent barriers to successful gene transfer. In this review, recent advances in the development of more efficient viral and non-viral gene transfer systems are discussed. In addition, the current status of gene therapy applied to ALI/ARDS-associated pulmonary diseases is reviewed. With the development of more efficient gene therapy vectors, gene therapy is a promising strategy for clinical application in the not too distant future. PMID:21742224

Lin, Xin; Dean, David A

2012-01-01

55

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

56

Cellular Targeting for Cochlear Gene Therapy  

Microsoft Academic Search

Gene therapy has considerable potential for the treatment of disorders of the inner ear. Many forms of inherited hearing loss have now been linked to specific locations in the genome, and for many of these the genes and specific mutations involved have been identified. This information provides the basis for therapy based on genetic approaches. However, a major obstacle to

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

2009-01-01

57

Gene therapy--why can it fail?  

PubMed

The success of reductionism in medicine has enabled the experimental expression of individual genes in complex living systems. The promise of gene therapy, permanent reversal or amelioration of disease symptoms without dependence on a long-lasting intake of drugs, has come within reach because of these conceptual and technical advances in molecular biology. However, there have been setbacks posing serious questions for the medical community. The incidents came at a time when technical advances in the manipulation of DNA had led to wide-spread testing of gene based therapies. In fact, the major limiting factor of this approach had been perceived to be gene delivery rather than toxicity. Here we discuss the hypothesis that knowledge of DNA sequences for relevant genes alone will not be sufficient to allow this promise to come to fruition, unless additional factors are recognized and addressed. The physiologic consequences of gene expression depend on gene dosage, transcriptional regulation by promoters, posttranscriptional editing, and interdependence among gene products, all of which vary among cells. The success of gene therapy will depend, in part, on insight into the factors summarized here, very much like successful drug therapy has depended on an understanding of the manifold influences of pharmacokinetics and pharmacodynamics. In principle, these considerations apply to all transfections, gene disruptions, and transgenic approaches and to potential clinical applications derived from them. Gaining insight and control over those factors may allow gene therapy to live up to current expectations. PMID:23484673

Weber, Georg F

2013-05-01

58

Development of Biomaterials for Gene Therapy  

Microsoft Academic Search

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

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

2000-01-01

59

A dual function fusion protein of Herpes simplex virus type 1 thymidine kinase and firefly luciferase for noninvasive in vivo imaging of gene therapy in malignant glioma  

Microsoft Academic Search

BACKGROUND: Suicide gene therapy employing the prodrug activating system Herpes simplex virus type 1 thymidine kinase (HSV-TK)\\/ ganciclovir (GCV) has proven to be effective in killing experimental brain tumors. In contrast, glioma patients treated with HSV-TK\\/ GCV did not show significant treatment benefit, most likely due to insufficient transgene delivery to tumor cells. Therefore, this study aimed at developing a

Ariane Söling; Christian Theiß; Stephanie Jungmichel; Nikolai G Rainov

2004-01-01

60

Gene therapy in India: a focus.  

PubMed

Gene therapy refers to the treatment of genetic diseases using normal copies of the defective genes. It has the potential to cure any genetic disease with long-lasting therapeutic benefits. It remained an enigma for a long period of time, which was followed by a series of setbacks in the late 1990s. Gene therapy has re-emerged as a therapeutic option with reports of success from recent clinical studies. The United States and Europe has been pioneers in this field for over two decades. Recently, reports of gene therapy have started coming in from Asian countries like China, Japan and Korea. This review focuses on the current status of gene therapy in India. PMID:24845517

Chodisetty, Sarvani; Nelson, Everette Jacob Remington

2014-06-01

61

Advanced Imaging Applications to Cardiac Resynchronization Therapy  

E-print Network

of Medicine and Radiology Director of Advanced CV Imaging Dartmouth 4pm, Wed, Jan. 31, 2007 AuditoriumAdvanced Imaging Applications to Cardiac Resynchronization Therapy Justin D. Pearlman Professor of the Center for Imaging Science For Cardiac Resynchronization Therapy the goal is to identify where cardiac

Zanibbi, Richard

62

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

E-print Network

original article© The American Society of Gene & Cell Therapy Molecular Therapy 1 Cell was on using DNA to treat disease--so called gene therapy. According to the principles of gene therapy translation of gene therapy has been wrought with concerns over its safety and thus remains an elusive goal.1

Cheng, Jianjun

63

Autosomal dominant genes (image)  

MedlinePLUS

In the case of autosomal dominant genes, a single abnormal gene on one of the autosomal chromosomes (one of the first 22 "non-sex" chromosomes) from either parent can cause the disease. One of the parents ...

64

Human Studies of Angiogenic Gene Therapy  

PubMed Central

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

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

2009-01-01

65

Gene therapy for inherited retinal degenerations.  

PubMed

Gene therapy is quickly becoming a reality applicable in the clinic for inherited retinal diseases. Progress over the past decade has moved proof-of-concept gene therapies from bench to bedside. The remarkable success in safety and efficacy, in the phase I/II clinical trials for the form of the severe childhood-onset blindness, Leber's Congenital Amaurosis (LCA) type II (due to mutations in the RPE65 gene) generated significant interest and opened up possibilities for a new era of retinal gene therapies. Success in these clinical trials was due to combining the favorable features of both the retina as a target organ and adeno-associated virus (AAV) as a vector. The retina offers several advantages for gene therapy approaches. It is an anatomically defined structure that is readily accessible for therapy and has some degree of immune privilege, making it suitable for application of viral vectors. AAV, on the other hand, is a non-pathogenic helper dependent virus that has little immunogenicity. This viral vector transduces quiescent cells efficiently and thanks to its small size diffuses well in the interneural matrix, making it suitable for applications in neural tissue. Building on this initial clinical success with LCA II, we have now many opportunities to extend this proof-of-concept to other retinal diseases. This article will discuss what are some of the most imminent targets for such therapies and what are the challenges that we face in moving these therapies to the clinic. PMID:24702845

Dalkara, Deniz; Sahel, José-Alain

2014-03-01

66

Gene therapy for autoimmune diseases: quo vadis?  

Microsoft Academic Search

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

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

2004-01-01

67

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). PMID:24328708

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

2014-01-01

68

ORIGINAL ARTICLE Retinoschisin gene therapy in photoreceptors, Mller glia  

E-print Network

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

Schaffer, David V.

69

Replicative retroviral vectors for cancer gene therapy  

Microsoft Academic Search

Poor efficiency of gene transfer into cancer cells constitutes the major bottleneck of current cancer gene therapy. We reasoned that because tumors are masses of rapidly dividing cells, they would be most efficiently transduced with vector systems allowing transgene propagation. We thus designed two replicative retrovirus-derived vector systems: one inherently replicative vector, and one defective vector propagated by a helper

Sounkary K Solly; Stephane Trajcevski; Charlotte Frisén; Georg W Holzer; Elisabeth Nelson; Béatrice Clerc; Evelyn Abordo-Adesida; Maria Castro; Pedro Lowenstein; David Klatzmann

2003-01-01

70

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. PMID:8778459

McGleenan, T

1995-01-01

71

Novel Cell and Gene Therapies for HIV  

PubMed Central

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

Hoxie, James A.; June, Carl H.

2012-01-01

72

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

PubMed

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

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

2014-02-01

73

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.

74

[Image guided radiation therapy (IGRT)].  

PubMed

Image guided radiation therapy (IGRT) is a major technical innovation of radiotherapy. It allows locating the tumor under the linear accelerator just before the irradiation, by direct visualization (3D mode soft tissue) or indirect visualization (2D mode and radio-opaque markers). The technical implementation of IGRT is done by very different complex devices. The most common modality, because available in any new accelerator, is the cone beam CT. The main experiment of IGRT focuses on prostate cancer. Preliminary studies suggest the use of IGRT combined with IMRT should increase local control and decrease toxicity, especially rectal toxicity. In head and neck tumors, due to major deformation, a rigid registration is insufficient and replanning is necessary (adaptive radiotherapy). The onboard imaging delivers a specific dose, needed to be measured and taken into account, in order not to increase the risk of toxicity. Studies comparing different modalities of IGRT according to clinical and economic endpoints are ongoing; to better define the therapeutic indications. PMID:20581000

Lagrange, J-L; de Crevoisier, R

2010-07-01

75

Gene Therapy Shows Potential for 'Bubble Boy' Disease  

MedlinePLUS

... sharing features on this page, please enable JavaScript. Gene Therapy Shows Potential for 'Bubble Boy' Disease Newer ... 2015) Wednesday, October 8, 2014 Related MedlinePlus Pages Genes and Gene Therapy Immune System and Disorders WEDNESDAY, ...

76

Gene therapy legislation in The Netherlands.  

PubMed

Several regulatory organisations are involved in the assessment of clinical gene therapy trials involving genetically modified organisms (GMOs) in The Netherlands. Medical, ethical and scientific aspects are, for instance, evaluated by the Central Committee on Research Involving Human Subjects (CCMO). The Ministry of Housing, Spatial Planning and the Environment (VROM) is the competent authority for the environmental risk assessment according to the deliberate release Directive 2001/18/EC. A Gene Therapy Office has been established in order to streamline the different national review processes and to enable the official procedures to be completed as quickly as possible. Although the Gene Therapy Office improved the application process at the national level, there is a difference of opinion between the EU member states with respect to the EU Directive according to which gene therapy trials are assessed, that urges for harmonisation. This review summarises the gene therapy legislation in The Netherlands and in particular The Netherlands rationale to follow Directive 2001/18/EC for the environmental risk assessment. PMID:17721872

Bleijs, D A; Haenen, I T W C; Bergmans, J E N

2007-10-01

77

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. PMID:23358189

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

2013-01-01

78

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. PMID:23265411

Fukui, Hideto; Raphael, Yehoash

2012-01-01

79

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

E-print Network

Genetic Therapy for Duchenne Muscular Dystrophy: Viral Vectors and Micro-Gene Therapy Taeyoung Koo therapy? Use of viral vectors to deliver functional genes to muscle - Adeno associated viral vector (AAV 248 Microgene for dystrophin What is Gene therapy? Use of viral vectors to deliver functional genes

Royal Holloway, University of London

80

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

81

NIH modifies gene therapy research guidelines.  

PubMed

In response to public comments on the first draft of its "Points to Consider in the Design and Submission of Human Somatic-Cell Gene Therapy Protocols," the Working Group on Human Gene Therapy of the National Institutes of Health has issued a revised set of guidelines for researchers. This second draft spells out the need for public review of gene therapy protocols, the Working Group's willingness to review selected protocols before the completion of animal studies, and requirements for informed consent to long-term follow-up and to autopsy in the event of death. The document also expresses the Working Group's concern that researchers and the public be kept fully informed of the results of such studies. PMID:11643786

Levine, Carol

1985-06-01

82

Development of gene therapy for blood disorders.  

PubMed

The concept of introducing genes into human cells for therapeutic purposes developed nearly 50 years ago as diseases due to defects in specific genes were recognized. Development of recombinant DNA techniques in the 1970s and their application to the study of mouse tumor viruses facilitated the assembly of the first gene transfer vectors. Vectors of several different types have now been developed for specific applications and over the past decade, efficacy has been demonstrated in many animal models. Clinical trials began in 1989 and by 2002 there was unequivocal evidence that children with severe combined immunodeficiency could be cured by gene transfer into primitive hematopoietic cells. Emerging from these successful trials was the realization that proto-oncogene activation by retroviral integration could contribute to leukemia. Much current effort is focused on development of safer vectors. Successful gene therapy applications have also been developed for control of graft-versus-host disease and treatment of various viral infections, leukemias, and lymphomas. The hemophilias seem amenable to gene therapy intervention and informative clinical trials have been conducted. The hemoglobin disorders, an early target for gene therapy, have proved particularly challenging although ongoing research is yielding new information that may ultimately lead to successful clinical trials. PMID:18441245

Nienhuis, Arthur W

2008-05-01

83

Gene therapy for human hemoglobinopathies.  

PubMed

Gene transfer of human globin genes into human pluripotent stem cells via viral vectors may soon be realized. The high level of globin gene expression believed to be required for the treatment of severe hemoglobinopathies necessitated the inclusion of cis-acting sequences (LCR). Retroviral vectors containing the LCR elements are prone to rearrangement, low titer, and poor expression. Inclusion of a "minilocus" containing four HS sites linked to a globin gene resulted in higher expression in transplanted mice, but rearrangement of the provirus still occurs, and it is unclear what significance these experiments have with regard to human marrow stem cell transduction. Recombinant AAV is among the newest of genetic transfer vectors. This once obscure virus possesses unique properties that distinguish it from all other vectors. Its major advantage is the lack of pathogenicity in humans. Wild-type AAV has the unusual ability to selectively integrate into the mammalian genome at a specific region, thus reducing the concern for genomic disruption and insertional mutagenesis. The ability of AAV to carry regulatory elements without interference from the viral template may enable greater control of transferred gene expression. Disadvantages currently include the inferior packaging systems which yield low numbers of recombinant virions which are contaminated with wild-type adenovirus. The small AAV genome that can be packaged (approximately 5 kb) rules out its use for transfer of larger genes. Recombinant AAV viruses do not appear to demonstrate the same site-specific genomic integration as wild-type viruses. Elucidation of the mechanism of site-specific integration should prove useful in the development of safe vectors for gene transfer as well as provide insight into the nature of DNA recombination in humans. PMID:8234372

Walsh, C E; Liu, J M; Miller, J L; Nienhuis, A W; Samulski, R J

1993-12-01

84

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. PMID:23606894

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

2013-01-01

85

Gene Therapy Progress and Prospects: Fetal gene therapy – first proofs of concept – some adverse effects  

Microsoft Academic Search

Somatic gene delivery in utero is a novel approach to gene therapy for genetic disease based on the hypothesis that prenatal intervention may avoid the development of severe manifestations of early-onset disease, allow targeting of otherwise inaccessible tissues including expanding stem cell populations, induce tolerance against the therapeutic transgenic protein and thereby provide permanent somatic gene correction. This approach is

C Coutelle; M Themis; S N Waddington; S M K Buckley; L G Gregory; M S Nivsarkar; A L David; D Peebles; B Weisz; C Rodeck

2005-01-01

86

GENE THERAPY Comment on Ohlfest et al, page 2691  

E-print Network

GENE THERAPY Comment on Ohlfest et al, page 2691 An ounce of prevention potentiates a pound-lasting tolerance to hFVIII and allows gene therapy to be performed during adulthood with a Sleeping Beauty be a very important advance. Gene therapy for hemophilia A involves trans- fer of a FVIII gene into cells

Ponder, Katherine P.

87

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

E-print Network

CHAPTER 4 Vectors of Gene Therapy KATHERINE PARKER PONDER, M.D. INTRODUCTION Currently, gene therapy refers to the transfer of a gene that encodes a functional protein into a cell or the transfer that direct RNA processing such as polyadenylation. A second class of gene therapy involves altering

Ponder, Katherine P.

88

Nonviral Vector Systems for Cancer Gene Therapy  

Microsoft Academic Search

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

Greg F. Walker; Ernst Wagner

89

Combined E7-dendritic cell-based immunotherapy and human sodium/iodide symporter radioiodine gene therapy with monitoring of antitumor effects by bioluminescent imaging in a mouse model of uterine cervical cancer.  

PubMed

Using a uterine cervical cancer cell line expressing human papillomavirus (HPV) 16 E7 antigen and bioluminescent imaging (BLI), we evaluated the therapeutic potential of combined immunotherapy using transfected dendritic cells (DC-E7) and human sodium/iodide symporter (hNIS) radioiodine gene therapy in a xenograft animal cancer model. Dendritic cells expressing either E7 antigen (DC-E7) or no-insert (DC-no insert) were made for immunization materials, and murine uterine cervical cancer cell line coexpressing E7, firefly luciferase, hNIS, and EGFP genes (TC-1/FNG) were prepared for the animal tumor model. C57BL/6 mice were divided into five therapy groups (phosphate-buffered saline [PBS], DC-no insert, DC-E7, I-131, and DC-E7+I-131 groups). Single therapy with either DC-E7 or I-131 induced greater retardation in tumor growth compared with PBS or DC-no insert groups, and it resulted in some tumor-free mice (DC-E7 and I-131 groups, 40% and 20%, respectively). Combination therapy with DC-E7 and I-131 dramatically inhibited tumor growth, thus causing complete disappearance of tumors in all mice, and these effects were further confirmed by BLI in vivo. In conclusion, complete disappearance of the tumor was achieved with combined DC-E7 vaccination and hNIS radioiodine gene therapy in a mouse model with E7-expressing uterine cervical cancer, and serial BLIs successfully demonstrated antitumor effects in vivo. PMID:22091632

Jeon, Yong Hyun; Lee, Ho Won; Lee, You La; Kim, Jung Eun; Hwang, Mi-Hye; Jeong, Shin Young; Lee, Sang-Woo; Ahn, Byeong-Cheol; Ha, Jeoung-Hee; Lee, Jaetae

2011-12-01

90

[Gene therapy for inherited retinal dystrophies].  

PubMed

The inherited retinal dystrophies comprise a large number of disorders characterized by a slow and progressive retinal degeneration. They are the result of mutations in genes that express in either the photoreceptor cells or the retinal pigment epithelium. The mode of inheritance can be autosomal dominant, autosomal recessive, X linked recessive, digenic or mitochondrial DNA inherited. At the moment, there is no treatment for these conditions and the patients can expect a progressive loss of vision. Accurate genetic counseling and support for rehabilitation are indicated. Research into the molecular and genetic basis of disease is continually expanding and improving the prospects for rational treatments. In this way, gene therapy, defined as the introduction of exogenous genetic material into human cells for therapeutic purposes, may ultimately offer the greatest treatment for the inherited retinal dystrophies. The eye is an attractive target for gene therapy because of its accessibility, immune privilege and translucent media. A number of retinal diseases affecting the eye have known gene defects. Besides, there is a well characterized animal model for many of these conditions. Proposals for clinical trials of gene therapy for inherited retinal degenerations owing to defects in the gene RPE65, have recently received ethical approval and the obtained preliminary results brought large prospects in the improvement on patient's quality of life. PMID:19820803

Côco, Monique; Han, Sang Won; Sallum, Juliana Maria Ferraz

2009-01-01

91

Advances in Ultrasound Mediated Gene Therapy Using Microbubble Contrast Agents  

PubMed Central

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

Sirsi, Shashank R.; Borden, Mark A.

2012-01-01

92

Imaging Tri-Fusion Multimodality Reporter Gene Expression in Living Subjects  

Microsoft Academic Search

Imaging reporter gene expression in living subjects with various imag- ing modalities is a rapidly accelerating area of research. Applications of these technologies to cancer research, gene therapy, and transgenic mod- els are rapidly expanding. We report construction and testing of several triple fusion reporter genes compatible with bioluminescence, fluores- cence and positron emission tomography (PET) imaging. A triple fusion

Pritha Ray; Abhijit De; Jung-Jun Min; Roger Y. Tsien; Sanjiv S. Gambhir

2004-01-01

93

Development of a percutaneous optical imaging system for tracking vascular gene expression: a feasibility study using human tissuelike phantoms  

Microsoft Academic Search

Noninvasive tracking of vascular gene delivery and expression forms an important part of successfully implementing vascular gene therapy methods for the treatment of atherosclerosis and various cardiovascular disorders. While ultrasound and MR imaging have shown promise in the monitoring of gene delivery to the vasculatures, optical imaging has shown promise for tracking gene expression. Optical imaging using bioreporter genes like

Sourav K. Kar; Ananda Kumar; Xiaoming Yang

2004-01-01

94

Foamy Virus Vectors for HIV Gene Therapy  

PubMed Central

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

Olszko, Miles E.; Trobridge, Grant D.

2013-01-01

95

The Dangerous Promise of Gene Therapy  

NSDL National Science Digital Library

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

Sophia Kolehmainen (Council for Responsible Genetics;)

2000-02-01

96

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. PMID:21453286

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

2011-01-01

97

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. PMID:16457645

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

2006-01-01

98

Cancer imaging and therapy with metal nanoparticles.  

PubMed

Nanotechnology offers unique opportunities for cancer detection, therapy and the ability to monitor therapeutic interventions. This potential has to be analyzed in context of challenges that need to be overcome in translation of nanoparticles to clinical applications including specific delivery in tissues and clearance from the body. Here, we will present a case study of plasmonic nanoparticles in cancer imaging and therapy. PMID:19964034

Sokolov, Konstantin; Tam, Jasmine; Tam, Justina; Travis, Kort; Larson, Tim; Aaron, Jesse; Harrison, Nathan; Emelianov, Stanislav; Johnston, Keith

2009-01-01

99

Legal regulation of human gene therapy.  

PubMed

The adequacy of existing legal mechanisms to regulate clinical trials of human gene therapy is examined. Existing legal controls include the federal Guidelines for Research Involving Recombinant DNA Molecules and federal regulations for the protection of human subjects. Another significant mechanism is provided by judicial oversight, i.e., judicial decisions involving recombinant DNA research. Human gene therapy does raise new issues that still must be resolved. At least two weaknesses exist in the present regulatory system: first, Recombinant DNA Advisory Committee (RAC) only has authority over federally funded research, not work done with private support, and second, RAC is not mandated to focus on difficult ethical issues, e.g., germ-line therapy, that arise from human genetic engineering technology. PMID:2078576

Areen, J; King, P

1990-01-01

100

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

E-print Network

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

Schaffer, David V.

101

Identity and the ethics of gene therapy.  

PubMed

Some conditions detrimental to human well-being, such as sickle-cell anaemia, cystic fibrosis, muscular dystrophy, Lesch-Nyhan disease and various immunodeficiencies, are genetically determined. One potential means of preventing the development of such conditions is the manipulation of genetic material in the conceptus of an organism which would otherwise develop such conditions. Genetic manipulations could take the form either of excising and substituting genetic material, excising but not substituting genetic material, adding but not excising genetic material or reorganizing existing genetic material. To succeed, manipulation would have to change genetic structure so as to change its informational content. It might be thought, however, that all or some such manipulations would involve causing particular individuals to cease to exist and involve bringing into existence new, distinct individuals. Gene therapy could not, therefore, be a procedure which improved the circumstances of the particular individual to whom it is applied. It might be suggested that once the metaphysics of identity and the facts of gene therapy are understood, certain interesting conclusions concerning the ethics of gene therapy emerge. Some such conclusions have been discussed in this journal by Noam J. Zohar and Jeffrey P. Kahn. More, however, needs to be said about them since neither Zohar nor Kahn draws the correct conclusions. While both have pertinent things to say, neither has given a completely clear account of the metaphysics of gene therapy and so neither has completely traced out the implication of the metaphysics for the ethics of gene therapy. This paper attempts to remedy these defects. PMID:11654027

Elliot, Robert

1993-01-01

102

Method for gene therapy involving suppression of an immune response  

US Patent & Trademark Office Database

A method for specifically suppressing the capacity of a mammal receiving gene therapy to mount an immune response to a given expressed gene of the deficient gene in question, which response is caused by the administration of "foreign" DNA encoding an antigenic protein or vectors comprising such DNA for expression of the deficient gene in the patient receiving gene therapy.

2000-07-25

103

Methods to improve cardiac gene therapy expression.  

PubMed

Gene therapy strategies are becoming a valuable approach for the treatment of heart failure. Some trials are ongoing and others are being organized. Vascular access in clinical experimentation is still the chosen modality of delivery, but many other approaches are in research and development. A successful gene therapy strategy involves not only the choice of the right vector and gene, but also the correct delivery strategy that allows for transduction of the highest percentage of cardiomyocytes, limited spilling of virus into other organs and the possibility to correlate the amount of injected virus to the rate of the expression within the cardiac tissue. The authors will first concentrate on clarifying what the barriers are that the virus has to overcome in order to reach the nuclei of the target organs and methodologies that have been tested to improve the range of expression. PMID:25340284

Scimia, Maria Cecilia; Sydnes, Kate E; Zuppo, Daniel A; Koch, Walter J

2014-11-01

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. PMID:12721516

2003-01-01

105

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. PMID:22337437

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

2011-01-01

106

Proton Therapy Verification with PET Imaging  

PubMed Central

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; Fakhri, Georges El

2013-01-01

107

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

E-print Network

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

Sun, Yu

108

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

109

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. PMID:22429662

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

2013-01-01

110

Gene Therapy Applications to Cancer Treatment  

PubMed Central

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

2003-01-01

111

2003 Freund Publishing House Ltd. 77 PROSPECTS FOR GENE THERAPY  

E-print Network

© 2003 Freund Publishing House Ltd. 77 PROSPECTS FOR GENE THERAPY IN HEARING LOSS Karen B. Avraham1 development /1/. Here, we cover the latest advances in gene therapy for alleviating or preventing hearing loss, cochlea, hair cells, Math1, retroviruses, adenoviruses INTRODUCTION Gene therapy is a technology based

Avraham, Karen

112

Gene Therapy for Protein C Deficiency 2831 J. Clin. Invest.  

E-print Network

Gene Therapy for Protein C Deficiency 2831 J. Clin. Invest. © The American Society for Clinical://www.jci.org Therapeutic Levels of Human Protein C in Rats after Retroviral Vector-mediated Hepatic Gene Therapy Shi that would prevent purpura fulminans, and that hepatic gene therapy might become a viable treatment

Ponder, Katherine P.

113

MINI REVIEW MODIFIED ADENOVIRUSES FOR CANCER GENE THERAPY  

E-print Network

MINI REVIEW MODIFIED ADENOVIRUSES FOR CANCER GENE THERAPY Anna KANERVA 1­3 and Akseli HEMMINKI 1,2 * 1 Cancer Gene Therapy Group, Rational Drug Design, Biomedicum Helsinki, University of Helsinki of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland Adenoviral gene therapy

Hemminki, Akseli

114

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

E-print Network

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

Hemminki, Akseli

115

The American Society of Gene Therapy original article  

E-print Network

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

Cai, Long

116

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

117

Is cancer gene therapy an empty suit?  

PubMed Central

Gene therapy as a treatment for cancer is regarded as high in promise, but low in delivery, a deficiency that has become more obvious with ever-increasing reports of the successful correction of monogenic disorders by this approach. We review the commercial and scientific obstacles that have led to these delays and describe how they are progressively being overcome. Recent and striking successes and correspondingly increased commercial involvement suggest that gene transfer could finally become a powerful method for development of safe and effective cancer therapeutic drugs. PMID:24079872

Brenner, Malcolm K; Gottschalk, Stephen; Leen, Ann M; Vera, Juan F

2014-01-01

118

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. PMID:23353080

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

2013-01-01

119

Gene therapy: prospects for glycolipid storage diseases.  

PubMed Central

Lysosomal storage diseases comprise a group of about 40 disorders, which in most cases are due to the deficiency of a lysosomal enzyme. Since lysosomal enzymes are involved in the degradation of various compounds, the diseases can be further subdivided according to which pathway is affected. Thus, enzyme deficiencies in the degradation pathway of glycosaminoglycans cause mucopolysaccharidosis, and deficiencies affecting glycopeptides cause glycoproteinosis. In glycolipid storage diseases enzymes are deficient that are involved in the degradation of sphingolipids. Mouse models are available for most of these diseases, and some of these mouse models have been used to study the applicability of in vivo gene therapy. We review the rationale for gene therapy in lysosomal disorders and present data, in particular, about trials in an animal model of metachromatic leukodystrophy. The data of these trials are compared with those obtained with animal models of other lysosomal diseases. PMID:12803926

Gieselmann, Volkmar; Matzner, Ulrich; Klein, Diana; Mansson, Jan Eric; D'Hooge, Rudi; DeDeyn, Peter D; Lullmann Rauch, Renate; Hartmann, Dieter; Harzer, Klaus

2003-01-01

120

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

121

[Gene therapy--current status and outlook].  

PubMed

None of the human gene transfer studies to date has shown definitive proof of clinical efficacy, despite more than 100 clinical protocols involving nearly 600 patients. In spite of the lack of positive results, tremendous hope permeates the field, biotechnology companies are getting started and raising millions of dollars from venture capital, and patients all over the world are agreeing to enroll in protocols involving this technology. Critics of the field claim that gene therapy has been overemphasized by researchers in academia, government and industry and by the scientific and popular media. Supporters of the field argue that the state of gene therapy is no different than other experimental therapies in its early stages. During the early stages of chemotherapy, agents were tested on hundreds of patients, often with a similar level of hope and no clinical effects. Despite the many controversies, one issue is shared by both groups: all of them recognize the tremendous potential of this technology to have an impact on human disease and share hope for long-term results. PMID:9011429

Hantzopoulos, P A; Gänsbacher, B

1996-10-01

122

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

E-print Network

original article© The American Society of Gene & Cell Therapy Molecular Therapy 1 publication 16 November 2010. doi:10.1038/mt.2010.249 IntroductIon The ultimate goal of gene therapy (IDUA) gene resulting in inactivation of the IDUA enzyme. The loss of IDUA protein results

Ford, James

123

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. PMID:18313477

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

2009-01-01

124

Gene therapy for Stargardt disease associated with ABCA4 gene.  

PubMed

Mutations in the photoreceptor-specific flippase ABCA4 lead to accumulation of the toxic bisretinoid A2E, resulting in atrophy of the retinal pigment epithelium (RPE) and death of the photoreceptor cells. Many blinding diseases are associated with these mutations including Stargardt's disease (STGD1), cone-rod dystrophy, retinitis pigmentosa (RP), and increased susceptibility to age-related macular degeneration. There are no curative treatments for any of these dsystrophies. While the monogenic nature of many of these conditions makes them amenable to treatment with gene therapy, the ABCA4 cDNA is 6.8 kb and is thus too large for the AAV vectors which have been most successful for other ocular genes. Here we review approaches to ABCA4 gene therapy including treatment with novel AAV vectors, lentiviral vectors, and non-viral compacted DNA nanoparticles. Lentiviral and compacted DNA nanoparticles in particular have a large capacity and have been successful in improving disease phenotypes in the Abca4 (-/-) murine model. Excitingly, two Phase I/IIa clinical trials are underway to treat patients with ABCA4-associated Startgardt's disease (STGD1). As a result of the development of these novel technologies, effective therapies for ABCA4-associated diseases may finally be within reach. PMID:24664763

Han, Zongchao; Conley, Shannon M; Naash, Muna I

2014-01-01

125

Preselective gene therapy for Fabry disease  

PubMed Central

Fabry disease is a lipid storage disorder resulting from mutations in the gene encoding the enzyme ?-galactosidase A (?-gal A; EC 3.2.1.22). We previously have demonstrated long-term ?-gal A enzyme correction and lipid reduction mediated by therapeutic ex vivo transduction and transplantation of hematopoietic cells in a mouse model of Fabry disease. We now report marked improvement in the efficiency of this gene-therapy approach. For this study we used a novel bicistronic retroviral vector that engineers expression of both the therapeutic ?-gal A gene and the human IL-2R? chain (huCD25) gene as a selectable marker. Coexpression of huCD25 allowed selective immunoenrichment (preselection) of a variety of transduced human and murine cells, resulting in enhanced intracellular and secreted ?-gal A enzyme activities. Of particular significance for clinical applicability, mobilized CD34+ peripheral blood hematopoietic stem/progenitor cells from Fabry patients have low-background huCD25 expression and could be enriched effectively after ex vivo transduction, resulting in increased ?-gal A activity. We evaluated effects of preselection in the mouse model of Fabry disease. Preselection of transduced Fabry mouse bone marrow cells elevated the level of multilineage gene-corrected hematopoietic cells in the circulation of transplanted animals and improved in vivo enzymatic activity levels in plasma and organs for more than 6 months after both primary and secondary transplantation. These studies demonstrate the potential of using a huCD25-based preselection strategy to enhance the clinical utility of ex vivo hematopoietic stem/progenitor cell gene therapy of Fabry disease and other disorders. PMID:11248095

Qin, Gangjian; Takenaka, Toshihiro; Telsch, Kimberly; Kelley, Leslie; Howard, Tazuko; Levade, Thierry; Deans, Robert; Howard, Bruce H.; Malech, Harry L.; Brady, Roscoe O.; Medin, Jeffrey A.

2001-01-01

126

Preselective gene therapy for Fabry disease.  

PubMed

Fabry disease is a lipid storage disorder resulting from mutations in the gene encoding the enzyme alpha-galactosidase A (alpha-gal A; EC ). We previously have demonstrated long-term alpha-gal A enzyme correction and lipid reduction mediated by therapeutic ex vivo transduction and transplantation of hematopoietic cells in a mouse model of Fabry disease. We now report marked improvement in the efficiency of this gene-therapy approach. For this study we used a novel bicistronic retroviral vector that engineers expression of both the therapeutic alpha-gal A gene and the human IL-2Ralpha chain (huCD25) gene as a selectable marker. Coexpression of huCD25 allowed selective immunoenrichment (preselection) of a variety of transduced human and murine cells, resulting in enhanced intracellular and secreted alpha-gal A enzyme activities. Of particular significance for clinical applicability, mobilized CD34(+) peripheral blood hematopoietic stem/progenitor cells from Fabry patients have low-background huCD25 expression and could be enriched effectively after ex vivo transduction, resulting in increased alpha-gal A activity. We evaluated effects of preselection in the mouse model of Fabry disease. Preselection of transduced Fabry mouse bone marrow cells elevated the level of multilineage gene-corrected hematopoietic cells in the circulation of transplanted animals and improved in vivo enzymatic activity levels in plasma and organs for more than 6 months after both primary and secondary transplantation. These studies demonstrate the potential of using a huCD25-based preselection strategy to enhance the clinical utility of ex vivo hematopoietic stem/progenitor cell gene therapy of Fabry disease and other disorders. PMID:11248095

Qin, G; Takenaka, T; Telsch, K; Kelley, L; Howard, T; Levade, T; Deans, R; Howard, B H; Malech, H L; Brady, R O; Medin, J A

2001-03-13

127

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

PubMed Central

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

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

2013-01-01

128

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

Microsoft Academic Search

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

Sourav Kar; Ananda Kumar; Xiaoming Yang

2004-01-01

129

Nanoparticle-mediated p53 gene therapy for tumor inhibition  

PubMed Central

The p53 tumor suppressor gene is mutated in 50% of human cancers, resulting in more aggressive disease with greater resistance to chemotherapy and radiation therapy. Advances in gene therapy technologies offer a promising approach to restoring p53 function. We have developed polymeric nanoparticles (NPs), based on poly (lactic-co-glycolic acid), that provide sustained intracellular delivery of plasmid DNA, resulting in sustained gene expression without vector-associated toxicity. Our previous studies with p53 gene-loaded NPs (p53NPs) demonstrated sustained antiproliferative effects in cancer cells in vitro. The objective of this study was to evaluate the efficacy of p53NPs in vivo. Tumor xenografts in mice were established with human p53-null prostate cancer cells. Animals were treated with p53NPs by either local (intratumoral injection) or systemic (intravenous) administration. Controls included saline, p53 DNA alone, and control NPs. Mice treated with local injections of p53NPs demonstrated significant tumor inhibition and improved animal survival compared with controls. Tumor inhibition corresponded to sustained and greater p53 gene and protein expression in tumors treated with p53NPs than with p53 DNA alone. A single intravenous dose of p53NPs was successful in reducing tumor growth and improving animal survival, although not to the same extent as with local injections. Imaging studies showed that NPs accumulate in tumor tissue after intravenous injection; however, further improvement in tumor targeting efficiency of p53NPs may be needed for better outcome. In conclusion, the NP-mediated p53 gene therapy is effective in tumor growth inhibition. NPs may be developed as nonviral vectors for cancer and other genetic diseases. PMID:22553503

Sharma, Blanka; Ma, Wenxue; Adjei, Isaac Morris; Panyam, Jayanth; Dimitrijevic, Sanja

2012-01-01

130

Revertant mosaicism in skin: natural gene therapy  

PubMed Central

Revertant mosaicism is a naturally occurring phenomenon involving spontaneous correction of a pathogenic mutation in a somatic cell. Recent studies suggest that it is not a rare event and that it could be clinically relevant to phenotypic expression and patient treatment. Indeed, revertant cell therapy represents a potential “natural gene therapy” because in vivo reversion obviates the need for further genetic correction. Revertant mosaicism has been observed in several inherited conditions, including epidermolysis bullosa, a heterogeneous group of blistering skin disorders. These diseases provide a useful model for studying revertant mosaicism because of the visual and accessible nature of skin. This overview highlights the latest developments in revertant mosaicism and the translational implications germane to heritable skin disorders. PMID:21195026

Lai-Cheong, Joey E.; McGrath, John A.; Uitto, Jouni

2011-01-01

131

Corneal Gene Therapy: Basic Science and Translational Perspective  

PubMed Central

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

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

2013-01-01

132

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

133

Passive imaging technology in aphasia therapy.  

PubMed

We describe a brief pilot study undertaken to investigate the potential benefit(s) of using a SenseCam in aphasia therapy. Five post-stroke persons with aphasia and their caregivers agreed to participate. Each person with aphasia wore the SenseCam for 1 day during the daytime. Slide shows and printed images were created from the images obtained and presented at a (videotaped) weekly group conversation session. Therapists' observations, reflections, and opinions were subsequently elicited in a group interview and online survey. Wearable, sensor-triggered automatic imaging devices offer potential advantages over both conventional cameras and generic pictures when used in aphasia therapy. We identified three advantages of a SenseCam over conventional imaging methods: Images can be acquired without the presence of the researcher, no action is required by the wearer for image acquisition and the continuous point of view is that of the wearer. Acquired images are of personal relevance to the wearer and may have greater efficacy for the person with aphasia in aiding conversation, and for the speech language therapist in setting functional language goals. PMID:21391108

Burke, Kiernan; Franklin, Sue; Gowan, Olive

2011-10-01

134

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. PMID:23077406

Rossmiller, Brian; Mao, Haoyu

2012-01-01

135

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

E-print Network

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

Utah, University of

136

review The American Society of Gene Therapy Molecular Therapy vol. 17 no. 7, 11251135 july 2009 1125  

E-print Network

review© The American Society of Gene Therapy Molecular Therapy vol. 17 no. 7, 1125­1135 july 2009, a direct, targeted attack or via gene therapy in which foreign genes are expressed therapeutically and release infectious virus. In gene therapy, expression of therapeu- tic foreign gene products either

Cai, Long

137

Interactive level set segmentation for image-guided therapy  

E-print Network

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

Kiryati, Nahum

138

Combined Multimodal Optical Imaging and Targeted Gene Silencing Using Stimuli-Transforming Nanotheragnostics  

E-print Network

optical imaging and gene therapy. Optical coherence tomography (OCT) that utilizes a low coherence light 21, 2010; E-mail: kwonyj@uci.edu Abstract: Combined diagnosis and therapy for cancer has been uptake and transfection (stimuli-enhanced therapy). In this study, the feasibility of achieving combined

Chen, Zhongping

139

Quantum Dot-Aptamer Conjugates for Synchronous Cancer Imaging, Therapy,  

E-print Network

Quantum Dot-Aptamer Conjugates for Synchronous Cancer Imaging, Therapy, and Sensing of Drug imaging, therapy, and sensing system. By functionalizing the surface of fluorescent QD with the A10 RNA the specificity and sensitivity of this nanoparticle conjugate as a cancer imaging, therapy and sensing system

Zhang, Liangfang

140

Predicting gene function from images of cells  

E-print Network

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

Jones, Thouis Raymond, 1971-

2007-01-01

141

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

Microsoft Academic Search

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

Shyam Goverdhana; Mariana Puntel; Weidong Xiong; Jeffrey Zirger; Carlos Barcia; James Curtin; Eric Soffer; Sonali Mondkar; Gwendalyn King; Jinwei Hu; S. A. Sciascia; M. Candolfi; D. S. Greengold; P. R. Lowenstein; M. G. Castro

2005-01-01

142

Imaging Cell Therapy for Myocardial Regeneration  

PubMed Central

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

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

2012-01-01

143

The companions: regulatory T cells and gene therapy  

PubMed Central

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

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

2009-01-01

144

Image-guided radiation therapy: Physician's perspectives  

PubMed Central

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

Gupta, T.; Narayan, C. Anand

2012-01-01

145

Prospectives for Gene Therapy of Retinal Degenerations  

PubMed Central

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

2012-01-01

146

Gene therapy progress and prospects cancer: oncolytic viruses  

E-print Network

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

Cai, Long

147

Longitudinal, multimodal functional imaging of microvascular response to photothermal therapy  

PubMed Central

Although studies have shown that photothermal therapy can coagulate selectively abnormal vasculature, the ability of this method to achieve consistent, complete removal of the vasculature is questionable. We present the use of multimodal, wide-field functional imaging to study, in greater detail, the biological response to selective laser injury. Specifically, a single-platform instrument capable of coregistered fluorescence imaging and laser speckle imaging was utilized to monitor vascular endothelial growth factor gene expression and blood flow, respectively, in a transgenic rodent model. Collectively, the longitudinal, in vivo data collected with our instrument suggest that the biological response to selective laser injury involves early-stage redistribution of blood flow, followed by increased vascular endothelial growth factor promoter activity to stimulate pro-angiogenic events. PMID:20890338

Bui, Albert K.; Teves, Kathleen M.; Indrawan, Elmer; Jia, Wangcun; Choi, Bernard

2012-01-01

148

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

149

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. PMID:24751795

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

2014-01-01

150

Gene therapy progress and prospects: Duchenne muscular dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder affecting 1\\/3500 male births. There is currently no effective treatment, but gene therapy approaches are offering viable avenues for treatment development. The last 10 years have seen the development of a number of strategies and tools for muscle gene therapy. However, the major hurdle has been the inability to deliver

K Foster; H Foster; J G Dickson

2006-01-01

151

Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs  

E-print Network

to those in the RV-treated animals. This is the first successful application of gene therapy in preventingTherapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs Katherine Parker Ponder of age with a retroviral vector (RV) expressing canine -glucuronidase (cGUSB). Five animals received RV

Ponder, Katherine P.

152

Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy  

E-print Network

Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy Timothy K. Lua, there is a pressing need for new antibacterial therapies that can be readily designed and implemented. In this work, we engineered bacteriophage to overexpress proteins and attack gene networks that are not directly

Collins, James J.

153

In Utero gene therapy: current challenges and perspectives  

Microsoft Academic Search

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

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

2005-01-01

154

Diagnostic Imaging for Dental Implant Therapy  

PubMed Central

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

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

2014-01-01

155

A snapshot of gene therapy in Latin America.  

PubMed

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

Linden, Rafael; Matte, Ursula

2014-03-01

156

Genes on Trial: An Evaluation of Gene Therapy in Print Media  

Microsoft Academic Search

The controversial field of gene therapy has faced much scrutiny in the media over the last two decades. After scientists determined the structure and function of DNA in the mid 20th century, three molecular biology techniques, sequencing, recombinant DNA and the polymerase chain reaction, set the stage for gene therapy. The goal of the therapy is to replace a person’s

Hana L Haver

2011-01-01

157

Gene therapy for cardiovascular disease mediated by ultrasound and microbubbles  

PubMed Central

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

2013-01-01

158

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

2012-03-01

159

Muscular Dystrophy Gene Therapy in Small Animal Models  

Microsoft Academic Search

\\u000a Muscular dystrophies are inherited neuromuscular disorders characterized by progressive muscle loss and weakness. The morbidity\\u000a and fatality associated with the diseases and a lack of effective treatment have prompted urgent search for novel therapeutics.\\u000a Gene therapy is one of the frontiers. Currently, adeno-associated viral (AAV) vector-mediated gene transfer offers a powerful\\u000a tool for muscular dystrophy gene therapy for both skeletal

Chunping Qiao; Xiao Xiao

160

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

161

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. PMID:23678451

Barar, Jaleh; Omidi, Yadollah

2012-01-01

162

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. PMID:21718180

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

2011-01-01

163

Hematopoietic stem cell gene therapy: progress toward therapeutic targets  

Microsoft Academic Search

The concept of hematopoietic stem cell gene therapy is as exciting as that of stem cell transplantation itself. The past 20 years of research have led to improved techniques for transferring and expressing genes in hematopoietic stem cells and preclinical models now routinely indicate the ease with which new genes can be expressed in repopulating stem cells of multiple species.

J L Vollweiler; S P Zielske; J S Reese; S L Gerson

2003-01-01

164

Cerenkov Luminescence Imaging (CLI) for Cancer Therapy Monitoring  

PubMed Central

In molecular imaging, positron emission tomography (PET) and optical imaging (OI) are two of the most important and thus most widely used modalities1-3. 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)4-6. 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 medium7,8. 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 18F decay was estimated to produce an average of 3 photons in water5. 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 others4,5,9,10,11. 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 study12. 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 inhibitor13,14. 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

165

Trojan horse at cellular level for tumor gene therapies.  

PubMed

Among innovative strategies developed for cancer treatments, gene therapies stand of great interest despite their well-known limitations in targeting, delivery, toxicity or stability. The success of any given gene-therapy is highly dependent on the carrier efficiency. New approaches are often revisiting the mythic trojan horse concept to carry therapeutic nucleic acid, i.e. DNAs, RNAs or small interfering RNAs, to pathologic tumor site. Recent investigations are focusing on engineering carrying modalities to overtake the above limitations bringing new promise to cancer patients. This review describes recent advances and perspectives for gene therapies devoted to tumor treatment, taking advantage of available knowledge in biotechnology and medicine. PMID:23542073

Collet, Guillaume; Grillon, Catherine; Nadim, Mahdi; Kieda, Claudine

2013-08-10

166

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

E-print Network

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

Cai, Long

167

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

E-print Network

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

Tian, Weidong

168

Development and Assessment of Gene Therapies for  

E-print Network

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

Kolstad, Kathleen Durgin

2009-01-01

169

Gene therapy: Recombinant adeno-associated virus vectors  

Microsoft Academic Search

Gene transfer using recombinant adeno-associated virus (rAAV) vectors shows great promise for human gene therapy. The broad\\u000a host range, low level of immune response, and longevity of gene expression observed with these vectors in numerous disease\\u000a paradigms has enabled the initiation of a number of clinical trials using this gene delivery system. This review presents\\u000a an overview of the current

Joseph R. Smith-Arica; Jeffrey S. Bartlett

2001-01-01

170

Genetic correction using engineered nucleases for gene therapy applications.  

PubMed

Genetic mutations in humans are associated with congenital disorders and phenotypic traits. Gene therapy holds the promise to cure such genetic disorders, although it has suffered from several technical limitations for decades. Recent progress in gene editing technology using tailor-made nucleases, such as meganucleases (MNs), zinc finger nucleases (ZFNs), TAL effector nucleases (TALENs) and, more recently, CRISPR/Cas9, has significantly broadened our ability to precisely modify target sites in the human genome. In this review, we summarize recent progress in gene correction approaches of the human genome, with a particular emphasis on the clinical applications of gene therapy. PMID:24329887

Li, Hongmei Lisa; Nakano, Takao; Hotta, Akitsu

2014-01-01

171

The use of genes for performance enhancement: doping or therapy?  

PubMed

Recent biotechnological advances have permitted the manipulation of genetic sequences to treat several diseases in a process called gene therapy. However, the advance of gene therapy has opened the door to the possibility of using genetic manipulation (GM) to enhance athletic performance. In such 'gene doping', exogenous genetic sequences are inserted into a specific tissue, altering cellular gene activity or leading to the expression of a protein product. The exogenous genes most likely to be utilized for gene doping include erythropoietin (EPO), vascular endothelial growth factor (VEGF), insulin-like growth factor type 1 (IGF-1), myostatin antagonists, and endorphin. However, many other genes could also be used, such as those involved in glucose metabolic pathways. Because gene doping would be very difficult to detect, it is inherently very attractive for those involved in sports who are prepared to cheat. Moreover, the field of gene therapy is constantly and rapidly progressing, and this is likely to generate many new possibilities for gene doping. Thus, as part of the general fight against all forms of doping, it will be necessary to develop and continually improve means of detecting exogenous gene sequences (or their products) in athletes. Nevertheless, some bioethicists have argued for a liberal approach to gene doping. PMID:22030863

Oliveira, R S; Collares, T F; Smith, K R; Collares, T V; Seixas, F K

2011-12-01

172

Prospects for gene therapy of inherited retinal disease.  

PubMed

Gene-based therapies offer the means to address gene defects responsible for inherited retinal disorders. A number of studies in experimental and preclinical models have demonstrated proof-of-principle that gene replacement therapy can mediate significant quantifiable improvements in ocular morphology and visual function. The first results of clinical trials of gene therapy for early-onset severe retinal dystrophy caused by defects in RPE65 show proof-of-concept for efficacy and short-term safety in humans. The challenges for gene therapy of conditions caused by gain-of-abnormal function are being addressed by strategies to knock down expression of the disease allele. Vector-mediated expression of neuroprotective proteins may offer a generic approach for preserving vision in single-gene and multi-gene retinal degenerations. Gene therapy is likely to be most successful where stable expression of the therapeutic transgene can be achieved at an appropriate level in diseases in which retinal development is unaffected and a significant number of target cells survive at the point of intervention. PMID:19151647

Bainbridge, J W B

2009-10-01

173

Progress & Prospects: Gene therapy in aging  

Microsoft Academic Search

Studies performed on various experimental model systems indicate that genetic interventions can increase longevity, even if in a highly protected laboratory condition. Generally, such interventions required partial or complete switching off of the gene and inhibiting the activity of its gene products, which normally have other well-defined roles in metabolic processes. Overexpression of some genes, such as stress response and

S I S Rattan; R Singh

2009-01-01

174

Careful adjustment of Epo non-viral gene therapy for ?-thalassemic anaemia treatment  

Microsoft Academic Search

BACKGROUND: In situ production of a secreted therapeutic protein is one of the major gene therapy applications. Nevertheless, the plasmatic secretion peak of transgenic protein may be deleterious in many gene therapy applications including Epo gene therapy. Epo gene transfer appears to be a promising alternative to recombinant Epo therapy for severe anaemia treatment despite polycythemia was reached in many

Emmanuelle E Fabre; Pascal Bigey; Yves Beuzard; Daniel Scherman; Emmanuel Payen

2008-01-01

175

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

E-print Network

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

Hemminki, Akseli

176

Abstract. Gene therapy is an exciting novel approach for treating cancers resistant to currently available modalities.  

E-print Network

Abstract. Gene therapy is an exciting novel approach for treating cancers resistant to currently of previous strategies. Adenoviral cancer gene therapy approaches lack cross-resistance with other treatment. Cancer gene therapy approaches 4. Adenovirus for gene therapy 5. Cancer trials with adenoviral vectors 6

Hemminki, Akseli

177

Clinical development of gene therapy for colorectal cancer  

Microsoft Academic Search

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,

David Kerr

2003-01-01

178

Current status of catheter- and stent-based gene therapy  

Microsoft Academic Search

Significant progress has been made in the field of cardiovascular gene therapy over the past decade. Animal models of human disease have helped in identifying potential therapeutic genes and have also assisted in the evaluation of an ideal vector. A number of percutaneous catheter systems have been used in animal models with limited success. Stents represent an attractive alternative for

F. Sharif; K. Daly; J. Crowley; T OBRIEN

2004-01-01

179

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

180

Gene therapy in nonhuman primate models of human autoimmune disease  

Microsoft Academic Search

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

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

2003-01-01

181

Imaging techniques for prostate cancer: implications for focal therapy  

PubMed Central

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

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

2012-01-01

182

Future aspects of immunotherapy and gene therapy in neuroblastoma.  

PubMed

Immunotherapy against cancer aims at stimulating the immune system or building an immune response against targeted tumor-associated antigens (TAAs). It was proposed theoretically as a potential therapy for cancer over a century ago but it became popular in the past two decades. Gene therapy represents a promising approach for reversing the neoplastic phenotype or driving tumor cells to self-destruction. Although survival rates of neuroblastoma (NB) with biologically favorable disease are greater than 90%, outcomes of patients with high risk disease are less than 40%. Stage 4 metastatic NB cases over 18 months of age are often incurable with multimodality chemotherapy regimens. In this article, translation of immuno-gene therapy strategies into clinical trials for NB are reviewed. Future aspects of immuno-gene therapy are discussed. PMID:19785063

Aktas, S

2009-09-01

183

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. PMID:24391438

Petrs-Silva, Hilda; Linden, Rafael

2014-01-01

184

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

185

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

E-print Network

review© The American Society of Gene & Cell Therapy Molecular Therapy vol. 19 no. 8, 1407­1415 aug. 2011 1407 IntroductIon Gene therapy has shown increasing promise in clinical trials for disorders in the development of gene delivery systems must continue to build upon the recent successes in the field and further

Schaffer, David V.

186

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

E-print Network

MOLECULAR THERAPY Vol. 4, No. 6, December 2001 Copyright © The American Society of Gene Therapy 586 Dake,8 Dale Huff,4 Alan W. Flake,2 Linda Couto,7 Mark A. Kay,8 and Katherine A. High1,* 1 The Children, Philadelphia, Pennsylvania 19104, USA 3 Division of Human Genetics and 4 Department of Pathology, The Children

Ford, James

187

MOLECULAR THERAPY Vol. 5, No. 2, February 2002 Copyright The American Society of Gene Therapy  

E-print Network

MOLECULAR THERAPY Vol. 5, No. 2, February 2002 Copyright © The American Society of Gene Therapy, Philadelphia, Pennsylvania 19104, USA 3 Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 hepatocytes. As newborn animals exhibit rapid growth, we evaluated the ability of MLV-based RV to transduce

Ponder, Katherine P.

188

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

Microsoft Academic Search

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

P Gonin; C Gaillard

2004-01-01

189

Intracellular delivery of potential therapeutic genes: prospects in cancer gene therapy.  

PubMed

Conventional therapies for malignant cancer such as chemotherapy and radiotherapy are associated with poor survival rates owing to the development of cellular resistance to cancer drugs and the lack of targetability, resulting in unwanted adverse effects on healthy cells and necessitating the lowering of therapeutic dose with consequential lower efficacy of the treatment. Gene therapy employing different types of viral and non-viral carriers to transport gene(s) of interest and facilitating production of the desirable therapeutic protein(s) has tremendous prospects in cancer treatments due to the high-level of specificity in therapeutic action of the expressed protein(s) with diminished off-target effects, although cancer cell-specific delivery of transgene(s) still poses some challenges to be addressed. Depending on the potential therapeutic target genes, cancer gene therapy could be categorized into tumor suppressor gene replacement therapy, immune gene therapy and enzyme- or prodrug-based therapy. This review would shed light on the current progress of delivery of potentially therapeutic genes into various cancer cells in vitro and animal models utilizing a variety of viral and non-viral vectors. PMID:25039616

Bakhtiar, Athirah; Sayyad, Mustak; Rosli, Rozita; Maruyama, Atsushi; Chowdhury, Ezharul H

2014-01-01

190

[Specific gene therapy for hereditary retinal dystrophies - an update].  

PubMed

Treatment possibilities based on specific gene therapy strategies have become reality for a small number of patients with hereditary retinal dystrophies and are currently under investigation in several clinical trials worldwide. The most advanced studies are for patients suffering from mutations in the RPE65 gene. In addition, studies are ongoing for patients with disease causing mutations in the MERTK, REP1, ABCA4, or Myosin7A gene. Depending on the size of the gene copy to be transferred, two vectors are currently used in clinical trials: vectors based on adeno-associated virus (AAV) or on lentivirus (equine infectious anaemia virus, EIAV). An important aspect of current research includes the capacity to objectively measure the treatment effect in patients, since this is currently limited. This article gives an overview of the current state of specific gene therapy for hereditary retinal dystrophies. PMID:24327302

Stieger, K; Lorenz, B

2014-03-01

191

An early history of gene transfer and therapy.  

PubMed

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

Wolff, J A; Lederberg, J

1994-04-01

192

Regulatable atrial natriuretic peptide gene therapy for hypertension  

PubMed Central

Hypertension (HTN) is a disease that begins with dysfunctional renal-sodium excretion and progresses to a syndrome of highly elevated systolic, diastolic, and mean arterial pressures. Inadequacies in the therapy of HTN have led to the investigation of the gene therapy of this disease by using systemic overproduction of vasodilatory peptides, such as atrial natriuretic peptide (ANP). However, gene-therapy approaches to HTN using ANP are limited by the need for long-term ANP gene expression and, most important, control of ANP gene expression. Here, we introduce a helper-dependent adenoviral vector carrying the mifepristone (Mfp)-inducible gene-regulatory system to control in vivo ANP expression. In the BPH/2 mouse model of HTN, Mfp-inducible ANP expression was seen for a period of >120 days after administration of vector. Physiological effects of ANP, including decreased systolic blood pressure, increased urinary cGMP output, and decreases in heart weight as a percentage of body weight were also under the control of Mfp. Given these capabilities, this vector represents a paradigm for the gene therapy of HTN. PMID:16162668

Schillinger, Kurt J.; Tsai, Sophia Y.; Taffet, George E.; Reddy, Anilkumar K.; Marian, Ali J.; Entman, Mark L.; Oka, Kazuhiro; Chan, Lawrence; O'Malley, Bert W.

2005-01-01

193

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

E-print Network

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

Schaffer, David V.

194

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

E-print Network

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

Schaffer, David V.

195

Molecular Imaging in Stem Cell Therapy for Spinal Cord Injury  

PubMed Central

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

Tian, Mei; Zhang, Hong

2014-01-01

196

Gene therapy: can neural stem cells deliver?  

Microsoft Academic Search

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

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

2006-01-01

197

Disability, gene therapy and eugenics - a challenge to John Harris  

PubMed Central

This article challenges the view of disability presented by Harris in his article, "Is gene therapy a form of eugenics?"1 It is argued that his definition of disability rests on an individual model of disability, where disability is regarded as a product of biological determinism or "personal tragedy" in the individual. Within disability theory this view is often called "the medical model" and it has been criticised for not being able to deal with the term "disability", but only with impairment. The individual model of disability presupposes a necessary causal link between a certain condition in the individual and disablement. The shortcomings of such a view of disability are stated and it is argued that in order to have an adequate ethical discourse on gene therapy perspectives from disability research need to be taken into consideration. Key Words: Disability theory • gene therapy • eugenics PMID:10786317

Reindal, S. M.

2000-01-01

198

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. PMID:20186255

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

2010-01-01

199

Targeting Co-Stimulatory Pathways in Gene Therapy  

PubMed Central

Gene therapy with recombinant viral vectors such as adenovirus and adenovirus-associated virus holds great promise in treating a wide range of diseases because of the high efficiency with which the viruses transfer their genomes into host cells in vivo. However, the activation of the host immune responses remains a major hurdle to successful gene therapy. Studies in the past two decades have elucidated the important role co-stimulation plays in the activation of both T and B cells. This review summarizes our current understanding of T cell co-stimulatory pathways, and strategies targeting these co-stimulatory pathways in gene therapy applications as well as potential future directions. PMID:22046171

Huang, Xiaopei; Yang, Yiping

2011-01-01

200

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. PMID:24860662

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

2014-01-01

201

Immunotherapy of Uveitis: is Gene Therapy in our Future?  

Microsoft Academic Search

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

Rachel R. Caspi

202

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. PMID:20711350

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

2010-01-01

203

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. PMID:23246627

MURPHY, ANDREA M.; RABKIN, SAMUEL D.

2013-01-01

204

Antisense Gene Silencing: Therapy for Neurodegenerative Disorders?  

PubMed Central

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

Nielsen, Troels T.; Nielsen, J?rgen E.

2013-01-01

205

Development of gene therapy for blood disorders: an update.  

PubMed

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

Nienhuis, Arthur W

2013-08-29

206

Development of gene therapy for blood disorders: an update  

PubMed Central

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

2013-01-01

207

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

208

Human gene therapy and the slippery slope argument.  

PubMed

The article investigates the validity of two different versions of the slippery slope argument construed in relation to human gene therapy: the empirical and the conceptual argument. The empirical version holds that our accepting somatic cell therapy will eventually cause our accepting eugenic medical goals. The conceptual version holds that we are logically committed to accepting such goals once we have accepted somatic cell therapy. It is argued that neither the empirical nor the conceptual version of the argument can provide a conclusive moral reason for banning somatic cell therapy. According to a third interpretation, referred to as the arbitrary result argument, the many apparent similarities between somatic cell therapy and eugenic-based human genetic engineering drive us to make principled choices concerning what differences and similarities between the two practices should be regarded as morally (ir)relevant. Decisions of this kind are likely to have unpredictable moral consequences. Thus formulated, the slippery slope argument has much plausibility. One objects to somatic cell therapy not so much because of what is at the bottom of the slope on which it lies, but because it is on a slope of which one does not know what is at the bottom. While the arbitrary result argument does not provide a conclusive reason for prohibiting human gene therapy, it reminds of a very important thing: when making bioethical decisions, we should be as specific and as consistent as possible about our basic moral and medical concepts. PMID:12168992

Launis, Veikko

2002-01-01

209

Engineered Adeno-Associated Viral Vectors for Gene Therapy in the Retina  

E-print Network

2008) Human gene therapy for RPE65 isomerase deficiencyRPE65 gene to the retinas of Leber congenital amaurosis (LCA) patients illustrates the potential of gene therapyRPE65 mutation, above all these clinical trials demonstrated the therapeutic potential and safety of gene replacement therapies

Byrne, Leah

2011-01-01

210

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

E-print Network

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

Fischer, Itzhak

211

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

E-print Network

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

Hemminki, Akseli

212

MRI Reporter Genes: Application to Imaging of Cell Survival, Proliferation, Migration, and Differentiation  

PubMed Central

Molecular imaging strives to detect molecular events at the level of the whole organism. In some cases, the molecule of interest can be detected either directly, or through the use of targeted contrast media. However many genes and proteins, and particularly those located in intracellular compartments, are not accessible for targeted agents. The transcriptional regulation of these genes can never the less be detected, though indirectly, through the use of reporter genes encoding for readily detectable proteins. Such reporter proteins can be expressed in the tissue of interest by genetically introducing the reporter gene in the target cells. Imaging of reporter genes has become a powerful tool in modern biomedical research. Typically, expression of fluorescent or bioluminescent proteins, or the reaction product of expressed enzymes and exogenous substrates, are examined using in vitro histological methods, or in vivo whole body imaging methods. Recent advances in MRI reporter gene methods raise the possibility that MRI could become a powerful tool for concomitant high resolution anatomical and functional imaging and for imaging of reporter gene activity. An immediate application of MRI reporter gene methods is for monitoring gene expression patterns in gene therapy and for in vivo imaging of the survival, proliferation, migration, and differentiation of pluripotent or multipotent cells used in cell based regenerative therapies for cancer, myocardial infarction, and neural degeneration. In this review, we characterize the variety of MRI reporter gene methods based on their applicability to report cell survival/proliferation, cell migration, and cell differentiation. In particular, we discuss which methods are best suited for translation to clinical use in regenerative therapies. PMID:23225197

Vandsburger, Moriel H; Radoul, Marina; Cohen, Batya; Neeman, Michal

2013-01-01

213

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

214

Gene supplementation therapy for recessive forms of inherited retinal dystrophies  

Microsoft Academic Search

Over the last decade, gene supplementation therapy for inherited retinal degeneration has come of age. Early proof-of-concept studies in animal models of disease showed modest, but genuine improvements in retinal function and\\/or survival. Further development of the vectors used for gene transfer to the retina has led to better treatment efficacy in a wide variety of animal models, leading in

A J Smith; J W B Bainbridge; R R Ali

2012-01-01

215

Stem and progenitor cell-mediated tumor selective gene therapy  

Microsoft Academic Search

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

K S Aboody; J Najbauer; M K Danks

2008-01-01

216

Beta-Adrenergic gene therapy for cardiovascular disease  

Microsoft Academic Search

Gene therapy using in vivo recombinant adenovirus-mediated gene transfer is an effective technique that offers great potential to improve existing drug treatments for the complex cardiovascular diseases of heart failure and vascular smooth muscle intimal hyperplasia. Cardiac-specific adenovirus-mediated transfer of the carboxyl-terminus of the ?-adrenergic receptor kinase (?ARKct), acting as a G??-?-adrenergic receptor kinase (?ARK)1 inhibitor, improves basal and agonist-induced

Andrea D Eckhart; Walter J Koch

2000-01-01

217

Novel adeno-associated viral vectors for retinal gene therapy  

Microsoft Academic Search

Vectors derived from adeno-associated virus (AAV) are currently the most promising vehicles for therapeutic gene delivery to the retina. Recently, subretinal administration of AAV2 has been demonstrated to be safe and effective in patients with a rare form of inherited childhood blindness, suggesting that AAV-mediated retinal gene therapy may be successfully extended to other blinding conditions. This is further supported

L H Vandenberghe; A Auricchio

2012-01-01

218

Polymer Transfected Primary Myoblasts- Mediated Angiogenic Gene Therapy for Ischemic Heart Disease.  

E-print Network

??Polymer transfected primary myoblasts-mediated angiogenic gene therapy is proposed as a new therapeutic regime for ischemic heart disease. The conventional drug therapy and surgical treatment… (more)

Ou, Mei

2010-01-01

219

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

E-print Network

to cancer research, gene therapy, and transgenic mod- els are rapidly expanding. We report construction to living animals with the help of a single tri-fusion reporter gene will have the potential to accelerate events, it is desirable to image reporter gene expression in individual cells, living animals, and humans

Tsien, Roger Y.

220

Large animal models and gene therapy  

Microsoft Academic Search

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

Margret Casal; Mark Haskins

2006-01-01

221

HSV Recombinant Vectors for Gene Therapy  

PubMed Central

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

Manservigi, Roberto; Argnani, Rafaela; Marconi, Peggy

2010-01-01

222

Multiphoton Biomedical Imaging and Photodynamic Therapy: Agents & Applications  

E-print Network

Multiphoton Biomedical Imaging and Photodynamic Therapy: Agents & Applications Kevin D. Belfield-reactive model Hydrophobic and hydrophilic dyes Two-Photon Photodynamic Therapy #12;"Two-photon laser scanning at the focus of the scanning pulsed-infrared laser beam, resulting in a much less harmful light dose during

Van Stryland, Eric

223

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

224

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

225

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. PMID:19127583

Isacson, Ole; Kordower, Jeffrey H.

2014-01-01

226

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. PMID:20378608

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

227

Gene and cell-based therapies for heart disease  

Microsoft Academic Search

Heart disease remains the prevalent cause of premature death and accounts for a significant proportion of all hospital admissions. Recent develop- ments in understanding the molecular mechanisms of myocardial disease have led to the identification of new therapeutic targets, and the availability of vectors with enhanced myocardial tropism offers the opportunity for the design of gene therapies for both protection

LUIS G. MELO; ALOK S. PACHORI; DELING KONG; MASSIMILIANO GNECCHI; KAI WANG; RICHARD E. PRATT; VICTOR J. DZAU

2004-01-01

228

Publications by Gene Therapy Center Members January 2012 -December 2012  

E-print Network

Publications by Gene Therapy Center Members January 2012 - December 2012 Center Members are in BOLD for hypertension and cardiovascular disease. Hypertension. 2012;59(4):755-62. PMCID: 3313828. 2. Abecassis M Ventricular Arrhythmiasin Mice with Duchenne Muscular Dystrophy. Heart Rhythm. 2012. 7. Barr RG, Ahmed FS

229

Towards gene therapy for the central nervous system  

Microsoft Academic Search

Gene therapy has generated enormous scientific, medical and public interest over the last decade. Clinical trials involving approximately 2000 patients worldwide have targeted simple genetic diseases such as cystic fibrosis, muscular dystrophy, adenosine deaminase deficiency, Gaucher's disease and familial hypercholesterolemia, as well as complex acquired diseases such as cancer and AIDS. The central nervous system is a new and particularly

Liana-Marie A Ashenden

1998-01-01

230

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

231

Stem cell therapy and gene transfer for regeneration  

Microsoft Academic Search

The committed stem and progenitor cells have been recently isolated from various adult tissues, including hematopoietic stem cell, neural stem cell, mesenchymal stem cell and endothelial progenitor cell. These adult stem cells have several advantages as compared with embryonic stem cells as their practical therapeutic application for tissue regeneration. In this review, we discuss the promising gene therapy application of

T Asahara; C Kalka; J M Isner

2000-01-01

232

Gutless adenoviral vectors — Promising tools for gene therapy  

Microsoft Academic Search

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

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

2002-01-01

233

Non-viral gene therapy for spinal cord regeneration  

PubMed Central

Spinal cord injury normally results in life-long disabilities and a broad range of secondary complications. Advances in therapeutic delivery during the past few decades offer hope for such victims. However, the limited functional improvement shown in in vivo studies hinders effective therapeutic application in clinical practice. Recent studies showed that gene vectors can transfect cells present in the lesion of an injured spinal cord (endogenous cells) and thereby produce therapeutic molecules with long-lasting biological effects that promote neural tissue regeneration. In this article we review recent advances in non-viral gene delivery into neural cells and their use for gene therapy in spinal cord injury. PMID:22634187

Yao, Li; Yao, Sheng; Daly, Bill; Hendry, William; Windebank, Anthony; Pandit, Abhay

2013-01-01

234

Multimodality Molecular Imaging of Stem Cells Therapy for Stroke  

PubMed Central

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

Zhang, Hong; Tian, Mei

2013-01-01

235

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

E-print Network

Therapy Practice · Academic units must be studied concurrently or as a pre-requisite to studying clinical) Principles of Imaging for Advanced Radiation Therapy Practice 1 (Academic Unit) Duration 13 weeks Delivery as relevant to the role of the imaging advanced practitioner, such as CT, MRI, PET and Ultrasound, and more

Albrecht, David

236

Image-guided, noninvasive, spatiotemporal control of gene expression  

PubMed Central

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

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

2009-01-01

237

original article The American Society of Gene & Cell Therapy Molecular Therapy vol. 18 no. 5, 873880 may 2010 873  

E-print Network

original article© The American Society of Gene & Cell Therapy Molecular Therapy vol. 18 no. 5, 873.11 Umbilical cord blood transplant of pregnant female mice stimulated stem cell migration no effect on lifespan. Combination therapy compared to either therapy alone resulted in synergistic effects

Orrock, John

238

Gene therapy for cardiovascular disease: perspectives and potential.  

PubMed

Cardiovascular disease is the most frequent cause of mortality in the western world, accounting for over 800,000 premature deaths per year in the EU alone. Cardiovascular disease is the second most common application for gene therapy clinical trials, which most frequently employ adenovirus serotype 5 (Ad5)-based vectors as delivery vehicles. Although interactions of Ad5 vectors with circulating proteins and cells can limit their efficacy after systemic administration, local gene delivery strategies show great potential in the cardiovascular setting, notably in the context of vascular delivery. Here we review the pathogenesis of bypass graft failure and in-stent restenosis, identifying potential therapeutic targets and discussing recent advances in the field of adenovirus biology and retargeting that, in concert, will potentially translate in coming years to more effective gene therapies for cardiovascular applications. PMID:23142171

Bradshaw, Angela C; Baker, Andrew H

2013-03-01

239

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

E-print Network

and Physiology II for Allied Health (3) or BSCI 20020 Biological Structure and Function (5) 5-6 Fulfills KentRoadmap: Radiologic Imaging Sciences - Radiation Therapy (with AAS Radiologic Technology) ­ Bachelor of Radiologic and Imaging Sciences Technology [RE-BRIT-RIS-RTAA] Regional College Catalog Year

Sheridan, Scott

240

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

PubMed Central

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

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

2012-01-01

241

Biomedical nanomaterials for imaging-guided cancer therapy  

NASA Astrophysics Data System (ADS)

To date, even though various kinds of nanomaterials have been evaluated over the years in order to develop effective cancer therapy, there is still significant challenges in the improvement of the capabilities of nano-carriers. Developing a new theranostic nanomedicine platform for imaging-guided, visualized cancer therapy is currently a promising way to enhance therapeutic efficiency and reduce side effects. Firstly, conventional imaging technologies are reviewed with their advantages and disadvantages, respectively. Then, advanced biomedical materials for multimodal imaging are illustrated in detail, including representative examples for various dual-modalities and triple-modalities. Besides conventional cancer treatment (chemotherapy, radiotherapy), current biomaterials are also summarized for novel cancer therapy based on hyperthermia, photothermal, photodynamic effects, and clinical imaging-guided surgery. In conclusion, biomedical materials for imaging-guided therapy are becoming one of the mainstream treatments for cancer in the future. It is hoped that this review might provide new impetus to understand nanotechnology and nanomaterials employed for imaging-guided cancer therapy.

Huang, Yuran; He, Sha; Cao, Weipeng; Cai, Kaiyong; Liang, Xing-Jie

2012-09-01

242

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

E-print Network

Laboratory Investigation Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy radiation therapy, rats Summary Purpose: Microbeam radiation therapy (MRT), a novel experimental animals and palliates advanced 9LGS tumors. This report, to our knowledge, is the first demonstration

Terasaki, Mark

243

IL-12 based gene therapy in veterinary medicine  

PubMed Central

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

2012-01-01

244

Gene therapy of chronic granulomatous disease: the engraftment dilemma.  

PubMed

The potential of gene therapy as a curative treatment for monogenetic disorders has been clearly demonstrated in a series of recent Phase I/II clinical trials. Among primary immunodeficiencies, gene transfer into hematopoietic stem (HSC)/progenitor cells has resulted in the long-term correction of immune and metabolic defects in treated patients. In most cases, successes were augmented by a recognized biological selection for successfully treated cells in vivo, perhaps even to some extent at the HSC level. In contrast, similar achievements have not turned into reality for immunodeficiencies in which gene-transduced cells lack selective advantages in vivo. This is the case for chronic granulomatous disease (CGD), a primary immunodeficiency, characterized by deficient antimicrobial activity in phagocytic cells. Several attempts to correct CGD by gene transfer in combination with bone marrow conditioning have resulted in low-level long-term engraftment and transient clinical benefits despite high levels of gene marking and high numbers of reinfused cells. This review summarizes the data from clinical trials for CGD and provides some insights into treatment options that may lead to a successful application of gene therapy for CGD. PMID:21045810

Grez, Manuel; Reichenbach, Janine; Schwäble, Joachim; Seger, Reinhard; Dinauer, Mary C; Thrasher, Adrian J

2011-01-01

245

Gene therapy: Biological pacemaker created by gene transfer  

NASA Astrophysics Data System (ADS)

The pacemaker cells of the heart initiate the heartbeat, sustain the circulation, and dictate the rate and rhythm of cardiac contraction. Circulatory collapse ensues when these specialized cells are damaged by disease, a situation that currently necessitates the implantation of an electronic pacemaker. Here we report the use of viral gene transfer to convert quiescent heart-muscle cells into pacemaker cells, and the successful generation of spontaneous, rhythmic electrical activity in the ventricle in vivo. Our results indicate that genetically engineered pacemakers could be developed as a possible alternative to implantable electronic devices.

Miake, Junichiro; Marbán, Eduardo; Nuss, H. Bradley

2002-09-01

246

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

247

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. PMID:23566838

Mukherjee, Sayandip; Thrasher, Adrian J.

2013-01-01

248

ErikaCheck,Washington The troubled field of gene therapy was  

E-print Network

fuels doubts over gene therapy Cash crisis US museums threatened by economic downturn p575 Pet problemErikaCheck,Washington The troubled field of gene therapy was dealt a fresh blow this week, after by geneticist Mark Kay at Stanford University, California, examined a modified virus used in gene-therapy trials

Kay, Mark A.

249

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

Federal Register 2010, 2011, 2012, 2013

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

2010-09-07

250

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

E-print Network

the progress achieved in the past 2 years on using gene therapy to treat hemophilia in animals and humans. Recent findings There has been substantial progress in using gene therapy to treat animals. Gene therapy for hemophilia Katherine P. Ponder Purpose of review This review will highlight

Ponder, Katherine P.

251

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

E-print Network

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

Schaffer, David V.

252

Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency  

E-print Network

Commentary Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency online 10 February 2009 Keywords: Gene therapy Ornithine transcarbamylase deficiency Clinical trial a b administration in a liver gene therapy trial of research subjects with a deficiency of ornithine transcarbamylase

Gleeson, Joseph G.

253

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

E-print Network

© The American Society of Gene & Cell Therapy letter to the editor large budgets by various contrasts sharply with the relatively limited budgets that have been available for gene therapy research. Typically, most gene therapy researchers work as small teams on a specific disease with a relatively small

Barbas III, Carlos F.

254

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

E-print Network

HUMAN GENE THERAPY 12:563­573 (March 20, 2001) Mary Ann Liebert, Inc. CMV-b-Actin Promoter Directs,4 and KATHERINE PARKER PONDER1,5 ABSTRACT Although AAV vectors show promise for hepatic gene therapy, the optimal), which derived from both liver and muscle. We conclude that neonatal gene therapy with an AAV vector

Ponder, Katherine P.

255

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

E-print Network

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

Kay, Mark A.

256

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

E-print Network

Mucopolysaccharidosis I Cats Mount a Cytotoxic T Lymphocyte Response after Neonatal Gene Therapy, as mucopolysaccharidosis I (MPS I) mice that received neonatal intravenous gene therapy with a high dose of a canine A after neonatal gene therapy. We conclude that cats, but not dogs, mount a potent CTL response to canine

Ponder, Katherine P.

257

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

E-print Network

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

Paris-Sud XI, Université de

258

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

E-print Network

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

Kay, Mark A.

259

A review of gene and stem cell therapy in cutaneous wound healing  

Microsoft Academic Search

Different therapies that effect wound repair have been proposed over the last few decades. This article reviews the emerging fields of gene and stem cell therapy in wound healing. Gene therapy, initially developed for treatment of congenital defects, is a new option for enhancing wound repair. In order to accelerate wound closure, genes encoding for growth factors or cytokines showed

Ludwik K. Branski; Gerd G. Gauglitz; David N. Herndon; Marc G. Jeschke

2009-01-01

260

Gene therapy for trigeminal pain in mice  

PubMed Central

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

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

2014-01-01

261

Current Perspectives on Imaging Cardiac Stem Cell Therapy  

PubMed Central

Molecular imaging is a new discipline that makes possible the noninvasive visualization of cellular and molecular processes in living subjects. In the field of cardiovascular regenerative therapy, imaging cell fate after transplantation is a high priority in both basic research and clinical translation. For cell-based therapy to truly succeed, we must be able to track the locations of delivered cells, the duration of cell survival, and any potential adverse effects. The insights gathered from basic research imaging studies will yield valuable insights into better designs for clinical trials. This review highlights the different types of stem cells used for cardiovascular repair, the development of various imaging modalities to track their fate in vivo, and the challenges of clinical translation of cardiac stem cell imaging in the future. PMID:20395348

Wu, Joseph C.; Abraham, M. Roselle; Kraitchman, Dara L.

2011-01-01

262

Image-guided focal therapy for prostate cancer.  

PubMed

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

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

2014-11-01

263

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. PMID:24124361

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

2013-01-01

264

Combining Cytotoxic and Immune-Mediated Gene Therapy to Treat Brain Tumors  

PubMed Central

Glioblastoma (GBM) is a type of intracranial brain tumor, for which there is no cure. In spite of advances in surgery, chemotherapy and radiotherapy, patients die within a year of diagnosis. Therefore, there is a critical need to develop novel therapeutic approaches for this disease. Gene therapy, which is the use of genes or other nucleic acids as drugs, is a powerful new treatment strategy which can be developed to treat GBM. Several treatment modalities are amenable for gene therapy implementation, e.g. conditional cytotoxic approaches, targeted delivery of toxins into the tumor mass, immune stimulatory strategies, and these will all be the focus of this review. Both conditional cytotoxicity and targeted toxin mediated tumor death, are aimed at eliminating an established tumor mass and preventing further growth. Tumors employ several defensive strategies that suppress and inhibit anti-tumor immune responses. A better understanding of the mechanisms involved in eliciting anti-tumor immune responses has identified promising targets for immunotherapy. Immunotherapy is designed to aid the immune system to recognize and destroy tumor cells in order to eliminate the tumor burden. Also, immune-therapeutic strategies have the added advantage that an activated immune system has the capability of recognizing tumor cells at distant sites from the primary tumor, therefore targeting metastasis distant from the primary tumor locale. Pre-clinical models and clinical trials have demonstrated that in spite of their location within the central nervous system (CNS), a tissue described as ‘immune privileged’, brain tumors can be effectively targeted by the activated immune system following various immunotherapeutic strategies. This review will highlight recent advances in brain tumor immunotherapy, with particular emphasis on advances made using gene therapy strategies, as well as reviewing other novel therapies that can be used in combination with immunotherapy. Another important aspect of implementing gene therapy in the clinical arena is to be able to image the targeting of the therapeutics to the tumors, treatment effectiveness and progression of disease. We have therefore reviewed the most exciting non-invasive, in vivo imaging techniques which can be used in combination with gene therapy to monitor therapeutic efficacy over time. PMID:16248789

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

2006-01-01

265

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. PMID:23553671

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

2014-01-01

266

Molecular imaging: the key to advancing cardiac stem cell therapy.  

PubMed

Cardiac stem cell therapy continues to hold promise for the treatment of ischemic heart disease despite the fact that early promising pre-clinical findings have yet to be translated into consistent clinical success. The latest human studies have collectively identified a pressing need to better understand stem cell behavior in humans and called for more incorporation of noninvasive imaging techniques into the design and evaluation of human stem cell therapy trials. This review discusses the various molecular imaging techniques validated to date for studying stem cells in living subjects, with a particular emphasis on their utilities in assessing the acute retention and the long-term survival of transplanted stem cells. These imaging techniques will be essential for advancing cardiac stem cell therapy by providing the means to both guide ongoing optimization and predict treatment response in humans. PMID:23561794

Chen, Ian Y; Wu, Joseph C

2013-08-01

267

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

268

Bioelectrical strategies for image-guided therapies  

E-print Network

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

Barley, Maya

2007-01-01

269

Gene-based therapy for alpha-1 antitrypsin deficiency.  

PubMed

Alpha-1 antitrypsin Deficiency (AATD) has been an attractive target for the development of gene therapy because it is a common single gene disorder, for which there would appear to be significant benefit to be gained for lung disease patients by augmentation of plasma levels of wild-type (M) alpha-1 antitrypsin (AAT). While a significant proportion of patients also have liver disease, which is unlikely to be benefitted by augmentation, the potential to treat or prevent lung disease by replacement of plasma levels to at least 11 microMolar (571 mcg/ml) is the basis upon which several protein replacement therapies have been licensed for human use. Further enhancing the likelihood of success of gene therapy is the fact that the AAT coding sequence is relatively short and the protein appears to function primarily in the plasma and extracellular space. This means that AAT production from any cell or tissue capable of secreting it could be useful therapeutically for augmentation. Based on these considerations, attempts have been made to develop AAT therapies using nonviral gene transfer, gammaretrovirus, recombinant adenovirus (rAd), and recombinant adeno-associated virus (rAAV) vectors. These have resulted in three phase I clinical trials (one of cationic liposome, one of rAAV2, and one of rAAV1) and one phase II clinical trial (with rAAV1). The results of the latter trial, while promising, demonstrated levels were only 3 to 5% of the target range. This indicates the need to further increase the dose of the vector and/or to increase the levels to within the therapeutic range. PMID:23527792

Mueller, Christian; Flotte, Terence R

2013-03-01

270

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

E-print Network

Roadmap: Radiologic Imaging Sciences ­ Radiation Therapy (Freshman or AS degree) ­ Bachelor of Radiologic Imaging Sciences Technology [RE-BRIT-RIS-RTFE] Regional College Catalog Year: 2012-2013 Page 1 Semester Seven (Summer): [2 Credit Hours] RIS 44000 Introduction to Radiologic Imaging Sciences 2 C

Sheridan, Scott

271

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

PubMed Central

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

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

2013-01-01

272

Gene therapy for the nervous system: challenges and new strategies.  

PubMed

Current clinical treatments for central nervous system (CNS) diseases, such as Parkinson's disease and glioblastoma do not halt disease progression and have significant treatment morbidities. Gene therapy has the potential to "permanently" correct disease by bringing in a normal gene to correct a mutant gene deficiency, knocking down mRNA of mutant alleles, and inducing cell-death in cancer cells using transgenes encoding apoptosis-inducing proteins. Promising results in clinical trials of eye disease (Leber's congenital aumorosis) and Parkinson's disease have shown that gene-based neurotherapeutics have great potential. The recent development of genome editing technology, such as zinc finger nucleases, TALENS, and CRISPR, has made the ultimate goal of gene correction a step closer. This review summarizes the challenges faced by gene-based neurotherapeutics and the current and recent strategies designed to overcome these barriers. We have chosen the following challenges to focus on in this review: (1) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier. The final section (4) focuses on promising pre-clinical/clinical studies of neurotherapeutics. PMID:25159276

Maguire, Casey A; Ramirez, Servio H; Merkel, Steven F; Sena-Esteves, Miguel; Breakefield, Xandra O

2014-10-01

273

Gene Therapy for Brain Tumors: Basic Developments and Clinical Implementation  

PubMed Central

Glioblastoma multiforme (GBM) is the most common and deadliest of adult primary brain tumors. Due to its invasive nature and sensitive location, complete resection remains virtually impossible. The resistance of GBM against chemotherapy and radiotherapy necessitate the development of novel therapies. Gene therapy is proposed for the treatment of brain tumors and has demonstrated pre-clinical efficacy in animal models. Here we review the various experimental therapies that have been developed for GBM including both cytotoxic and immune stimulatory approaches. We also review the combined conditional cytotoxic immune stimulatory therapy that our lab has developed which is dependent on the adenovirus mediated expression of the conditional cytotoxic gene, Herpes Simplex Type 1 Thymidine Kinase (TK) and the powerful DC growth factor Fms-like tyrosine kinase 3 ligand (Flt3L). Combined delivery of these vectors elicits tumor cell death and an anti-tumor adaptive immune response that requires TLR2 activation. The implications of our studies indicate that the combined cytotoxic and immunotherapeutic strategies are effective strategies to combat deadly brain tumors and warrant their implementation in human Phase I clinical trials for GBM. PMID:22906921

Assi, Hikmat; Candolfi, Marianela; Baker, Gregory; Mineharu, Yohei; Lowenstein, Pedro R; Castro, Maria G

2012-01-01

274

The mifepristone-inducible gene regulatory system in mouse models of disease and gene therapy.  

PubMed

The mifepristone (Mfp)-inducible gene regulatory system is designed to allow control of the spatiotemporal expression of transgenes in vivo in a ligand-dependent manner. This regulatory system is composed of two components: (1) a chimeric transactivator protein that activates transgene transcription only in the presence of the progesterone antagonist Mfp, and (2) a target transgene placed in the context of a promoter which is responsive only to the Mfp-bound chimeric transactivator. Incorporation of the components of the Mfp-inducible gene regulatory system into transgenic mice has resulted in the establishment of several novel, Mfp-dependent models of disease. Similarly, adaptation of the Mfp-inducible system for use in gene knockout models has resulted in the development of new gene ablation technology which is both tissue-specific and Mfp-dependent. Additionally, the Mfp-inducible gene regulatory system has been used in animal experiments involving somatic gene therapy, where it has shown considerable promise in the regulation of both reporter and therapeutic gene expression. This review focuses on recent application of the Mfp-inducible system to transgenic models, gene knockout models, and somatic gene therapy experiments. In so doing, it demonstrates the considerable promise that future use of this system holds for better understanding and treatment of human disease. PMID:12240599

Ngan, Elly S W; Schillinger, Kurt; DeMayo, Francesco; Tsai, Sophia Y

2002-04-01

275

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. 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

276

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

277

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. PMID:21034670

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

278

Image Registration: Enabling Technology for Image Guided Surgery and Therapy  

Microsoft Academic Search

Imaging looks inside the patient's body, exposing the patient's anatomy beyond what is visible on the surface. Medical imaging has a very successful history for medical diagnosis. It also plays an increasingly important role as enabling technology for minimally invasive procedures. Interventional procedures (e.g. catheter based cardiac interventions) are traditionally supported by intra-procedure imaging (X-ray fluoro, ultrasound). There is realtime

Frank Sauer

2005-01-01

279

Optoacoustic Imaging for Guiding and Monitoring HIFU Therapy  

NASA Astrophysics Data System (ADS)

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

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

2011-09-01

280

Image-Guidance for Stereotactic Body Radiation Therapy  

SciTech Connect

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

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

2007-07-01

281

Vasoactive Intestinal Peptide-mediated Gene Therapy for Diabetes.  

PubMed

All patients with type 1 diabetes (T1DM) and most patients with type 2 diabetes (T2DM) become insulin dependent due to the progressive nature of the disease, eventually leading to beta-cell loss. The increase in apoptosis, but not the decrease in new islet formation or beta-cell replication, is blamed for the loss of beta-cell mass observed in patients with T2DM. Thus, therapeutic approaches that either interfere with apoptosis of beta cells and/or increase beta-cell mass have the potential not only for managing hyperglycemia but also for reversing disease progression. Vasoactive intestinal peptide (VIP) is a neuropeptide of the secretin family just like GLP1 and PACAP with equipotent insulinotropic effects. More importantly, it is an effective anti-inflammatory agent involved in suppression of Th1 immune response and activation of regulatory T cells for inducing immune tolerance. For this reason, VIP is now considered to be an emerging therapeutic agent for autoimmune diseases such as rheumatoid arthritis, ulcerative colitis, multiple sclerosis, and T1DM. Despite all these advantages, VIP is extremely sensitive to peptidases (DPP-4) present in most tissues. Thus, multiple injections of VIP at high doses are required to observe any therapeutic effect. Contrary to using peptide forms of therapeutic agents, some gene therapy vectors can provide long-term and stable gene expression. Thus, viral and non-viral VIP gene delivery methods have been under development. Despite the successful results obtained from these studies, especially against autoimmune diseases, some limitations of using gene therapy vectors were revealed in recent studies. For example, the clinical efficacy of plasmid DNA transfer is low. Adenoviral vectors only provide transient gene expression due to the antigenic character of adenoviral epitopes. AAV has limited cargo capacity and low transduction efficiency. Compared with other gene therapy vectors, lentiviral vectors appear to be the vector of choice when considering long-term gene expression, transduction efficacy, and safety. Consequently, the testing of the efficacy of lentivirus-mediated VIP gene delivery against diabetes became an essential issue to discuss in experimental animal model of diabetes. PMID:25262738

Sanlio?lu, Salih

2014-01-01

282

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

283

original article The American Society of Gene & Cell Therapy Molecular Therapy vol. 19 no. 10, 19051912 oct. 2011 1905  

E-print Network

In addi- tion, stem cell-based therapies have also demonstrated therapeutic potential in SMA and spinaloriginal article© The American Society of Gene & Cell Therapy Molecular Therapy vol. 19 no. 10, 1905­1912 oct. 2011 1905 Stem cell-derived motor neurons (MNs) are increasingly utilized for modeling

Schaffer, David V.

284

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

E-print Network

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

Cai, Long

285

Targeting tumors with nanobodies for cancer imaging and therapy.  

PubMed

The use of monoclonal antibodies has revolutionized both cancer therapy and cancer imaging. Antibodies have been used to directly inhibit tumor cell proliferation or to target drugs to tumors. Also in molecular imaging, monoclonal antibodies have found their way to the clinic. Nevertheless, distribution within tumors is hampered by their size, leading to insufficient efficacy of cancer treatment and irregular imaging. An attractive alternative for monoclonal antibodies are nanobodies or VHHs. These are the variable domain of heavy-chain antibodies from animals from the Camelidae family that were first discovered in 1993. Stimulated by the ease of nanobody selection, production, and low immunogenicity potential, a number of nanobodies specific to different disease-related targets have been developed. For cancer therapy, nanobodies have been employed as antagonistic drugs, and more recently, as targeting moieties of effector-domaINS and of drug delivery systems. In parallel, nanobodies have also been employed for molecular imaging with modalities such as nuclear and optical imaging. In this review, we discuss recent developments in the application of nanobodies as targeting moieties in cancer therapy and cancer imaging. With such a wide range of successful applications, nanobodies have become much more than simple antagonists. PMID:24035975

Oliveira, Sabrina; Heukers, Raimond; Sornkom, Jirawas; Kok, Robbert J; van Bergen En Henegouwen, Paul M P

2013-12-28

286

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. PMID:15946903

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

287

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

Microsoft Academic Search

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

F Rolling

2004-01-01

288

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. PMID:22272373

Naidoo, Jerusha; Young, Deborah

2012-01-01

289

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. PMID:23251412

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

290

Image-guided interventional therapy for cancer with radiotherapeutic nanoparticles.  

PubMed

One of the major limitations of current cancer therapy is the inability to deliver tumoricidal agents throughout the entire tumor mass using traditional intravenous administration. Nanoparticles carrying beta-emitting therapeutic radionuclides that are delivered using advanced image-guidance have significant potential to improve solid tumor therapy. The use of image-guidance in combination with nanoparticle carriers can improve the delivery of localized radiation to tumors. Nanoparticles labeled with certain beta-emitting radionuclides are intrinsically theranostic agents that can provide information regarding distribution and regional dosimetry within the tumor and the body. Image-guided thermal therapy results in increased uptake of intravenous nanoparticles within tumors, improving therapy. In addition, nanoparticles are ideal carriers for direct intratumoral infusion of beta-emitting radionuclides by convection enhanced delivery, permitting the delivery of localized therapeutic radiation without the requirement of the radionuclide exiting from the nanoparticle. With this approach, very high doses of radiation can be delivered to solid tumors while sparing normal organs. Recent technological developments in image-guidance, convection enhanced delivery and newly developed nanoparticles carrying beta-emitting radionuclides will be reviewed. Examples will be shown describing how this new approach has promise for the treatment of brain, head and neck, and other types of solid tumors. PMID:25016083

Phillips, William T; Bao, Ande; Brenner, Andrew J; Goins, Beth A

2014-09-30

291

Ultrasound imaging of thermal therapy in in vitro liver  

Microsoft Academic Search

The objective of this work was to image liver tissue heated to temperatures below the vaporization threshold as a function of time, to test the feasibility of real-time ultrasound monitoring to control lesion size during minimally invasive thermal therapy (MITT). Two experiments were devised. In one experiment, a thermal gradient was established in a rectangular volume of tissue to correlate

M. R. Gertner; A. E. Worthington; B. C. Wilson; M. D. Sherar

1998-01-01

292

3D SHADED GRAPIDCS IN RADIO-~ THERAPY AND DIAGNOSTIC IMAGING  

E-print Network

of Computer Science New West Hall 035 A Chapel Hill. N.C. 27514 #12;3D Shaded Graphics in Radiotherapy-by-slice techniques, we are developing methods that operate directly in 3D (or in 2D for single slices and begin3D SHADED GRAPIDCS IN RADIO- ~ THERAPY AND DIAGNOSTIC IMAGING Tecbnical Report 86-004 S. M. Pi

North Carolina at Chapel Hill, University of

293

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

PubMed

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

Glinka, Elena M

2012-09-01

294

Ovarian cancer gene therapy using HPV-16 pseudovirion carrying the HSV-tk gene.  

PubMed

Ovarian cancer is the leading cause of death from all gynecological cancers and conventional therapies such as surgery, chemotherapy, and radiotherapy usually fail to control advanced stages of the disease. Thus, there is an urgent need for alternative and innovative therapeutic options. We reason that cancer gene therapy using a vector capable of specifically delivering an enzyme-encoding gene to ovarian cancer cells will allow the cancer cell to metabolize a harmless prodrug into a potent cytotoxin, which will lead to therapeutic effects. In the current study, we explore the use of a human papillomavirus (HPV) pseudovirion to deliver a herpes simplex virus thymidine kinase (HSV-tk) gene to ovarian tumor cells. We found that the HPV-16 pseudovirion was able to preferentially infect murine and human ovarian tumor cells when administered intraperitoneally. Furthermore, intraperitoneal injection of HPV-16 pseudovirions carrying the HSV-tk gene followed by treatment with ganciclovir led to significant therapeutic anti-tumor effects in murine ovarian cancer-bearing mice. Our data suggest that HPV pseudovirion may serve as a potential delivery vehicle for ovarian cancer gene therapy. PMID:22815887

Hung, Chien-Fu; Chiang, An Jen; Tsai, Hsiao-Hsuan; Pomper, Martin G; Kang, Tae Heung; Roden, Richard R; Wu, T-C

2012-01-01

295

Angiogenic gene therapy for heart disease: a review of animal studies and clinical trials  

Microsoft Academic Search

The current published clinical literature on angiogenic gene therapy for the treatment of myocardial ischemia does not include a single randomized, placebo-controlled trial. Based on current clinical literature, it is an unproven therapy. Successful animal studies combined with published reports of good outcomes in patients enrolled in uncontrolled trials has led to the expectation that angiogenic gene therapy will ultimately

H. Kirk Hammond; M. Dan McKirnan

2001-01-01

296

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

297

Achromatopsia as a Potential Candidate for Gene Therapy  

PubMed Central

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.

2013-01-01

298

Cationic Polyene Phospholipids as DNA Carriers for Ocular Gene Therapy  

PubMed Central

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

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

2014-01-01

299

Future of adenoviruses in the gene therapy of arthritis.  

PubMed

Recombinant adenoviruses are straightforward to produce at high titres, have a promiscuous host-range, and, because of their ability to infect nondividing cells, lend themselves to in vivo gene delivery. Such advantages have led to their widespread and successful use in preclinical studies of arthritis gene therapy. While adenoviral vectors are well suited to 'proof of principle' experiments in laboratory animals, there are several barriers to their use in human studies at this time. Transient transgene expression limits their application to strategies, such as synovial ablation, which do not require extended periods of gene expression. Moreover, there are strong immunological barriers to repeat dosing. In addition, safety concerns predicate local, rather than systemic, delivery of the virus. Continued engineering of the adenoviral genome is producing vectors with improved properties, which may eventually overcome these issues. Promising avenues include the development of 'gutted' vectors encoding no endogenous viral genes and of adenovirus-AAV chimeras. Whether these will offer advantages over existing vectors, which may already provide safe, long-term gene expression following in vivo delivery, remains to be seen. PMID:11299054

Evans, C H; Ghivizzani, S C; Oligino, T A; Robbins, P D

2001-01-01

300

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

301

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

302

Tissue-engineered skeletal muscle organoids for reversible gene therapy.  

PubMed

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 postmitotic cells in tissue engineered organs has several advantages over other forms of muscle gene therapy. PMID:8934233

Vandenburgh, H; Del Tatto, M; Shansky, J; Lemaire, J; Chang, A; Payumo, F; Lee, P; Goodyear, A; Raven, L

1996-11-10

303

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

Microsoft Academic Search

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

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

2005-01-01

304

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

E-print Network

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

Paris-Sud XI, Université de

305

The Hopes and Fears of In Utero Gene Therapy for Genetic Disease—A Review  

Microsoft Academic Search

Somatic gene delivery in utero is a novel approach to gene therapy for genetic disease. It is based on the concept that application of gene therapy vectors to the fetus in utero may prevent the development of early disease related tissue damage, may allow targeting of otherwise inaccessible organs, tissues and still expanding stem cell populations and may also provide

C. Coutelle; M. Themis; S. Waddington; L. Gregory; M. Nivsarkar; S. Buckley; T. Cook; C. Rodeck; D. Peebles; A. David

2003-01-01

306

Molecular Imaging in Traditional Chinese Medicine Therapy for Neurological Diseases  

PubMed Central

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

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

2013-01-01

307

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

E-print Network

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

Omiecinski, Curtis

308

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

E-print Network

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

Tedford, Nathan C

2007-01-01

309

Evaluation of biolistic gene transfer methods in vivo using non-invasive bioluminescent imaging techniques  

PubMed Central

Background Gene therapy continues to hold great potential for treating many different types of disease and dysfunction. Safe and efficient techniques for gene transfer and expression in vivo are needed to enable gene therapeutic strategies to be effective in patients. Currently, the most commonly used methods employ replication-defective viral vectors for gene transfer, while physical gene transfer methods such as biolistic-mediated ("gene-gun") delivery to target tissues have not been as extensively explored. In the present study, we evaluated the efficacy of biolistic gene transfer techniques in vivo using non-invasive bioluminescent imaging (BLI) methods. Results Plasmid DNA carrying the firefly luciferase (LUC) reporter gene under the control of the human Cytomegalovirus (CMV) promoter/enhancer was transfected into mouse skin and liver using biolistic methods. The plasmids were coupled to gold microspheres (1 ?m diameter) using different DNA Loading Ratios (DLRs), and "shot" into target tissues using a helium-driven gene gun. The optimal DLR was found to be in the range of 4-10. Bioluminescence was measured using an In Vivo Imaging System (IVIS-50) at various time-points following transfer. Biolistic gene transfer to mouse skin produced peak reporter gene expression one day after transfer. Expression remained detectable through four days, but declined to undetectable levels by six days following gene transfer. Maximum depth of tissue penetration following biolistic transfer to abdominal skin was 200-300 ?m. Similarly, biolistic gene transfer to mouse liver in vivo also produced peak early expression followed by a decline over time. In contrast to skin, however, liver expression of the reporter gene was relatively stable 4-8 days post-biolistic gene transfer, and remained detectable for nearly two weeks. Conclusions The use of bioluminescence imaging techniques enabled efficient evaluation of reporter gene expression in vivo. Our results demonstrate that different tissues show different expression kinetics following gene transfer of the same reporter plasmid to different mouse tissues in vivo. We evaluated superficial (skin) and abdominal organ (liver) targets, and found that reporter gene expression peaked within the first two days post-transfer in each case, but declined most rapidly in the skin (3-4 days) compared to liver (10-14 days). This information is essential for designing effective gene therapy strategies in different target tissues. PMID:21635760

2011-01-01

310

Towards gene therapy based on femtosecond optical transfection  

NASA Astrophysics Data System (ADS)

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

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

2012-06-01

311

Using lentiviral vectors for efficient pancreatic cancer gene therapy.  

PubMed

Pancreatic cancer (PC) remains a life-threatening disease. Efficient therapeutic gene delivery to PC-derived cells continues to present challenges. We used self-inactivated lentiviral vectors to transduce PC-derived cells in vitro and in vivo. We showed that lentiviral vectors transduce PC-derived cell lines with high efficiency (>90%), regardless of the differentiation state of the cell. Next, we transferred human interferon beta (hIFN-beta) gene. Expression of hIFN-beta in PC cells using lentiviral vectors resulted in the inhibition of cell proliferation and the induction of cell death by apoptosis. In vivo, lentiviral administration of hIFN-beta prevented PC tumor progression for up to 15 days following gene therapy, and induced tumor regression/stabilization in 50% of the mice treated. Again, hIFN-beta expression resulted in cancer cell proliferation inhibition and apoptosis induction. We provide evidence that human immunodeficiency virus (HIV)-1-based lentiviral vectors are very efficient for gene transfer in PC-derived cells in vitro and in vivo. As a consequence, delivery of hIFN-beta stopped PC tumor progression. Thus, our approach could be applied to the 85% of PC patients with a locally advanced disease. PMID:19911032

Ravet, E; Lulka, H; Gross, F; Casteilla, L; Buscail, L; Cordelier, P

2010-05-01

312

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

313

Gene therapy: A possible aid to cancer radiotherapy.  

PubMed

Extract: Cancer remains a major health problem despite great advances in radiation and other therapeutic modalities. The increasing success of radiotherapy owes to many factors, including the more sophisticated equipment that provides improved treatment techniques and the variety of natural or synthetic subatomic particles available for treatment. This is made possible, in part, by better imaging techniques such as computed tomography (CT, multiple x-rays are combined by computer to give a 2-D image), magnetic resonance imaging (MRI, magnet causes hydrogen atoms to become polarized and their "spin" is measured and summated to create an image of an internal structure), and positron emission tomography (PET, images created of positron decay by radioactive isotopes administered and taken up by the tissue of interest -- in this case the tumor). These new technologies allow one to greatly improve tumor targeting and to better visualize the radiation delivered to all anatomic sites within the patient. All forms of ionizing radiation (radiation that can split atoms and molecules into charged particles and radicals) can destroy any type of cancer cell if a sufficiently high dose is delivered. Normal tissue injury limits the dose of radiation a physician can deliver and thus limits the cancer control rate. Photons (x-ray therapy) are the most common particles used in radiation treatment. PMID:20704940

Gridley, Daila S; Slater, James M

2004-12-01

314

IEEE Eng Med Biol Mag. Author manuscript Issues in image-guided therapy  

E-print Network

IEEE Eng Med Biol Mag. Author manuscript Page /1 5 Issues in image-guided therapy Haigron Pascal 1 ; computer assisted surgery ; computer vision ; image guided therapy ; medical robotics Medical robotics, Computer Assisted Surgery (CAS), Image-Guided Therapy (IGT) and the like emerged more than 20 years ago

Paris-Sud XI, Université de

315

Gene Therapy: The Potential Applicability of Gene Transfer Technology to the Human Germline  

PubMed Central

The theoretical possibility of applying gene transfer methodologies to the human germline is explored. Transgenic methods for genetically manipulating embryos may in principle be applied to humans. In particular, microinjection of retroviral vector appears to hold the greatest promise, with transgenic primates already obtained from this approach. Sperm-mediated gene transfer offers potentially the easiest route to the human germline, however the requisite methodology is presently underdeveloped. Nuclear transfer (cloning) offers an alternative approach to germline genetic modification, however there are major health concerns associated with current nuclear transfer methods. It is concluded that human germline gene therapy remains for all practical purposes a future possibility that must await significant and important advances in gene transfer technology. PMID:15912200

2004-01-01

316

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. PMID:18300702

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

2009-01-01

317

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

E-print Network

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

Boyer, Edmond

318

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. PMID:18990940

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

2008-01-01

319

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

320

Image-guided bolus electron conformal therapy - a case study.  

PubMed

We report on our initial experience with daily image guidance for the treatment of a patient with a basal cell carcinoma of the nasal dorsum using bolus electron conformal therapy. We describe our approach to daily alignment using treatment machine-integrated megavoltage (MV) planar imaging in conjunction with cone beam CT (CBCT) volumetric imaging to ensure the best possible setup reproducibility. Based on MV imaging, beam aperture misalignment with the intended treatment region was as large as 0.5 cm in the coronal plane. Four of the five fractions analyzed show induced shifts when compared to digitally reconstructed radiographs (DRR), in the range of 0.2-0.5 cm. Daily inspection of CBCT images show that the bolus device can have significant tilt in any given direction by as much as 13° with respect to beam axis. In addition, we show that CBCT images reveal air gaps between bolus and skin that vary from day to day, and can potentially degrade surface dose coverage. Retrospective dose calculation on CBCT image sets shows that when daily shifts based on MV imaging are not corrected, geometrical miss of the planning target volume (PTV) can cause an underdosing as large as 14% based on DVH analysis of the dose to the 90% of the PTV volume. PMID:21330977

Zeidan, Omar A; Chauhan, Bhavin D; Estabrook, William W; Willoughby, Twyla R; Manon, Rafael R; Meeks, Sanford L

2011-01-01

321

Molecular imaging of apoptosis for early prediction of therapy efficiency.  

PubMed

Evasion of apoptosis is one of the hallmarks of cancer and any effective therapy primarily attempts to induce apoptosis. The evaluation of the degree of success of cancer therapy is currently mainly based on clinical and laboratory parameters and in a later stage on tumor shrinkage. However, none of these parameters provide an objective and early analysis of a therapeutic effect. Molecular imaging may provide a tool for this purpose by using not only pathophysiological but also biochemical effects of the therapy. First in the field, FDG-PET has been explored and demonstrated to offer insight in the amount of viable cells, even though false positives are commonly due to the lack of specificity of this particular radiopharmaceutical. More specific markers target the dying cells instead of those remaining alive. Specific apoptosis markers have been developed of which the radiolabeled Annexin A5 is the most intensely studied probe. Site-specific labeling strategies have improved this imaging probe with good results both in pre-clinical studies and in clinical trials, with promises for clinical applications. Caspase sensitive probes, such as the isatines, can also effectively image apoptosis but are limited due to the high background activities. More recent discoveries of small apoptosis sensitive probes, such as (18)F-ML10, are currently being explored. In this review, the most important apoptosis sensitive probes are described from both a pre-clinical and a clinical perspective, highlighting their potential but also their limitations as an early marker for therapeutic success. It seems that apoptosis imaging can help to guide therapy, not by replacing the current methodology but by providing additional and useful information. PMID:24025102

De Saint-Hubert, Marijke; Bauwens, Matthias; Mottaghy, Felix M

2014-01-01

322

Acute Stroke Imaging for Thrombolytic Therapy – An Update  

Microsoft Academic Search

More than ten years after its approval intravenous thrombolysis with rtPA still is the only approved therapy for acute ischemic stroke. In this review we aim to give an up-to-date overview of acute stroke imaging within and outside of approved indications for thrombolysis. We discuss the potential applications of modern CT techniques such as CT angiography and perfusion CT as

Martin Köhrmann; Eric Jüttler; Hagen B. Huttner; Tim Nowe; Peter D. Schellinger

2007-01-01

323

Future of local bone regeneration - Protein versus gene therapy.  

PubMed

The most promising attempts to achieve bone regeneration artificially are based on the application of mediators such as bone morphogenetic proteins (BMPs) directly to the deficient tissue site. BMPs, as promoters of the regenerative process, have the ability to induce de novo bone formation in various tissues, and many animal models have demonstrated their high potential for ectopic and orthotopic bone formation. However, the biological activity of the soluble factors that promote bone formation in vivo is limited by diffusion and degradation, leading to a short half-life. Local delivery remains a problem in clinical applications. Several materials, including hydroxyapatite, tricalcium phosphate, demineralised bone matrices, poly-lactic acid homo- and heterodimers, and collagen have been tested as carriers and delivery systems for these factors in a sustained and appropriate manner. Unfortunately these delivery vehicles often have limitations in terms of biodegradability, inflammatory and immunological rejection, disease transmission, and most importantly, an inability to provide a sustained, continuous release of these factors at the region of interest. In coping with these problems, new approaches have been established: genes encoding these growth factor proteins can be delivered to the target cells. In this way the transfected cells serve as local "bioreactors", as they express the exogenous genes and secrete the synthesised proteins into their vicinity. The purpose of this review is to present the different methods of gene versus growth factor delivery in tissue engineering. Our review focuses on these promising and innovative methods that are defined as regional gene therapy and provide an alternative to the direct application of growth factors. Various advantages and disadvantages of non-viral and viral vectors are discussed. This review identifies potential candidate genes and target cells, and in vivo as well as ex vivo approaches for cell transduction and transfection. In explaining the biological basis, this paper also refers to current experimental and clinical applications. PMID:20434921

Fischer, J; Kolk, A; Wolfart, St; Pautke, C; Warnke, P H; Plank, C; Smeets, R

2011-01-01

324

Gene Profiling Technique to Accelerate Stem Cell Therapies for Eye Diseases  

MedlinePLUS

... for eye diseases News and Events News Brief Gene profiling technique to accelerate stem cell therapies for ... The method simultaneously measures the expression of multiple genes, allowing scientists to quickly characterize cells according to ...

325

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa  

PubMed Central

Hereditary retinal blindness is caused by mutations in genes expressed in photoreceptors or retinal pigment epithelium. Gene therapy in mouse and dog models of a primary retinal pigment epithelium disease has already been translated to human clinical trials with encouraging results. Treatment for common primary photoreceptor blindness, however, has not yet moved from proof of concept to the clinic. We evaluated gene augmentation therapy in two blinding canine photoreceptor diseases that model the common X-linked form of retinitis pigmentosa caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, which encodes a photoreceptor ciliary protein, and provide evidence that the therapy is effective. After subretinal injections of adeno-associated virus-2/5–vectored human RPGR with human IRBP or GRK1 promoters, in vivo imaging showed preserved photoreceptor nuclei and inner/outer segments that were limited to treated areas. Both rod and cone photoreceptor function were greater in treated (three of four) than in control eyes. Histopathology indicated normal photoreceptor structure and reversal of opsin mislocalization in treated areas expressing human RPGR protein in rods and cones. Postreceptoral remodeling was also corrected: there was reversal of bipolar cell dendrite retraction evident with bipolar cell markers and preservation of outer plexiform layer thickness. Efficacy of gene therapy in these large animal models of X-linked retinitis pigmentosa provides a path for translation to human treatment. PMID:22308428

Beltran, William A.; Cideciyan, Artur V.; Lewin, Alfred S.; Iwabe, Simone; Khanna, Hemant; Sumaroka, Alexander; Chiodo, Vince A.; Fajardo, Diego S.; Roman, Alejandro J.; Deng, Wen-Tao; Swider, Malgorzata; Aleman, Tomas S.; Boye, Sanford L.; Genini, Sem; Swaroop, Anand; Hauswirth, William W.; Jacobson, Samuel G.; Aguirre, Gustavo D.

2012-01-01

326

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. PMID:24023896

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

2013-01-01

327

Enhancement of plasmid-mediated gene therapy for muscular dystrophy by directed plasmid integration  

PubMed Central

Plasmid-mediated gene therapy can restore dystrophin expression in skeletal muscle in the mdx mouse, a model of Duchenne muscular dystrophy. However, sufficient long-term expression and distribution of dystrophin remain a hurdle for translating this technology into a viable treatment for Duchenne muscular dystrophy. To improve plasmid-mediated gene therapy for muscle diseases, we studied the effects of targeted plasmid integration using a phage integrase (?C31) that can mediate the integration of suitably modified plasmids into the mammalian genome. Using a luciferase expression plasmid, we monitored plasmid gene expression noninvasively in living mice by bioluminescence imaging. Coinjection of an integrase plasmid resulted in 5- to 10-fold higher levels of sustained luciferase expression. Likewise, plasmid-mediated dystrophin expression in mdx muscle was enhanced by integration. Using a combination of dystrophin and luciferase plasmids, we analyzed the functional benefit of dystrophin expression in the dystrophic muscle. The expression of dystrophin slowed the loss of luciferase expression associated with muscle degeneration, and that protection was enhanced by targeted integration of the dystrophin plasmid. In the presence of integrase, dystrophin expression was distributed along a much greater length of individual fibers, and this was associated with increased protection against degenerative changes. These data demonstrate the importance of both the level and distribution of dystrophin expression to achieve therapeutic efficacy, and that the efficacy can be enhanced by targeted plasmid integration. PMID:16387861

Bertoni, Carmen; Jarrahian, Sohail; Wheeler, Thurman M.; Li, Yining; Olivares, Eric C.; Calos, Michele P.; Rando, Thomas A.

2006-01-01

328

Prospective on the potential of imaging gene expression  

SciTech Connect

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

Taylor, Scott E; Budinger, Thomas F.

2000-06-01

329

Photoacoustic imaging of lacZ gene expression  

E-print Network

for molecular imaging research. © 2007 Society of Photo-Optical Instrumentation Engineers. DOI: 10 protein enables whole body imaging of small animals, although at low spatial resolution due to multiplePhotoacoustic imaging of lacZ gene expression in vivo Li Li,a, Roger J. Zemp,a, Gina Lungu,b George

Wang, Lihong

330

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

E-print Network

HUMAN GENE THERAPY 19:1261­1271 (November 2008) © Mary Ann Liebert, Inc. DOI: 10.1089/hum.2008.060 Efficiency of High- and Low-Voltage Pulse Combinations for Gene Electrotransfer in Muscle, Liver, Tumor Gene electrotransfer is gaining momentum as an efficient methodology for nonviral gene transfer

Paris-Sud XI, Université de

331

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

PubMed Central

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

Fernandez-Fernandez, Alicia; Manchanda, Romila

2011-01-01

332

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

PubMed

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

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

2011-12-01

333

Implementation of Image-Guidance Techniques in Radiation Therapy  

NASA Astrophysics Data System (ADS)

For more than 100 years, physicists have been a vital part of the medical team required to deliver radiation therapy. Their role encompasses the verification of dose accuracy to the development and implementation of new techniques, the most recent of which is the incorporation of daily image guidance to account for inter- and intra-fraction target changes. For example, computed tomography (CT) integrated into radiotherapy treatment units allows the image-guided treatment of the prostate where the target location depends on the degree of rectal filling--a parameter that changes on timescales from minutes to weeks. Different technology is required for the adequate treatment of small lung tumours since respiration occurs on timescales of seconds. This presentation will review current image-guided techniques.

Thomas, Michael; Clark, Brenda; MacPherson, Miller; Montgomery, Lynn; Gerig, Lee

2008-06-01

334

Efficient gene delivery and multimodal imaging by lanthanide-based upconversion nanoparticles.  

PubMed

Nanoparticles have been explored as nonviral gene carriers for years because of the simplicity of surface modification and lack of immune response. Lanthanide-based upconversion nanoparticles (UCNPs) are becoming attractive candidates for biomedical applications in virtue of their unique optical properties and multimodality imaging ability. Here, we report a UCNPs-based structure with polyethylenimine coating for both efficient gene transfection and trimodality imaging. Cytotoxicity tests demonstrated that the nanoparticles exhibited significantly decreased cytotoxicity compared to polyethylenimine polymer. Further, in vitro studies revealed that the gene carriers are able to transfer the enhanced green fluorescence protein (EGFP) plasmid DNA into Hela cells in higher transfection efficiency than PEI. Gene silencing was also examined by delivering bcl-2 siRNA into Hela cells, resulting in significant downregulation of target bcl-2 mRNA. More importantly, we demonstrated the feasibility of upconversion gene carriers to serve as effective contrast agents for MRI/CT/UCL trimodality imaging both in vitro and in vivo. The facile fabrication process, great biocompatibility, enhanced gene transfection efficiency, and great bioimaging ability can make it promising for application in gene therapy. PMID:25291048

Wang, Lin; Liu, Jianhua; Dai, Yunlu; Yang, Qiang; Zhang, Yuanxin; Yang, Piaoping; Cheng, Ziyong; Lian, Hongzhou; Li, Chunxia; Hou, Zhiyao; Ma, Ping'an; Lin, Jun

2014-11-01

335

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

PubMed Central

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

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

2009-01-01

336

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. PMID:19711944

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

337

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. PMID:22131873

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

2011-01-01

338

Liver-directed Neonatal Gene Therapy Prevents Cardiac, Bone, Ear, and Eye Disease in  

E-print Network

Liver-directed Neonatal Gene Therapy Prevents Cardiac, Bone, Ear, and Eye Disease-L-iduronidase (IDUA) activity results in accumulation of glycosaminoglycans in many cells. Gene therapy could program and light. In contrast, MPS I mice that received high-dose RV had normal echocardiograms, BMD, auditory

Ponder, Katherine P.

339

Clostridial spores as live 'Trojan horse' vectors for cancer gene therapy: comparison with viral delivery systems  

Microsoft Academic Search

Solid tumours account for 90% of all cancers. Gene therapy represents a potential new modality for their treatment. Up to now, several approaches have been developed, but the most efficient ones are the viral vector based gene therapy systems. However, viral vectors suffer from several deficiencies: firstly most vectors currently in use require intratumoural injection to elicit an effect. This

Ming Q Wei; Ruimei Ren; David Good; Jozef Anné

2008-01-01

340

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

E-print Network

Hum Gene Ther . Author manuscript Page /1 15 Developing cell therapy techniques for respiratory, in a murine model of acute epithelial airway injury already used in gene therapy experiments on cystic ; Animals ; Bronchoalveolar Lavage ; DNA Primers ; genetics ; Embryonic Stem Cells ; transplantation

Paris-Sud XI, Université de

341

Worsening of Cardiomyopathy Using Deflazacort in an Animal Model Rescued by Gene Therapy  

Microsoft Academic Search

We have previously demonstrated that gene therapy can rescue the phenotype and extend lifespan in the delta-sarcoglycan deficient cardiomyopathic hamster. In patients with similar genetic defects, steroids have been largely used to slow down disease progression. Aim of our study was to evaluate the combined effects of steroid treatment and gene therapy on cardiac function. We injected the human delta-sarcoglycan

Ida Luisa Rotundo; Stefania Faraso; Elvira De Leonibus; Gerardo Nigro; Carmen Vitiello; Alessio Lancioni; Daniele Di Napoli; Sigismondo Castaldo; Vincenzo Russo; Fabio Russo; Giulio Piluso; Alberto Auricchio; Vincenzo Nigro

2011-01-01

342

Optimization of PAMAM-gold nanoparticle conjugation for gene therapy.  

PubMed

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

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

2014-02-01

343

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

344

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. PMID:23617430

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

2013-01-01

345

N3-substituted thymidine bioconjugates for cancer therapy and imaging.  

PubMed

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

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

2013-04-01

346

Nonviral Gene Delivery to Mesenchymal Stem Cells Using Cationic Liposomes for Gene and Cell Therapy  

PubMed Central

Mesenchymal stem cells (MSCs) hold a great promise for application in several therapies due to their unique biological characteristics. In order to harness their full potential in cell-or gene-based therapies it might be advantageous to enhance some of their features through gene delivery strategies. Accordingly, we are interested in developing an efficient and safe methodology to genetically engineer human bone marrow MSC (BM MSC), enhancing their therapeutic efficacy in Regenerative Medicine. The plasmid DNA delivery was optimized using a cationic liposome-based reagent. Transfection efficiencies ranged from ~2% to ~35%, resulting from using a Lipid/DNA ratio of 1.25 with a transgene expression of 7 days. Importantly, the number of plasmid copies in different cell passages was quantified for the first time and ~20,000 plasmid copies/cell were obtained independently of cell passage. As transfected MSC have shown high viabilities (>90%) and recoveries (>52%) while maintaining their multipotency, this might be an advantageous transfection strategy when the goal is to express a therapeutic gene in a safe and transient way. PMID:20625411

Madeira, C.; Mendes, R. D.; Ribeiro, S. C.; Boura, J. S.; Aires-Barros, M. R.; da Silva, C. L.; Cabral, J. M. S.

2010-01-01

347

Perspectives on gene therapy for lysosomal storage diseases that affect hematopoiesis.  

PubMed

Successful gene therapy for lysosomal storage diseases that involve the bone marrow and hematopoiesis is hindered by the hostile microenvironments created by these diseases and the irreversibility of the pathologic manifestations. Of the 40 lysosomal storage diseases, Gaucher disease type I, Niemann-Pick B, and mucopolysaccharidosis type I have hematopoietic involvement, are treatable by enzyme therapy, and respond to bone marrow transplantation. These storage diseases provide the basis for continued development of gene therapy. PMID:12901334

Grabowski, Gregory A

2003-07-01

348

Vector systems for prenatal gene therapy: principles of non-viral vector design and production.  

PubMed

Gene therapy vectors based on viruses are the most effective gene delivery systems in use today and although efficient at gene transfer their potential toxicity (Hacein-Bey-Abina et al., Science 302:415-419, 2003) provides impetus for the development of safer non-viral alternatives. An ideal vector for human gene therapy should deliver sustainable therapeutic levels of gene expression without affecting the viability of the host at either the cellular or somatic level. Vectors, which comprise entirely human elements, may provide the most suitable method of achieving this. Non-viral vectors are attractive alternatives to viral gene delivery systems because of their low toxicity, relatively easy production, and great versatility. The development of more efficient, economically prepared, and safer gene delivery vectors is a crucial prerequisite for their successful clinical application and remains a primary strategic task of gene therapy research. PMID:22648771

Wong, Suet Ping; Argyros, Orestis; Harbottle, Richard P

2012-01-01

349

Fast magnetic resonance temperature imaging for focused ultrasound thermal therapy  

NASA Astrophysics Data System (ADS)

The current standard for temperature sensitive imaging using magnetic resonance (MR) is 2-D, spoiled, fast gradient-echo (fGRE) phase-difference imaging exploiting temperature dependent changes in the proton resonance frequency (PRF). The echo-time (TE) for optimal sensitivity is larger than the typical repetition time (TR) of an fGRE sequence. Since TE must be less than TR in the fGRE sequence, this limits the technique's achievable sensitivity, spatial, and temporal resolution. This adversely affects both accuracy and volume coverage of the measurements. Accurate measurement of the rapid temperature changes associated with pulsed thermal therapies, such as high-intensity focused ultrasound (FUS), at optimal temperature sensitivity requires faster acquisition times than those currently available. Use of fast MR acquisition strategies, such as interleaved echo-planar and spiral imaging, can provide the necessary increase in temporal performance and sensitivity while maintaining adequate signal-to-noise and in-plane spatial resolution. This research explored the adaptation and optimization of several fast MR acquisition methods for thermal monitoring of pulsed FUS thermal therapy. Temperature sensitivity, phase- difference noise and phase-difference to phase- difference-to noise ratio for the different pulse sequences were evaluated under varying imaging parameters in an agar gel phantom to establish optimal sequence parameters for temperature monitoring. The temperature sensitivity coefficient of the gel phantom was measured, allowing quantitative temperature extrapolations. Optimized fast sequences were compared based on the ability to accurately monitor temperature changes at the focus of a high-intensity focused ultrasound unit, volume coverage, and contrast-to-noise ratio in the temperature maps. Operating parameters, which minimize complex phase- difference measurement errors introduced by use of the fast-imaging methods, were established.

Stafford, Roger Jason

350

Baseline 18F-FDG PET image derived parameters for therapy response prediction in oesophageal cancer  

E-print Network

1 Baseline 18F-FDG PET image derived parameters for therapy response prediction in oesophageal for therapy response Keywords: oesophageal cancer, response to therapy, PET scan, tumour volume, total lesion of tumour measurements on 18F-FDG PET pretreatment scan regarding therapy response in oesophageal cancer

Paris-Sud XI, Université de

351

Image-guided ablative therapies for lung cancer.  

PubMed

Lung cancer is the commonest cause of death in adults. Although the treatment of choice is surgical resection with lobectomy, many patients are nonsurgical candidates because of medical comorbidities. Patients may also have recurrent disease after resection or radiotherapy and some patients refuse surgical options. Image-guided ablation has been recently introduced as a safe, alternative treatment of localized disease in carefully selected patients. This article discusses the principles, technique, and follow-up of the 3 main ablative therapies currently used in the lung, radiofrequency ablation, microwave ablation, and percutaneous cryotherapy. PMID:22974782

Sharma, Amita; Abtin, Fereidoun; Shepard, Jo-Anne O

2012-09-01

352

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

E-print Network

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

Silcox, Christina Elise

2014-01-01

353

Perfluorocarbon Nanoparticles for Physiological and Molecular Imaging and Therapy  

PubMed Central

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

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

2014-01-01

354

Gold Nanoconstructs for Multimodal Diagnostic Imaging and Photothermal Cancer Therapy  

NASA Astrophysics Data System (ADS)

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

Coughlin, Andrew James

355

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

E-print Network

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

Levy, Doron

356

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

E-print Network

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. 1.

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

357

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

PubMed Central

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

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

2010-01-01

358

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

Federal Register 2010, 2011, 2012, 2013

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

2013-05-08

359

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

PubMed

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

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

2012-01-01

360

Electroporation-mediated pain-killer gene therapy for mononeuropathic rats  

Microsoft Academic Search

The relatively low expression levels achieved from transferred genes have limited the application of nonviral vectors for gene transfer into the spinal cord in vivo. Thus, the aim of this study was to evaluate the efficacy of electroporation-mediated pro-opiomelanocortin (POMC) gene therapy for neuropathic pain using an animal model of chronic constrictive injury (CCI). Firstly, the optimal pulse characteristics (voltage,

C-R Lin; L-C Yang; T-H Lee; C-T Lee; H-T Huang; W-Z Sun; J-T Cheng

2002-01-01

361

564. Delivery of Episomal Vectors Carrying Large Genomic Regions for Gene Therapy  

Microsoft Academic Search

Effective gene therapy requires sustained levels of gene expression over long periods of time. Gene delivery into mammalian cells by viral vectors is very efficient, but there are dangers due to immunogenicity and insertional mutagenesis. Our aim here is to develop non-viral delivery of large genomic loci that are maintained as episomes in cells. Non-viral delivery has the advantages of

Wing T. Cheung; Catherine Grillot-Courvalin; Clare Huxley

2005-01-01

362

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

E-print Network

HUMAN GENE THERAPY 19:1249­1260 (November 2008) © Mary Ann Liebert, Inc. DOI: 10.1089/hum.2008.059 Physiological Effects of High- and Low-Voltage Pulse Combinations for Gene Electrotransfer in Muscle Pernille and Lluis M. Mir3 Abstract Gene transfer by electroporation is gaining momentum now that high-level, long

Paris-Sud XI, Université de

363

732. A Novel Double-Pseudotyped Viral Vector for Gene Therapy  

Microsoft Academic Search

A major goal of gene therapy is to achieve highly efficient and specific delivery of therapeutic genes into target cells. While current gene delivery vectors have been successful in many cases, there are still some barriers. These include low titer, low specificity, short-term expression, inconvenient vector design for different targets and inefficient targeting of certain tissues due to the lack

Ning Chai; Gary Kobinger; Giancarlo Tanzi; James Wilson; Paul Bates

2004-01-01

364

ORIGINAL ARTICLE Retroviral vector insertions in T-lymphocytes used for suicide gene therapy  

E-print Network

ORIGINAL ARTICLE Retroviral vector insertions in T-lymphocytes used for suicide gene therapy occur. The transfer of a suicide gene into donor T-lymphocytes (TLCs) allows selective elimination of Gv, there is an urgent need also to analyze retroviral integration sites in TLCs. We examined suicide gene- transduced

Granada, Universidad de

365

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

Microsoft Academic Search

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

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

2006-01-01

366

Analysis Of S/MAR Vectors For Gene Therapy A Thesis Submitted For The Degree Of Doctor Of Philosophy  

E-print Network

1 Analysis Of S/MAR Vectors For Gene Therapy In Muscle A Thesis Submitted For The Degree Of Doctor caused by this condition are being investigated, one of which is gene therapy. This approach is used of this vector for use as a gene therapy vector in muscle cells in order to treat MD. In this study, the long

Sheldon, Nathan D.

367

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

E-print Network

[CANCER RESEARCH 64, 5390­5397, August 1, 2004] Effective Gene-Viral Therapy for Telomerase Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical Gene-viral therapy, which uses replication-selective transgene-express- ing viruses to manage tumors

Tian, Weidong

368

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

E-print Network

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

Warburton, Peter E.

369

Accepting Risk in Clinical Research: Is the Gene Therapy Field Becoming Too Risk-averse?  

PubMed Central

Risk is an inescapable aspect of clinical research and is increasingly pertinent to the gene therapy field as the imperative for clinical trial activity grows. In recent years, the widely reported occurrence of serious adverse events (SAEs) in gene therapy studies, including trials for ornithine transcarbamylase (OTC) deficiency, X-linked severe combined immunodeficiency (SCID-X1), and rheumatoid arthritis, has heightened fear in public perceptions of gene therapy. Although it is essential to be cognizant of the risks involved in gene therapy research, there is a danger that gene therapy may become too risk-averse. If the field is to make progress, it is necessary to understand how risk is defined in gene therapy research, how understandings of risk differ, how risk is assessed, how decisions about risk are made, and how gene therapy risks are communicated to subjects and research participants during the informed consent process. In addition to minimizing the risks of clinical research through extensive preclinical safety studies, attention should be given to how decisions about risk and risk acceptability are made by researchers and subjects, and to the methods used to communicate risks to patients. Critical attention to risk will help ensure that the safety of subjects is protected, while also enabling research to develop better treatments for patients. PMID:19773741

Deakin, Claire T; Alexander, Ian E; Kerridge, Ian

2009-01-01

370

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

PubMed

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

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

2014-02-01

371

Recent progress in gene therapy for Parkinson's disease.  

PubMed

Parkinson's disease (PD) is an age-related and the second most common neurodegenerative disorder beyond Alzheimer's disease. A neuropathological hallmark of PD is a prominent loss of dopaminergic neurons in the substantia nigra projecting into the caudate and putamen. Oral administration of L-dopa and/or dopamine agonists ameliorates cardinal motor symptoms of PD. However, an intermittent and long-term treatment with L-dopa frequently induces adverse side effects such as motor fluctuations and dyskinesia. As alternative therapeutic strategies, the following four approaches are currently under evaluation for clinical gene therapy trials in PD; 1) recombinant adeno-associated virus 2 system encoding aromatic L-amino acid decarboxylase (AADC), 2) glutamic acid decarboxylase (GAD) and 3) Neurturin, and 4) equine infectious anemia virus-based lentiviral system encoding AADC, tyrosine hydroxylase (TH) and GTP cyclohydrolase I (GCH) in a single transcriptional unit. GAD and Neurturin have been assessed in double blind placebocontrolled phase II studies; GAD showed a significant improvement in motor function, and Neurturin, although it failed to show significant effects at 12 months post-treatment, exhibited promising outcomes in additional examinations at 18 months. The other two approaches also represented significant effects in phase I or I/II studies. Adverse side effects due to surgery have not been observed. Here, we review preclinical and clinical trials encouraging further investigations of curative treatment for the patients suffering from PD. PMID:22834832

Nakata, Y; Yasuda, T; Mochizuki, H

2012-12-01

372

Cancer gene therapy using a survivin mutant adenovirus  

PubMed Central

We have constructed a replication-deficient adenovirus encoding a nonphosphorylatable Thr34?Ala mutant of the apoptosis inhibitor survivin (pAd-T34A) to target tumor cell viability in vitro and in vivo. Infection with pAd-T34A caused spontaneous apoptosis in cell lines of breast, cervical, prostate, lung, and colorectal cancer. In contrast, pAd-T34A did not affect cell viability of proliferating normal human cells, including fibroblasts, endothelium, or smooth muscle cells. Infection of tumor cells with pAd-T34A resulted in cytochrome c release from mitochondria, cleavage of approximately 46-kDa upstream caspase-9, processing of caspase-3 to the active subunits of approximately 17 and 19 kDa, and increased caspase-3 catalytic activity. When compared with chemotherapeutic regimens, pAd-T34A was as effective as taxol and considerably more effective than adriamycin in induction of tumor cell apoptosis and enhanced taxol-induced cell death. In three xenograft breast cancer models in immunodeficient mice, pAd-T34A suppressed de novo tumor formation, inhibited by approximately 40% the growth of established tumors, and reduced intraperitoneal tumor dissemination. Tumors injected with pAd-T34A exhibited loss of proliferating cells and massive apoptosis by in situ internucleosomal DNA fragmentation. These data suggest that adenoviral targeting of the survivin pathway may provide a novel approach for selective cancer gene therapy. PMID:11581299

Mesri, Mehdi; Wall, Nathan R.; Li, Jia; Kim, Richard W.; Altieri, Dario C.

2001-01-01

373

Factor IX variants improve gene therapy efficacy for hemophilia B.  

PubMed

Intramuscular injection of adeno-associated viral (AAV) vector to skeletal muscle of humans with hemophilia B is safe, but higher doses are required to achieve therapeutic factor IX (F.IX) levels. The efficacy of this approach is hampered by the retention of F.IX in muscle extracellular spaces and by the limiting capacity of muscle to synthesize fully active F.IX at high expression rates. To overcome these limitations, we constructed AAV vectors encoding F.IX variants for muscle- or liver-directed expression in hemophilia B mice. Circulating F.IX levels following intramuscular injection of AAV-F.IX-K5A/V10K, a variant with low-affinity to extracellular matrix, were 2-5 fold higher compared with wild-type (WT) F.IX, while the protein-specific activities remained similar. Expression of F.IX-R338A generated a protein with 2- or 6-fold higher specific activity than F.IX-WT following vector delivery to skeletal muscle or liver, respectively. F.IX-WT and variant forms provide effective hemostasis in vivo upon challenge by tail-clipping assay. Importantly, intramuscular injection of AAV-F.IX variants did not trigger antibody formation to F.IX in mice tolerant to F.IX-WT. These studies demonstrate that F.IX variants provide a promising strategy to improve the efficacy for a variety of gene-based therapies for hemophilia B. PMID:15550487

Schuettrumpf, Joerg; Herzog, Roland W; Schlachterman, Alexander; Kaufhold, Antje; Stafford, Darrel W; Arruda, Valder R

2005-03-15

374

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. PMID:17644360

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

375

Development of Chimeric Gene Regulators for Cancer-specific Gene Therapy with both Transcriptional and Translational Targeting  

Microsoft Academic Search

Cancer gene therapy has been of great challenge in achieving maximal high levels of specificity and more rational efficiency\\u000a in target cancer cell. We herein developed a novel approach for cancer-specific gene therapy using both transcriptional and\\u000a translational targeting regulation. We integrated the tumor-specific gene promoter of hTERT, the 5?UTR of bFGF-2, the enhancer\\u000a of woodchuck hepatitis virus post-transcriptional regulatory

Yu Xiang Fang; Xiao Bo Zhang; Wei Wei; Yi Wen Liu; Jin Zhong Chen; Jing Lun Xue; Ling Tian

2010-01-01

376

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. PMID:23692378

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

377

Development of an interleukin 2 receptor targeted gene therapy vehicle  

E-print Network

The effectiveness of most chemotherapeutic regimens is limited by the toxicity of the therapy to normal healthy cells. Therapies to selectively modulate abnormal T cells bearing the interleukin 2 receptor (IL-2R) have been developed to treat...

Wattanakaroon, Wanida

2006-08-16

378

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

PubMed Central

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

2014-01-01

379

News Note: Gene Therapy Method Slows Tumor Growth in Mice  

Cancer.gov

NCI researchers have developed a novel method in mice of delivering genes to cancer cells, that when expressed, promote cell death. These genes, known as suicide genes, cause a cell to kill itself through a process known as apoptosis. The new technique uses the survivin gene promoter to express the suicide gene and induce apoptosis in cancer cells. This method of gene delivery effectively targeted tumor cells with a minimum effect on normal cells.

380

Subretinal injection of gene therapy vectors and stem cells in the perinatal mouse eye.  

PubMed

The loss of sight affects approximately 3.4 million people in the United States and is expected to increase in the upcoming years.(1) Recently, gene therapy and stem cell transplantations have become key therapeutic tools for treating blindness resulting from retinal degenerative diseases. Several forms of autologous transplantation for age-related macular degeneration (AMD), such as iris pigment epithelial cell transplantation, have generated encouraging results, and human clinical trials have begun for other forms of gene and stem cell therapies.(2) These include RPE65 gene replacement therapy in patients with Leber's congenital amaurosis and an RPE cell transplantation using human embryonic stem (ES) cells in Stargardt's disease.(3-4) Now that there are gene therapy vectors and stem cells available for treating patients with retinal diseases, it is important to verify these potential therapies in animal models before applying them in human studies. The mouse has become an important scientific model for testing the therapeutic efficacy of gene therapy vectors and stem cell transplantation in the eye.(5-8) In this video article, we present a technique to inject gene therapy vectors or stem cells into the subretinal space of the mouse eye while minimizing damage to the surrounding tissue. PMID:23207897

Wert, Katherine J; Skeie, Jessica M; Davis, Richard J; Tsang, Stephen H; Mahajan, Vinit B

2012-01-01

381

Dye-loaded ferritin nanocages for multimodal imaging and photothermal therapy.  

PubMed

Multimodal imaging-guided photothermal therapy (PTT), for the therapy of cancer, based on a ferritin (FRT) nanocage loaded with the near-infrared dye IR820 (designated DFRT) is demonstrated. The dual roles of DFRT (in imaging and PTT) are successfully balanced by using two different excitation wavelengths: 550 nm for high quantum-yield fluorescence imaging on the one hand and 808 nm for photoacoustic imaging and PTT with high photothermal conversion efficiency on the other. PMID:25123089

Huang, Peng; Rong, Pengfei; Jin, Albert; Yan, Xuefeng; Zhang, Molly Gu; Lin, Jing; Hu, Hao; Wang, Zhe; Yue, Xuyi; Li, Wanwan; Niu, Gang; Zeng, Wenbin; Wang, Wei; Zhou, Kechao; Chen, Xiaoyuan

2014-10-01

382

TRAIL-Based Radio-Gene Therapy for Prostate Cancer.  

National Technical Information Service (NTIS)

A recombinant gene was constructed, encoding the soluble form of the human Flt3L gene (hFlex) at the 5' end and the human TRAIL gene at the 3' end. This plasmid (phFlex/TRAIL) was administrated by the hydrodynamic-based gene delivery. As a result, tumor g...

J. J. Song

2004-01-01

383

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

PubMed Central

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

Limbach, K. J.; Paoletti, E.

1996-01-01

384

Moral obligation and the human germ-line gene therapy debate  

E-print Network

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

Clark, Alan B

2012-06-07

385

Development and Safety Assessment of Lentiviral Vector Gene Therapy for SCID-X1.  

E-print Network

??abstract__Abstract__ This thesis work focuses on exploring ways to improve hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency disease (SCID-X1) using lentiviral vectors… (more)

M.W. Huston (Marshall W.)

2013-01-01

386

Scientists Use Gene Therapy to Create 'Biological Pacemaker' in Pig Hearts  

MedlinePLUS

... enable JavaScript. Scientists Use Gene Therapy to Create 'Biological Pacemaker' in Pig Hearts Technique might one day ... transform ordinary pig heart muscle cells into a "biological pacemaker," a feat that might one day lead ...

387

Advances in AAV Vector Development for Gene Therapy in the Retina  

E-print Network

687 Chapter 86 Advances in AAV Vector Development for Gene Therapy in the Retina Timothy P. Day in the retina. AAV has been used to treat a growing number of animal models of inherited retinal degeneration

Schaffer, David V.

388

Dopamine D? receptor gene variation: impact on electroconvulsive therapy response and ventral striatum responsiveness in depression.  

PubMed

Dysfunction of dopamine D? receptors, particularly in the mesocorticolimbic system, has been linked to the pathogenesis of major depression. Preclinical data show enhanced D? receptor binding in the striatum upon antidepressant medication and electroconvulsive therapy (ECT). Thus, the potential impact of dopamine D? receptor gene (DRD3) variation on ECT outcome in treatment-resistant major depression was evaluated by applying a combined molecular and imaging genetic approach. Altogether, 10 representative variants covering 95.4% of DRD3 gene variation were investigated for association with response to ECT in a sample of 104 (71 female, 33 male) Caucasian patients with pharmacorefractory major depression. Additionally, ventral striatum responsiveness to happy faces was assessed in two independent samples of depressed patients (total N=54) by means of functional magnetic resonance imaging at 3 T. Significant association of DRD3 rs3732790, rs3773679 and rs9817063 variants with response (uncorrected p=0.02-0.03) and remission (uncorrected p=0.01) after ECT was discerned. Logistic regression analyses revealed association of rs3732790 (uncorrected p=0.009; corrected p=0.045) and rs3773679 (uncorrected p=0.009; corrected p=0.045) with remission when applying a recessive model of inheritance. The rs3732790T allele conferring a more favourable treatment response was furthermore found to be associated with stronger striatal responsiveness to happy facial expressions (sample 1: cluster-corrected p=0.002; sample 2: p=0.023). In summary, the present study suggests some impact of DRD3 gene variation on ECT response, potentially mediated by alteration of striatal engagement during the processing of emotionally rewarding stimuli. PMID:22093107

Dannlowski, Udo; Domschke, Katharina; Birosova, Eva; Lawford, Bruce; Young, Ross; Voisey, Joanne; Morris, C Phillip; Suslow, Thomas; Konrad, Carsten; Kugel, Harald; Ohrmann, Patricia; Bauer, Jochen; Schöning, Sonja; Zavorotnyy, Maxim; Diemer, Julia; Arolt, Volker; Baune, Bernhard T; Zwanzger, Peter

2013-08-01

389

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

PubMed

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

Biju, Vasudevanpillai

2014-02-01

390

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. PMID:20588732

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

2010-01-01

391

Influence of p53 on herpes simplex virus type 1 vectors for cancer gene therapy  

Microsoft Academic Search

Herpes simplex virus type 1 (HSV 1) vectors are under investigation for use in gene therapy for colorectal cancer liver metastases.\\u000a Approximately 60% of colorectal cancers possess p53 mutations, and p53 mutations can cause tumor cell resistance to radiation\\u000a therapy and chemotherapy. p53 is also known to colocalize with at least one HSV 1 protein and influence HSV 1 gene

Sam S. Yoon; Nancy M. Carroll; E. Antonio Cbiocca; Kenneth K. Tanabe

1999-01-01

392

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

PubMed Central

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

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

2004-01-01

393

Herpes Simplex Virus Thymidine Kinase-Mediated Suicide Gene Therapy Using Nano\\/Microbubbles and Ultrasound  

Microsoft Academic Search

A physical method using ultrasound (US) and nano\\/microbubbles (NBs) can deliver exogenous molecules noninvasively into a specific target site. In this study, we evaluated the application of this technology to cancer gene therapy using prodrug activation therapy. Low-intensity pulsed ultrasound (1 MHz; 1.3 W\\/cm2) and NBs were used to transduce the herpes simplex thymidine kinase (HSVtk) gene in vitro, leading

Atsuko Aoi; Yukiko Watanabe; Shiro Mori; Masahiko Takahashi; Georges Vassaux; Tetsuya Kodama

2008-01-01

394

New methods of real-time control imaging for ion therapy D. Dauvergne1*  

E-print Network

Positron Emission Tomography So far the only operating control system available during ion therapy is PET3 1 New methods of real-time control imaging for ion therapy D. Dauvergne1* , M. Battaglia1 , G at providing a real-time control of the dose distribution during ion therapy. These studies are undertaken

Paris-Sud XI, Université de

395

Conformal Bulk Ablation And Therapy Monitoring Using Intracorporeal Image-Treat  

E-print Network

are reported including tissue modification caused by the thermal therapy. The dual-modality arrays developedConformal Bulk Ablation And Therapy Monitoring Using Intracorporeal Image-Treat Ultrasound Arrays I Road, Cincinnati, OH 45242 Guided Therapy Systems2 , 33 S. Sycamore St., Mesa, AZ 85202 Abstract

Mast, T. Douglas

396

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

E-print Network

Therapy By MaiThao Le, Torayuki Okuyama, Shi-Rong Cai, Susan C. Kennedy, William M. Bowling, M. Wayne Flye- tained for the life of the animals, because retroviral vectors integrate into the chromosome gene therapy for hemo- philia.rats at levels sufficient to maintain hemostasis in humans (10% to 43

Ponder, Katherine P.

397

Influence of Immune Responses in Gene/Stem Cell Therapies for Muscular Dystrophies  

PubMed Central

Muscular dystrophies (MDs) are a heterogeneous group of diseases, caused by mutations in different components of sarcolemma, extracellular matrix, or enzymes. Inflammation and innate or adaptive immune response activation are prominent features of MDs. Various therapies under development are directed toward rescuing the dystrophic muscle damage using gene transfer or cell therapy. Here we discussed current knowledge about involvement of immune system responses to experimental therapies in MDs. PMID:24959590

Sitzia, Clementina; Erratico, Silvia; Torrente, Yvan

2014-01-01

398

Rational design of a triple reporter gene for multimodality molecular imaging.  

PubMed

Multimodality imaging using noncytotoxic triple fusion (TF) reporter genes is an important application for cell-based tracking, drug screening, and therapy. The firefly luciferase (fl), monomeric red fluorescence protein (mrfp), and truncated herpes simplex virus type 1 thymidine kinase SR39 mutant (ttksr39) were fused together to create TF reporter gene constructs with different order. The enzymatic activities of TF protein in vitro and in vivo were determined by luciferase reporter assay, H-FEAU cellular uptake experiment, bioluminescence imaging, and micropositron emission tomography (microPET). The TF construct expressed in H1299 cells possesses luciferase activity and red fluorescence. The tTKSR39 activity is preserved in TF protein and mediates high levels of H-FEAU accumulation and significant cell death from ganciclovir (GCV) prodrug activation. In living animals, the luciferase and tTKSR39 activities of TF protein have also been successfully validated by multimodality imaging systems. The red fluorescence signal is relatively weak for in vivo imaging but may expedite FACS-based selection of TF reporter expressing cells. We have developed an optimized triple fusion reporter construct DsRedm-fl-ttksr39 for more effective and sensitive in vivo animal imaging using fluorescence, bioluminescence, and PET imaging modalities, which may facilitate different fields of biomedical research and applications. PMID:24809057

Hsieh, Ya-Ju; Hwu, Luen; Ke, Chien-Chih; Yeh, Skye Hsin-Hsien; Lin, Chien-Feng; Chen, Fu-Du; Wang, Hsin-Ell; Lin, Kang-Ping; Chen, Ran-Chou; Liu, Ren-Shyan

2014-01-01

399

High quantum efficiency megavoltage imaging with thick scintillator detectors for image guided radiation therapy  

NASA Astrophysics Data System (ADS)

In image guided radiation therapy (IGRT), imaging devices serve as guidance systems to aid patient set-up and tumor volume localization. Traditionally, 2-D megavoltage x-ray imagers, referred to as electronic portal imaging devices (EPIDs), have been used for planar target localization, and have recently been extended to perform 3-D volumetric reconstruction via cone-beam computed tomography (CBCT). However, current EPIDs utilize thin and inefficient phosphor screen detectors and are subsequently limited by poor soft tissue visualization, which limits their use for CBCT. Therefore, the use of thick scintillation media as megavoltage x-ray detectors for greater x-ray sensitivity and enhanced image quality has recently been of significant interest. In this research, two candidates for thick scintillators: CsI(Tl) and terbium doped scintillation glass were investigated in separate imaging configurations. In the first configuration, a thick scintillation crystal (TSC) consisting of a thick, monolithic slab of CsI(Tl) was coupled to a mirror-lens-camera system. The second configuration is based on a fiber-optic scintillation glass array (FOSGA), wherein the scintillation glass is drawn into long fiber-optic conduits, inserted into a grid-type housing constructed out of polymer-tungsten alloy, and coupled to an array of photodiodes for digital read-out. The imaging prototypes were characterized using theoretical studies and imaging measurements to obtain fundamental metrics of imaging performance. Spatial resolution was measured based on a modulation transfer function (MTF), noise was evaluated in terms of a noise power spectrum (NPS), and overall contrast was characterized in the form of detective quantum efficiency (DQE). The imaging studies were used to optimize the TSC and FOSGA imagers and propose prototype configurations for order-of-magnitude improvements in overall image quality. In addition, a fast and simple technique was developed to measure the MTF, NPS, and DQE metrics for clinical EPID and CBCT systems based on a novel adaptation of a traditional line-pair resolution bar-pattern. This research provides two significant benefits to radiotherapy: the characterization of a new generation of thick scintillator based megavoltage x-ray imagers for CBCT based IGRT, and the novel adaptation of fundamental imaging metrics from imaging research to routine clinical performance monitoring.

Gopal, Arun

400

Developing protocols for recombinant adeno-associated virus-mediated gene therapy in space.  

PubMed

With the advent of the era of International Space Station (ISS) and Mars exploration, it is important more than ever to develop means to cure genetic and acquired diseases, which include cancer and AIDS, for these diseases hamper human activities. Thus, our ultimate goal is to develop protocols for gene therapy, which are suitable to humans on the earth as well as in space. Specifically, we are trying to cure the hemoglobinopathies, beta-thalassemia (Cooley's anemia) and sickle cell anemia, by gene therapy. These well-characterized molecular diseases serve as models for developing ex vivo gene therapy, which would apply to other disorders as well. For example, the procedure may become directly relevant to treating astronauts for space-anemia, immune suppression and bone marrow derived tumors, e.g. leukemia. The adeno-associated virus serotype 2 (AAV2) is a non-pathogenic human parvovirus with broad host-range and tissue specificity. Exploiting these characteristics we have been developing protocols for recombinant AAV2 (rAAV)-based gene therapy. With the rAAV constructs and hematopoietic stem cell (HSC) culture systems in hand, we are currently attempting to cure the mouse model of beta-thalassemia [C57BL/6- Hbbth/Hbbth, Hb(d-minor)] by HSC transplantation (HST) as well as by gene therapy. This paper describes the current status of our rAAV-gene therapy research. PMID:12697549

Ohi, S

2000-07-01

401

RNAi-based Gene Therapy for Dominant Limb Girdle Muscular Dystrophies  

PubMed Central

Limb Girdle Muscular Dystrophy (LGMD) refers to a group of 25 genetic diseases linked by common clinical features, including wasting of muscles supporting the pelvic and shoulder girdles. Cardiac involvement may also occur. Like other muscular dystrophies, LGMDs are currently incurable, but prospective gene replacement therapies targeting recessive forms have shown promise in pre-clinical and clinical studies. In contrast, little attention has been paid to developing gene therapy approaches for dominant forms of LGMD, which would likely benefit from disease gene silencing. Despite the lack of focus to date on developing gene therapies for dominant LGMDs, the field is not starting at square one, since translational studies on recessive LGMDs provided a framework that can be applied to treating dominant forms of the disease. In this manuscript, we discuss the prospects of treating dominantly inherited forms of LGMD with gene silencing approaches. PMID:22856606

Liu, Jian; Harper, Scott Q.

2014-01-01

402

Development of a percutaneous optical imaging system for tracking vascular gene expression: a feasibility study using human tissuelike phantoms  

NASA Astrophysics Data System (ADS)

Noninvasive tracking of vascular gene delivery and expression forms an important part of successfully implementing vascular gene therapy methods for the treatment of atherosclerosis and various cardiovascular disorders. While ultrasound and MR imaging have shown promise in the monitoring of gene delivery to the vasculatures, optical imaging has shown promise for tracking gene expression. Optical imaging using bioreporter genes like Green Fluorescent Protein (GFP), Red Fluorescent Protein (RFP) and Luciferase to track and localize the therapeutic gene have helped provide an in vivo detection method of the process. The usage of GFP and RFP entails the detection of the fluorescent signal emitted by them on excitation with light of appropriate wavelength. We have developed a novel percutaneous optical imaging system that may be used for in vivo tracking vascular fluorescent gene expression in deep-seated vessels. It is based on the detection of the fluorescent signal emitted from GFP tagged cells. This phantom study was carried out to investigate the performance of the optical imaging system and gain insights into its performance record and study improvisation possibilities.

Kar, Sourav K.; Kumar, Ananda; Yang, Xiaoming

2004-05-01

403

Gene therapy in kidney transplantation : towards local immune suppression.  

E-print Network

??Kidney transplantation is inevitably faced with overcoming the immune response to the grafted organ, necessitating immunosuppressive therapy. Further, the immunogenicity of the graft is augmented… (more)

Sandovici, Maria

2006-01-01

404

Image-guided therapy: evolution and breakthrough Pascal Haigron1,2,4  

E-print Network

by independent imaging modalities or by a stand-alone dual-mode device integrating imaging and therapeutic-assisted interventions and robotic systems [1], the demand of more efficient and safer therapies remains challenging, to miniaturize the sensors and actuators and to conduct preoperatively planned minimally invasive therapies, we

Paris-Sud XI, Université de

405

Biological response determinants in HSV-tk + ganciclovir gene therapy for prostate cancer.  

PubMed

The limitations of current forms of prostate cancer therapy have driven researchers to search for new alternatives. Previously we showed cytopathic effect related to HSV-tk in prostate cancer. In this study we present initial results of a neoadjuvant HSV-tk gene therapy trial and address some of the potential mechanistic aspects of its effect in human tissues. We enrolled 23 men with clinically localized prostate cancer but high risk for recurrence in this Phase I-II trial. Intraprostatic viral injections (one to four) were followed by 2 weeks of ganciclovir and prostatectomy 2-4 weeks later. Toxicity was modest. Surgical specimens were embedded fully and whole-mount slides were imaged and analyzed for areas of cytopathic effect. The larger the tumor the greater the cytopathic effect. The effect also seems to be related to areas of high CAR expression. However, the number of injection sites did not influence effect. Local (CD8+ cells and macrophages) and systemic immune response (CD8+ and activated CD8+, IL-12) was increased in patients treated with HSV-tk. Increased apoptosis and decreased microvessel density were also noted in these patients. The results suggest a tumor-specific effect mediated by systemic and local immune response, antiangiogenic effect, and modulation of apoptosis. PMID:16480930

Ayala, Gustavo; Satoh, Takefumi; Li, Rile; Shalev, Moshe; Gdor, Yehoshua; Aguilar-Cordova, Estuardo; Frolov, Anna; Wheeler, Thomas M; Miles, Brian J; Rauen, Kate; Teh, Bin S; Butler, E Brian; Thompson, Timothy C; Kadmon, Dov

2006-04-01

406

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. PMID:22203706

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

2013-01-01

407

Radiosynthesis of 4-[(2-chloroethyl)(2-[(11)C]ethyl)amino]-phenoxycarbonyl-l-glutamic acid a half mustard prodrug as a potential probe for imaging antibody- and gene-directed enzyme prodrug therapy with positron emission tomography.  

PubMed

The potential antibody directed prodrug therapy half-mustard prodrug 4-[(2-chloroethyl)(2-ethyl)amino]-phenoxycarbonyl-L-glutamic acid was synthesised by reductive alkylation of 4-[(2-chloroethyl)amino]-phenoxycarbonyl-L-glutamic acid using acetaldehyde. 4-[(2-chloroethyl)[(11)C](2-ethyl)amino]phenoxycarbonyl-L-glutamic acid was synthesized with 18-22% decay corrected radiochemical yield in 45 min from EOB by reductive alkylation of 4-[(2-chloroethyl)amino]-phenoxycarbonyl-L-glutamic acid using [(11)C]acetaldehyde. [(11)C]Acetaldehyde was prepared in 60% decay corrected radiochemical yield by oxidation of [(11)C]ethanol over heated copper oxide. The radiosynthesis of [(11)C]ethanol was re-examined and optimized. 4-[(2-chloroethyl)(2-ethyl)amino]-phenoxycarbonyl-L-glutamic acid was found to have affinity for carboxypeptidase G2; the K(m) and V(max) were 99.4-115.9 microM (n=3) and 3.6-5.0 microM/min, respectively, at a carboxypeptidase G2 concentration of 0.0247 U/ml. PMID:15110346

Malik, Nazreen; Luthra, S K Sajinder K; Burke, Phil; Price, P M Patrica M; Aboagye, E O Eric O; Latigo, John; Zhao, Yongjun; Brady, Frank

2004-06-01

408

Gene Therapy of Inherited Retinopathies: A Long and Successful Road from Viral Vectors to Patients  

PubMed Central

Abstract Inherited retinopathies (IRs) are common and untreatable blinding conditions inherited mostly as monogenic due to mutations in genes expressed in retinal photoreceptors (PRs) and in retinal pigment epithelium (RPE). Over the last two decades, the retina has emerged as one of the most favorable target tissues for gene therapy given its small size and its enclosed and immune-privileged environment. Different types of viral vectors have been developed, especially those based on the adeno-associated virus (AAV), which efficiently deliver therapeutic genes to PRs or RPE upon subretinal injections. Dozens of successful proofs of concept of the efficacy of gene therapy for recessive and dominant IRs have been generated in small and large models that have paved the way to the first clinical trials using AAV in patients with Leber congenital amaurosis, a severe form of childhood blindness. The results from these initial trials suggest that retinal gene therapy with AAV is safe in humans, that vision can be improved in patients that have suffered from severe impairment of visual function, in some cases for decades, and that readministration of AAV to the subretinal space is feasible, effective, and safe. However, none of the trials could match the levels of efficacy of gene therapy observed in a dog model of the disease, suggesting that there is room for improvement. In conclusion, these results bode well for further testing of AAV-mediated retinal gene therapy in patients with other monogenic and complex forms of blindness. PMID:22734691

Colella, Pasqualina

2012-01-01

409

Spatially weighted mutual information image registration for image guided radiation therapy  

SciTech Connect

Purpose: To develop a new metric for image registration that incorporates the (sub)pixelwise differential importance along spatial location and to demonstrate its application for image guided radiation therapy (IGRT). Methods: It is well known that rigid-body image registration with mutual information is dependent on the size and location of the image subset on which the alignment analysis is based [the designated region of interest (ROI)]. Therefore, careful review and manual adjustments of the resulting registration are frequently necessary. Although there were some investigations of weighted mutual information (WMI), these efforts could not apply the differential importance to a particular spatial location since WMI only applies the weight to the joint histogram space. The authors developed the spatially weighted mutual information (SWMI) metric by incorporating an adaptable weight function with spatial localization into mutual information. SWMI enables the user to apply the selected transform to medically ''important'' areas such as tumors and critical structures, so SWMI is neither dominated by, nor neglects the neighboring structures. Since SWMI can be utilized with any weight function form, the authors presented two examples of weight functions for IGRT application: A Gaussian-shaped weight function (GW) applied to a user-defined location and a structures-of-interest (SOI) based weight function. An image registration example using a synthesized 2D image is presented to illustrate the efficacy of SWMI. The convergence and feasibility of the registration method as applied to clinical imaging is illustrated by fusing a prostate treatment planning CT with a clinical cone beam CT (CBCT) image set acquired for patient alignment. Forty-one trials are run to test the speed of convergence. The authors also applied SWMI registration using two types of weight functions to two head and neck cases and a prostate case with clinically acquired CBCT/MVCT image sets. The SWMI registration with a Gaussian weight function (SWMI-GW) was tested between two different imaging modalities: CT and MRI image sets. Results: SWMI-GW converges 10% faster than registration using mutual information with an ROI. SWMI-GW as well as SWMI with SOI-based weight function (SWMI-SOI) shows better compensation of the target organ's deformation and neighboring critical organs' deformation. SWMI-GW was also used to successfully fuse MRI and CT images. Conclusions: Rigid-body image registration using our SWMI-GW and SWMI-SOI as cost functions can achieve better registration results in (a) designated image region(s) as well as faster convergence. With the theoretical foundation established, we believe SWMI could be extended to larger clinical testing.

Park, Samuel B.; Rhee, Frank C.; Monroe, James I.; Sohn, Jason W. [Department of Radiation Oncology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106 (United States); School of Electrical Engineering and Computer Science, Hanyang University, 1271 Sangrok-gu Sa-3-dong, Ansan, Gyeonggi 426-791 (Korea, Republic of); Medical Physics Services Ltd., 430 Saddlespur Road, Webster Groves, Missouri 63119 (United States); Department of Radiation Oncology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106 (United States)

2010-09-15

410

Understanding the Tumor Microenvironment and Radioresistance by Combining Functional Imaging With Global Gene Expression  

PubMed Central

The objective of this review is to present an argument for performing joint analyses between functional imaging with global gene expression studies. The reason for making this link is that tumor microenvironmental influences on functional imaging can be uncovered. Such knowledge can lead to (1) more informed decisions regarding how to use functional imaging to guide therapy and (2) discovery of new therapeutic targets. As such, this approach could lead to identification of patients who need aggressive treatment tailored toward the phenotype of their tumor vs those who could be spared treatment that carries risk for more normal tissue complications. Only a handful of papers have been published on this topic thus far, but all show substantial promise. PMID:24012344

Dewhirst, Mark W.; Chi, Jen-Tsan

2013-01-01

411

Antiangiogenic gene therapy with soluble VEGF-receptors -1, -2 and -3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma.  

PubMed

We compared effects of antiangiogenic gene therapy with a combination of soluble sVEGFR-1, sVEGFR-2 and sVEGFR-3 to chemotherapy with carboplatin and paclitaxel and to antiangiogenic monoclonal anti-VEGF-antibody bevacizumab in an intraperitoneal ovarian cancer xenograft model in mice (n = 80). Gene therapy was also combined with chemotherapy. Therapy was initiated when sizable tumors were confirmed in magnetic resonance imaging (MRI). Adenovirus-mediated gene transfer was performed intravenously (2 × 109 pfu), while chemotherapy and monoclonal anti-VEGF-antibody were dosed intraperitoneally. The study groups were as follows: AdLacZ control (n = 21); combination of AdsVEGFR-1, -2 and -3 (n = 21); combination of AdsVEGFR-1, -2, -3 and paclitaxel (n = 9); bevacizumab (n = 14); paclitaxel (n = 9) and carboplatin (n = 5). Effectiveness was assessed by survival time and surrogate measures such as sequential MRI, immunohistochemistry, microvessel density and tumor growth. Antiangiogenic gene therapy combined with paclitaxel significantly prolonged the mean survival of mice (25 days) compared to the controls (15 days) and all other treatment groups (p = 0.001). Bevacizumab treatment did not have any significant effect on the survival. Tumors of the mice treated by gene therapy were significantly smaller than in the control group (p = 0.021). The mean vascular density and total vascular area were also significantly smaller in the tumors of the gene therapy group (p = 0.01). These results show potential of the antiangiogenic gene therapy to improve efficacy of chemotherapy with paclitaxel and support testing of this approach in a phase I clinical trial for the treatment of ovarian cancer. PMID:22336998

Sopo, Minna; Anttila, Maarit; Sallinen, Hanna; Tuppurainen, Laura; Laurema, Anniina; Laidinen, Svetlana; Hamalainen, Kirsi; Tuunanen, Pasi; Koponen, Jonna K; Kosma, Veli-Matti; Heinonen, Seppo; Alitalo, Kari; Yla-Herttuala, Seppo

2012-11-15

412

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

PubMed Central

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

Borrás, Teresa

2011-01-01

413

Modular flexibility of dystrophin: Implications for gene therapy of Duchenne muscular dystrophy  

Microsoft Academic Search

Attempts to develop gene therapy for Duchenne muscular dystrophy (DMD) have been complicated by the enormous size of the dystrophin gene. We have performed a detailed functional analysis of dystrophin structural domains and show that multiple regions of the protein can be deleted in various combinations to generate highly functional mini- and micro-dystrophins. Studies in transgenic mdx mice, a model

Scott Q. Harper; Michael A. Hauser; Christiana DelloRusso; Dongsheng Duan; Robert W. Crawford; Stephanie F. Phelps; Hollie A. Harper; Ann S. Robinson; John F. Engelhardt; Susan V. Brooks; Jeffrey S. Chamberlain

2002-01-01

414

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

E-print Network

Microneedle Electrode Array for Electroporation of Skin for Gene Therapy Seong-O Choi1 , Jung gene transfection for DNA vaccines, we designed and fabricated a microneedle array with electrical functionality. This microneedle array was mechanically strong enough to penetrate human skin in vivo

415

Effective healing of diabetic skin wounds by using nonviral gene therapy based on minicircle vascular  

E-print Network

- sent a powerful tool for the treatment of diabetic foot ulcers and other diseases that are refractory to treatment. Copyright © 2012 John Wiley & Sons, Ltd. Keywords gene therapy; foot ulcer; minicircle DNA; nonviral gene delivery carrier; PAM-RG4; VEGF; wound healing Introduction Foot ulcers are one of the most

Park, Jong-Sang

416

HUMAN GENE THERAPY 13:15051514 (August 10, 2002) Mary Ann Liebert, Inc.  

E-print Network

and Alvarez, 2002). All ovarian cancer gene therapy trials published have relied on intraperi- toneal and Ascites Neutralizing Antibodies in Ovarian Cancer Patients Treated with Intraperitoneal Adenoviral Gene of adenovirus to ovarian cancer patients results in induction of NAbs in ascites or serum. Also, it is not known

Hemminki, Akseli

417

RESEARCH ARTICLE A model for the analysis of nonviral gene therapy  

E-print Network

in gene delivery and expression while maintaining the advantages of this method. Optimization depends. Quantitative and reproducible methods that can be disseminated and utilized by multiple investiga- torsRESEARCH ARTICLE A model for the analysis of nonviral gene therapy GA Banks1 , RJ Roselli1 , R Chen

418

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

DOEpatents

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

Smith, Desmond J. (Oakland, CA); Rubin, Edward M. (Berkeley, CA)

2000-01-01

419

Irradiated Esophageal Cells are Protected from Radiation-Induced Recombination by MnSOD Gene Therapy  

E-print Network

Irradiated Esophageal Cells are Protected from Radiation-Induced Recombination by MnSOD Gene. Irradiated Esophageal Cells are Protected from Radiation- Induced Recombination by MnSOD Gene Therapy. Radiat in esophageal cells. These results demonstrate the efficacy of MnSOD-PL for suppressing radiation-induced HR

Engelward, Bevin

420

Reliable Generation of Stable High Titer Producer Cell Lines for Gene Therapy  

Microsoft Academic Search

Objective: Retroviral vectors represent one of the most robust technologies for in vivo expression of heterologous gene sequences and are still the most commonly used vectors in clinical gene therapy trials. The production of high titer retroviral preparations, however, can be a problematic procedure for certain constructs. Methods: GALV- or RD114-pseudotyped retroviral particles carrying selectable fluorescence markers or drug resistance

Ina Rattmann; Veronika Kleff; Anja Feldmann; Carsten Ludwig; Ursula Regina Sorg; Bertram Opalka; Thomas Moritz; Michael Flasshove

2007-01-01

421

Adeno-associated virus mediated gene therapy for retinal degenerative diseases.  

PubMed

Retinal gene therapy holds great promise for the treatment of inherited and noninherited blinding diseases such as retinitis pigmentosa and age-related macular degeneration. The most widely used vectors for ocular gene delivery are based on adeno-associated virus (AAV) because it mediates long-term transgene expression in a variety of retinal cell types and elicits minimal immune responses. Inherited retinal diseases are nonlethal and have a wide level of genetic heterogeneity. Many of the genes have now been identified and their function elucidated, providing a major step towards the development of gene-based treatments. Extensive preclinical evaluation of gene transfer strategies in small and large animal models is key to the development of successful gene-based therapies for the retina. These preclinical studies have already allowed the field to reach the point where gene therapy to treat inherited blindness has been brought to clinical trial.In this chapter, we focus on AAV-mediated specific gene therapy for inherited retinal degenerative diseases, describing the disease targets, the preclinical studies in animal models and the recent success of the LCA-RPE65 clinical trials. PMID:22034031

Stieger, Knut; Cronin, Therese; Bennett, Jean; Rolling, Fabienne

2011-01-01

422

Occurrence of leukaemia following gene therapy of X-linked SCID  

Microsoft Academic Search

Recombinant viral vectors have allowed gene transfer to be developed as a promising approach to the treatment of genetic diseases. Recently, gene therapy of children with X-linked severe combined immune deficiency resulted in impressive levels of immune reconstitution — a triumph that was later overshadowed by the development of leukaemia in two patients. What were the causes of this cancer,

Donald B. Kohn; Michel Sadelain; Joseph C. Glorioso

2003-01-01

423

Targeting Lentivectors to CD34+ Hematopoietic Stem Cells for Gene Therapy  

E-print Network

Targeting Lentivectors to CD34+ Hematopoietic Stem Cells for Gene Therapy Leslie Bailey*, Lili Yang progenitor cells located in bone marrow, hematopoietic stem cells (HSCs), can provide a life-long source, our group developed a new method to target genes to specific cell types in vivo using lentivectors

Southern California, University of

424

862. Improved Efficacy of Adenovirus-Mediated Gene Therapy for GSD-II Disease by Selective Depletion of Kupffer Cells  

Microsoft Academic Search

Glycogen storage disease type II (GSD-II) is a fatal genetic muscle disorder caused by a massive accumulation of glycogen in multiple muscle groups, and is caused by the deficiency of intralysosomal acid alpha glucosidase (GAA). Two approaches to the treatment of GSD-II are currently being pursued in our research group: enzyme replacement therapy and gene therapy. Relative to gene therapy,

Shaoxi Liao; Ruth Everett; Fang Xu; Delila Serra; Nico Van Rooijen; Andrea Amalfitano

2004-01-01

425

Image-Guided Radiation Therapy: the potential for imaging science research to improve cancer treatment outcomes  

NASA Astrophysics Data System (ADS)

The role of medical imaging in the planning and delivery of radiation therapy (RT) is rapidly expanding. This is being driven by two developments: Image-guided radiation therapy (IGRT) and biological image-based planning (BIBP). IGRT is the systematic use of serial treatment-position imaging to improve geometric targeting accuracy and/or to refine target definition. The enabling technology is the integration of high-performance three-dimensional (3D) imaging systems, e.g., onboard kilovoltage x-ray cone-beam CT, into RT delivery systems. IGRT seeks to adapt the patient's treatment to weekly, daily, or even real-time changes in organ position and shape. BIBP uses non-anatomic imaging (PET, MR spectroscopy, functional MR, etc.) to visualize abnormal tissue biology (angiogenesis, proliferation, metabolism, etc.) leading to more accurate clinical target volume (CTV) delineation and more accurate targeting of high doses to tissue with the highest tumor cell burden. In both cases, the goal is to reduce both systematic and random tissue localization errors (2-5 mm for conventional RT) conformality so that planning target volume (PTV) margins (varying from 8 to 20 mm in conventional RT) used to ensure target volume coverage in the presence of geometric error, can be substantially reduced. Reduced PTV expansion allows more conformal treatment of the target volume, increased avoidance of normal tissue and potential for safe delivery of more aggressive dose regimens. This presentation will focus on the imaging science challenges posed by the IGRT and BIBP. These issues include: Development of robust and accurate nonrigid image-registration (NIR) tools: Extracting locally nonlinear mappings that relate, voxel-by-voxel, one 3D anatomic representation of the patient to differently deformed anatomies acquired at different time points, is essential if IGRT is to move beyond simple translational treatment plan adaptations. NIR is needed to map segmented and labeled anatomy from the pretreatment planning images to each daily treatment position image and to deformably map delivered dose distributions computed on each time instance of deformed anatomy, back to the reference 3D anatomy. Because biological imaging must be performed offline, NIR is needed to deformably map these images onto CT images acquired during treatment. Reducing target and organ contouring errors: As IGRT significantly reduces impact of differences between planning and treatment anatomy, RT targeting accuracy becomes increasingly dominated by the remaining systematic treatment-preparation errors, chiefly error in delineating the clinical target volume (CTV) and organs-at-risk. These delineation errors range from 1 mm to 5 mm. No single solution to this problem exists. For BIBP, a better understanding of tumor cell density vs. signal intensity is required. For anatomic CT imaging, improved image reconstruction techniques that improve contrast-to-noise ratio, reduce artifacts due to limited projection data, and incorporate prior information are promising. More sophisticated alternatives to the current concept fixed boundary anatomic structures are needed, e.g., probabilistic CTV representations that incorporate delineation uncertainties. Quantifying four-dimensional (4D) anatomy: For adaptive treatment planning to produce an optimal time sequence of delivery parameters, a 4D anatomic representation, the spatial trajectory through time of each tissue voxel, is needed. One approach is to use sequences of deformation vector fields derived by non-rigidly registering each treatment image to the reference planning CT. One problem to be solved is prediction of future deformed anatomies from past behavior so that time delays inherent in any adaptive replanning feedback loop can be overcome. Another unsolved problem is quantification 4D anatomy uncertainties and how to incorporate such uncertainties into the treatment planning process to avoid geometric ``miss'' of the target tissue.

Williamson, Jeffrey

2008-03-01

426

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

PubMed Central

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

McCrudden, Cian M; McCarthy, Helen O

2014-01-01

427

Oncostatin M Gene Therapy Attenuates Liver Damage Induced by Dimethylnitrosamine in Rats  

PubMed Central

To assess the usefulness of oncostatin M (osm) gene therapy in liver regeneration, we examined whether the introduction of OSM cDNA enhances the regeneration of livers damaged by dimethylnitrosamine (DMN) in rats. Repeated injection of OSM cDNA enclosed in hemagglutinating virus of Japan envelope into the spleen resulted in the exclusive expression of OSM protein in Kupffer cells of the liver, which was accompanied by increases in body weight, liver weight, and serum albumin levels and the reduction of serum liver injury parameters (bilirubin, aspartate aminotransferase, and alanine aminotransferase) and a serum fibrosis parameter (hyaluronic acid). Histological examination showed that osm gene therapy reduced centrilobular necrosis and inflammatory cell infiltration and augmented hepatocyte proliferation. The apoptosis of hepatocytes and fibrosis were suppressed by osm gene therapy. Time-course studies on osm gene therapy before or after DMN treatment showed that this therapy was effective not only in enhancing regeneration of hepatocytes damaged by DMN but in preventing hepatic cytotoxicity caused by subsequent treatment with DMN. These results indicate that OSM is a key mediator for proliferation and anti-apoptosis of hepatocytes and suggest that osm gene therapy is useful, as preventive and curative means, for the treatment of patients with liver damage. PMID:17640959

Hamada, Tetsuhiro; Sato, Ayuko; Hirano, Tadamichi; Yamamoto, Takashi; Son, Gakuhei; Onodera, Masayuki; Torii, Ikuko; Nishigami, Takashi; Tanaka, Minoru; Miyajima, Atsushi; Nishiguchi, Shuhei; Fujimoto, Jiro; Tsujimura, Tohru

2007-01-01

428

Silk-elastinlike protein polymer hydrogels for localized adenoviral gene therapy of head and neck tumors.  

PubMed

Vector dissemination, transient gene expression, and rapid clearance are major obstacles to successful human gene therapy. In this study, we investigated the effect of silk-elastinlike protein polymer (SELP) hydrogels on biodistribution and anticancer efficacy of adenoviral gene therapy in a head and neck cancer model. Transcriptional activities of adenovirus carrying beta-galactosidase (Ad-LacZ) and luciferase (Ad-Luc) reporter genes were evaluated in (nu/nu) mice with head and neck cancer as a function of polymer concentration. Antitumor efficacy of thymidine kinase encoding adenovirus (Ad-Tk) and ganciclovir (GSV) combination was also evaluated. SELP (4 wt %) matrices localized viral release, minimized dissemination to liver, and enhanced reporter gene expression levels by 4-8-fold compared to virus alone. SELP- Ad-Tk with GSV reduced tumor volume significantly compared to the virus alone. SELPs provide a means for temporal and spatial control of viral gene delivery to head and neck tumors. PMID:19722557

Greish, Khaled; Araki, Koji; Li, Daqing; O'Malley, Bert W; Dandu, Ramesh; Frandsen, Jordan; Cappello, Joseph; Ghandehari, Hamidreza

2009-08-10

429

Silk-Elastinlike Protein Polymer Hydrogels for Localized Adenoviral Gene Therapy of Head and Neck Tumors  

PubMed Central

Vector dissemination, transient gene expression and rapid clearance are major obstacles to successful human gene therapy. In this study, we investigated the effect of silk-elastinlike protein polymer (SELP) hydrogels, on biodistribution and anticancer efficacy of adenoviral gene therapy in a head and neck cancer model. Transcriptional activities of adenovirus carrying ?-galactosidase (Ad-LacZ) and luciferase (Ad-Luc) reporter genes were evaluated in (nu/nu) mice with head and neck cancer, as a function of polymer concentration. Antitumor efficacy of thymidine kinase encoding adenovirus (Ad-Tk) and ganciclovir (GSV) combination was also evaluated. 4 wt% SELP matrices localized viral release, minimized dissemination to liver and enhanced reporter gene expression levels by 4–8 fold compared to virus alone. SELP- Ad-Tk with GSV reduced tumor volume significantly compared to the virus alone. SELPs provide a means for temporal and spatial control of viral gene delivery to head and neck tumors. PMID:19722557

Greish, Khaled; Araki, Koji; Li, Daqing; O'Malley, Bert W.; Dandu, Ramesh; Frandsen, Jordan; Cappello, Joseph; Ghandehari, Hamidreza

2009-01-01