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1

Human gene therapy and imaging: cardiology  

Microsoft Academic Search

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

Joseph C. Wu; Seppo Yla-Herttuala

2005-01-01

2

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

Microsoft Academic Search

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

JJ Min; SS Gambhir

2004-01-01

3

New approaches for imaging in gene therapy  

Microsoft Academic Search

Gene therapy is increasingly used experimentally and clinically to replace defective genes and:or impart new functions to cells and tissues. With the recent advances in vector design, improvements in transgene and prodrug activation strategies, gene therapy has been applied to a wide variety of diseases, tissues and organ systems. It is now clear that our specialty will play a critical

Patrick Wunderbaldinger; Alexei Bogdanov Jr; Ralph Weissleder

4

Molecular imaging of gene therapy for cancer  

Microsoft Academic Search

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

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

2004-01-01

5

Non-invasive Imaging in Gene Therapy  

Microsoft Academic Search

Several methods are available for non-invasive imaging of gene delivery and transgene expression, including magnetic resonance imaging (MRI), single photon emission tomography (SPECT)\\/positron emission tomography (PET), and fluorescence and bioluminescence imaging. However, these imaging modalities differ greatly in terms of their sensitivity, cost, and ability to measure the signal. Whereas MRI can produce a resolution of approximately 50 ?m, optical

Jani Kristian Räty; Timo Liimatainen; Minna Unelma Kaikkonen; Olli Gröhn; Kari Jumani Airenne; Seppo Ylä-Herttuala

2007-01-01

6

Radionuclide reporter gene imaging for cardiac gene therapy  

Microsoft Academic Search

Introduction  In the field of cardiac gene therapy, angiogenic gene therapy has been most extensively investigated. The first clinical trial\\u000a of cardiac angiogenic gene therapy was reported in 1998, and at the peak, more than 20 clinical trial protocols were under\\u000a evaluation. However, most trials have ceased owing to the lack of decisive proof of therapeutic effects and the potential\\u000a risks

Masayuki Inubushi; Nagara Tamaki

2007-01-01

7

Human gene therapy and imaging in neurological diseases  

PubMed Central

Molecular imaging aims to assess non-invasively disease-specific biological and molecular processes in animal models and humans in vivo. Apart from precise anatomical localisation and quantification, the most intriguing advantage of such imaging is the opportunity it provides to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Further, molecular imaging can be used to address basic scientific questions, e.g. transcriptional regulation, signal transduction or protein/protein interaction, and will be essential in developing treatment strategies based on gene therapy. Most importantly, molecular imaging is a key technology in translational research, helping to develop experimental protocols which may later be applied to human patients. Over the past 20 years, imaging based on positron emission tomography (PET) and magnetic resonance imaging (MRI) has been employed for the assessment and “phenotyping” of various neurological diseases, including cerebral ischaemia, neurodegeneration and brain gliomas. While in the past neuro-anatomical studies had to be performed post mortem, molecular imaging has ushered in the era of in vivo functional neuro-anatomy by allowing neuroscience to image structure, function, metabolism and molecular processes of the central nervous system in vivo in both health and disease. Recently, PET and MRI have been successfully utilised together in the non-invasive assessment of gene transfer and gene therapy in humans. To assess the efficiency of gene transfer, the same markers are being used in animals and humans, and have been applied for phenotyping human disease. Here, we review the imaging hallmarks of focal and disseminated neurological diseases, such as cerebral ischaemia, neurodegeneration and glioblastoma multiforme, as well as the attempts to translate gene therapy’s experimental knowledge into clinical applications and the way in which this process is being promoted through the use of novel imaging approaches.

Jacobs, Andreas H.; Winkler, Alexandra; Castro, Maria G.; Lowenstein, Pedro

2010-01-01

8

In vivo imaging of gene and cell therapies.  

PubMed

Molecular imaging can be broadly defined as the in vivo characterization and measurement of biological processes at the cellular and molecular level. In contrast to commonly used clinical imaging, it sets forth to probe the molecular abnormalities that are the basis of disease, rather than imaging the end effects of these molecular alterations. Development of new imaging technologies requires a multidisciplinary collaboration between biologists, chemists, physicists, and imaging scientists to create novel agents, signal amplification strategies, and imaging techniques that successfully address these questions. In this article we attempt to present some of the recent developments and show how molecular imaging can be used, at least experimentally, to assess specific molecular targets for gene- and cell-based therapies. In particular, we place emphasis on the development and use of experimental small-animal models, which are particularly inclined toward this approach, primarily in combination with magnetic resonance (MR), radionuclide, and optical imaging. In the future, specific imaging of disease targets will allow earlier detection and characterization of disease, as well as earlier and direct molecular assessment of treatment efficacy. PMID:11698119

Allport, J R; Weissleder, R

2001-11-01

9

The Application of Nanoparticles in Gene Therapy and Magnetic Resonance Imaging  

PubMed Central

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

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

2012-01-01

10

Gene therapy imaging in patients for oncological applications  

Microsoft Academic Search

Thus far, traditional methods for evaluating gene transfer and expression have been shown to be of limited value in the clinical arena. Consequently there is a real need to develop new methods that could be repeatedly and safely performed in patients for such purposes. Molecular imaging techniques for gene expression monitoring have been developed and successfully used in animal models,

Iván Peñuelas; Uwe Haberkorn; Shahriar Yaghoubi; Sanjiv S. Gambhir

2005-01-01

11

MR Imaging and Gene Therapy of Breast Cancer.  

National Technical Information Service (NTIS)

The main purpose of this Career Development Award is for the P.1. to receive training in the field of Cancer Biology and Virology, so that she can apply her expertise, Magnetic Resonance Imaging, for developing non-invasive techniques to monitor gene ther...

M. Su

2000-01-01

12

Positron emission tomography reporter gene imaging in the myocardium: for monitoring of angiogenic gene therapy in ischemic heart disease.  

PubMed

Cardiac angiogenic gene therapy has emerged as a novel treatment approach for patients with intractable ischemic heart disease, aiming at facilitating neovascularization to augment blood flow in the ischemic myocardium by introducing genes encoding for angiogenic factors. While several clinical trials for cardiac angiogenic gene therapy are currently in progress, there remains a discrepancy between impressive preclinical results and their limited clinical findings. On the other hand, positron emission tomography (PET) reporter gene imaging has been developed to monitor expression of transgenes in vivo. PET reporter genes encode for proteins that retain complementary positron-emitting tracers (PET reporter probes), and theoretically any therapeutic gene can be linked and coexpressed with an appropriate PET reporter gene. Consequently, PET reporter gene imaging with a PET reporter probe affords external determination of the location, magnitude, and duration of expression of therapeutic genes noninvasively. Since PET imaging can be performed in various species ranging from mice to humans, in vivo cardiac PET reporter gene imaging could play a critical role in identifying the "missing link" as a powerful translational research tool. In this article, we discuss the role of PET reporter gene imaging in basic and clinical research on cardiac angiogenic gene therapy. PMID:16305630

Inubushi, Masayuki; Tamaki, Nagara

13

Gene Therapy  

PubMed Central

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

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

2009-01-01

14

Gene therapy  

Microsoft Academic Search

Gene therapy is not yet possible, but may become feasible soon, particularly for well understood gene defects. Although treatment of a patient raises no ethical problems once it can be done well, changing the genes of an early embryo is more difficult, controversial and unlikely to be required clinically.

Bob Williamson

1982-01-01

15

Gene Therapy  

NSDL National Science Digital Library

This learning resource is a guide for teachers of sciences in helping students to learn about Gene therapy. This lesson uses multiple activities, which engage students in learning about current genetic research and the ethical implications of this research.

Scientific American Frontiers (;)

2007-09-26

16

Gene Therapy  

Microsoft Academic Search

Severe genetic disorders are potentially correctable by the addition of a normal gene into tissues. Although the technical problems involving integration, stable expression, and insertional damage to the treated cell are not yet fully solved, enough scientific progress has already been made to consider somatic cell gene therapy acceptable from both the ethical and scientific viewpoints. The resolutions to problems

Arie Drugan; Orlando J. Miller; Mark I. Evans

1987-01-01

17

Optimization of Adenoviral Vectors to Direct Highly Amplified Prostate-Specific Expression for Imaging and Gene Therapy  

Microsoft Academic Search

Gene expression-based imaging coupled to gene therapy will permit the prediction of therapeutic outcome. A significant challenge for successful gene therapy is to achieve a high-level of specific gene expression; however, tissue-specific promoters are weak. We postulate that if the weak activity of tissue-specific promoters can be amplified to the levels of strong viral promoters, which have been successful in

Makoto Sato; Mai Johnson; Liqun Zhang; Baohui Zhang; Kim Le; Sanjiv S. Gambhir; Michael Carey; Lily Wu

2003-01-01

18

Combined in vivo bioluminescence and fluorescence imaging for cancer gene therapy.  

PubMed

Nasopharyngeal carcinoma is intimately associated with the Epstein-Barr virus (EBV), which we have exploited therapeutically by constructing an EBV-specific synthetic enhancer sequence, within an adenoviral vector, denoted as adv.oriP. The achievement of tumor targeting provides therapeutic potential when delivered systemically, which could impact on distant metastases. We demonstrate here the feasibility and potential utility of combined, minimally invasive in vivo bioluminescence and fluorescence imaging to monitor adenoviral infection of subcutaneous C666-1 nasopharyngeal xenograft tumors stably expressing the DsRed2 gene. Fluorescence imaging was used to monitor the location and size of the C6661.DsRed2 tumors, whereas bioluminescence imaging demonstrated the distribution and specificity of a transcriptionally targeted adenoviral vector, adv.oriP.fluc, expressing the firefly luciferase gene. Fluorescence, bioluminescence, and photographic images were aligned using grids to examine colocalization of adenovirus and tumors. Bioluminescence and fluorescence co-localized in 92% (11/12) of tumors at 24 hr and 100% (12/12) at 96 hr after adv.oriP.fluc (10(9) ifu) was administered intravenously. Nonspecific luciferase signal was detected in the liver area. The combined imaging was therefore successful in monitoring the uptake of systemically administered adenovirus in implanted tumors. This may ultimately lead to an effective noninvasive method to monitor the response of metastases to adenoviral gene therapy. PMID:15802052

Mocanu, J D; Moriyama, E H; Chia, M C; Li, J-H; Yip, K W; Huang, D P; Bastianutto, C; Wilson, B C; Liu, F-F

2004-10-01

19

Noninvasive imaging of hypoxia-inducible factor-1? gene therapy for myocardial ischemia.  

PubMed

Abstract Hypoxia-inducible factor-1 alpha (HIF-1?) gene therapy holds great promise for the treatment of myocardial ischemia. Both preclinical and clinical evaluations of this therapy are underway and can benefit from a vector strategy that allows noninvasive assessment of HIF-1? expression as an objective measure of gene delivery. We have developed a novel bidirectional plasmid vector (pcTnT-HIF-1?-VP2-TSTA-fluc), which employs the cardiac troponin T (cTnT) promoter in conjunction with a two-step transcriptional amplification (TSTA) system to drive the linked expression of a recombinant HIF-1? gene (HIF-1?-VP2) and the firefly luciferase gene (fluc). The firefly luciferase (FLuc) activity serves as a surrogate for HIF-1?-VP2 expression, and can be noninvasively assessed in mice using bioluminescence imaging after vector delivery. Transfection of cultured HL-1 cardiomyocytes with pcTnT-HIF-1?-VP2-TSTA-fluc led to a strong correlation between FLuc and HIF-1?-dependent vascular endothelial growth factor expression (r(2)=0.88). Intramyocardial delivery of pcTnT-HIF-1?-VP2-TSTA-fluc into infarcted mouse myocardium led to persistent HIF-1?-VP2 expression for 4 weeks, even though it improved neither CD31+ microvessel density nor echocardiographically determined left ventricular systolic function. These results lend support to recent findings of suboptimal efficacy associated with plasmid-mediated HIF-1? therapy. The imaging techniques developed herein should be useful for further optimizing HIF-1?-VP2 therapy in preclinical models of myocardial ischemia. PMID:23937265

Chen, Ian Y; Gheysens, Olivier; Li, Zongjin; Rasooly, Julia A; Wang, Qian; Paulmurugan, Ramasamy; Rosenberg, Jarrett; Rodriguez-Porcel, Martin; Willmann, Juergen K; Wang, David S; Contag, Christopher H; Robbins, Robert C; Wu, Joseph C; Gambhir, Sanjiv S

2013-10-01

20

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

PubMed Central

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

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

2010-01-01

21

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

2012-08-23

22

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

SciTech Connect

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

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

1996-05-01

23

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

24

Gene Therapy  

Microsoft Academic Search

\\u000a Technological developments in gene isolation and DNA sequencing have been important factors contributing to the knowledge\\u000a of the genes associated with numerous diseases. This information has been critical for enhancing our understanding of the\\u000a genetic basis of disease and the role that specific genes play in human phys

Arianna Malgieri; Paola Spitalieri; Giuseppe Novelli; Federica C. Sangiuolo

25

Gene Therapy.  

National Technical Information Service (NTIS)

Blood cells are used as cellular vehicles for gene transfer. In one embodiment, the invention is directed to a method of enhancing the therapeutic effects of blood cells. For example, there is provided a method of enhancing the therapeutic effects of bloo...

W. F. Anderson R. M. Blaese S. A. Rosenberg

1989-01-01

26

Noninvasive Imaging of Cardiac Gene Expression and Its Future Implications for Molecular Therapy  

Microsoft Academic Search

Innovative approaches for cardiovascular molecular therapy are rapidly evolving, and translational efforts from experimental to clinical application are increasing. Gene and cell therapy hold promise for treatment of heart disease, but despite progress, some basic principles are still under development. Open issues are, e.g., related to the optimal method for delivery, to therapeutic efficacy, to time course and magnitude of

Frank M. Bengel

2005-01-01

27

Gene Therapy and Radiation  

Microsoft Academic Search

\\u000a Owing to a low efficiency of gene transfer when delivered systemically, gene therapy may find its greatest utility in the\\u000a clinic when combined with loco-regional cancer treatment such as radiation therapy. Although a variety of gene therapy strategies\\u000a have been combined with radiation in preclinical models, only a handful have been translated into the clinic. Overall, combining\\u000a gene therapy with

Svend O. Freytag; Kenneth N. Barton; Farzan Siddiqui; Mohamed Elshaikh; Hans Stricker; Benjamin Movsas

28

PET/CT imaging of human somatostatin receptor 2 (hsstr2) as reporter gene for gene therapy  

NASA Astrophysics Data System (ADS)

Localized information on region-selective gene expression in small animals is widely obtained by use of reporter genes inducing light emission. Using these reporter genes for imaging deep inside the human body fluorescent probes are hindered by attenuation, scattering and possible fluorescence quenching. This can be overcome by use of radio-peptide receptors as reporter genes. Therefore, the feasibility of the somatostatin receptor 2 expression vector system for expression imaging was checked against a control vector containing luciferase gene. For in vivo transduction of vector DNA into the rat forelimb muscles the in vivo electroporation technique was chosen because of its high regio-selectivity. The gene expression was imaged by high-sensitive CCD camera (luciferase activity) and by PET/CT using a Ga-68-DOTATOC as radio peptide probe. The relative sstr2 expression was enhanced by gene transduction at maximum to a factor of 15. The PET/CT images could be fully quantified. The above demonstrated feasibility of radio-peptide PET/CT reporter gene imaging may serve in the future as a tool for full quantitative understanding of regional gene expression, especially in large animals and humans.

Hofmann, M.; Gazdhar, A.; Weitzel, T.; Schmid, R.; Krause, T.

2006-12-01

29

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

Microsoft Academic Search

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

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

2010-01-01

30

Gene therapies for osteoarthritis  

Microsoft Academic Search

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

Christopher H. Evans

2004-01-01

31

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

32

Gene Therapy for Cancer  

Microsoft Academic Search

The basic strategies for gene therapy that have been explored include immunogene therapy such as cytokine gene transfer,\\u000a selective prodrug activation, so-called suicide genes, transfer of a tumor suppressor gene, and inhibition of activated oncogenes\\u000a by antisense mechanisms. Many therapeutic protocols have so far been registered in the office of the Recombinant DNA Advisory\\u000a Committee, NIH, as of June 1999.

Yoshio Gunji; Takenori Ochiai; H. Shimada; H. Matsubara

2000-01-01

33

Gene therapy in surgery  

Microsoft Academic Search

Summary  \\u000a Background: With the increasing body of knowledge in molecular biology, gene transfer respectively gene therapy becomes more and more\\u000a a valid therapeutic option.\\u000a \\u000a \\u000a Methods: This is a critical review of gene therapy protocols for treatment of different types of cancer. Furthermore, the pathophysiological\\u000a mechanism, therapeutically strategies as well as experimental approaches toward gene transfer in septic shock and organ

M. A. Rogy; Julie M. Baumhofer; Britta Beinhauer; H. Brandmeier; P. Eisenburger; U. M. Losert; Ramila Philip

1997-01-01

34

History of gene therapy.  

PubMed

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

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

2013-04-23

35

Gene therapy for immunodeficiency  

Microsoft Academic Search

Since the early 1990s, primary immunodeficiency (ID) disorders have played a major role in the development of human gene therapy.\\u000a Adenosine deaminase (ADA) deficiency was the first disease to be treated with a gene therapy approach in humans, and was also\\u000a the first condition for which therapeutic gene transfer into the hematopoietic stem cell has been attempted in the clinical

Fabio Candotti

2001-01-01

36

Osteoarthritis gene therapy  

Microsoft Academic Search

Osteoarthritis (OA) is the Western world's leading cause of disability. It is incurable, costly and responds poorly to treatment. This review discusses strategies for treating OA by gene therapy. As OA affects a limited number of weight-bearing joints and has no major extra-articular manifestations, it is well suited to local, intra-articular gene therapy. Possible intra-articular sites of gene transfer include

CH Evans; JN Gouze; E Gouze; PD Robbins; SC Ghivizzani

2004-01-01

37

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

38

Gene therapy of cancer  

Microsoft Academic Search

There are several approaches to the gene therapy of cancer. Genes can be introduced into cancer cells to either sensitize\\u000a them for killing by subsequent treatment with drugs, or to normalize their growth. In addition, genes can be added to tumor\\u000a cells to provoke an accentuated immune response against these cells leading to cancer cell death. Alternatively, drug resistance\\u000a genes

Arthur Bank

1995-01-01

39

Gene therapy in surgery  

Microsoft Academic Search

Summary\\u000a Background  With the increasing body of knowledge in molecular biology, gene transfer respectively gene therapy becomes more and more\\u000a a valid therapeutic option.\\u000a \\u000a \\u000a \\u000a Methods  This is a critical review of gene therapy protocols for treatment of different types of cancer. Furthermore, the pathophysiological\\u000a mechanism, therapeutically strategies as well as experimental approaches toward gene transfer in septic shock and organ transplantation\\u000a are

M. A. Rogy; Julie M. Baumhofer; Britta Beinhauer; H. Brandmeier; P. Eisenburger; U. M. Losert; Ramila Philip

1996-01-01

40

Cellular & Gene Therapy Research  

Center for Biologics Evaluation and Research (CBER)

... Tumor Vaccines & Biotechnology. Development of Safe and Effective Tumor Vaccines and Gene Therapy Products Raj Puri, MD, PhD; ... More results from www.fda.gov/biologicsbloodvaccines/scienceresearch/biologicsresearchareas

41

Gene therapy of cancer  

Microsoft Academic Search

Recent advances in the understanding of the molecular pathogenesis of cancer herald breakthroughs in the treatment of this collection of diseases, which are still usually incurable in advanced stages. In particular, there is a high expectation of gene and immunogene therapy. A recent meeting1The 3rd European Conference on Gene Therapy of Cancer was held at Berlin, Germany, on 11–13 September

Farzin Farzaneh; Uwe Trefzer; Wolfram Sterry; Peter Walden

1998-01-01

42

Tumor Suppressor Gene Therapy  

Microsoft Academic Search

\\u000a Recent advances in genetics, molecular biology, and molecular pharmacology have resulted in the development of molecularly\\u000a targeted therapies. Targeting specific molecular pathways essential for the survival of cancer cells would personalize treatment\\u000a with the potential to improve outcome and minimize toxicities. In this chapter, we review gene-based targeted therapies for\\u000a cancer. Discussion focuses on replacement therapies for abnormal p53 function

Jack A. Roth; John Nemunaitis; Lin Ji; Rajagopal Ramesh

43

Gene Therapy: Ethical Issues  

Microsoft Academic Search

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

Isaac Rabino

2003-01-01

44

Gene therapy for brain tumors  

Microsoft Academic Search

Gene therapy’ can be defined as the transfer of genetic material into a patient’s cells for therapeutic purposes. To date,\\u000a a diverse and creative assortment of treatment strategies utilizing gene therapy have been devised, including gene transfer\\u000a for modulating the immune system, enzyme prodrug (‘suicide gene’) therapy, oncolytic therapy, replacement\\/ therapeutic gene\\u000a transfer, and antisense therapy. For malignant glioma, gene-directed

Kanti Bansal; Herbert H. Engelhard

2000-01-01

45

Gene therapy for restenosis  

Microsoft Academic Search

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

Roy C. Smith; Kenneth Walsh

2000-01-01

46

Genetics Home Reference: What is gene therapy?  

MedlinePLUS

... How Genes Work Mutations and Health Inheritance Consultation Testing Therapy Human Genome Project Genomic Research Next Handbook > Gene Therapy > What is gene therapy? Gene therapy is an ... are testing several approaches to gene therapy, including: Replacing a ...

47

Gene Therapy and Immune Senescence  

Microsoft Academic Search

Gene therapy can be classified according to the vector used for gene therapy and the transgene that will be expressed as a\\u000a result of the gene therapy. One consideration for gene therapy is that certain vectors have larger capacities than others\\u000a to incorporate genes. The second consideration is the duration of therapy, which depends upon the immune response after delivery

Jian Chen; Hui-Chen Hsu; John D. Mountz

48

Gene therapy in periodontics  

PubMed Central

GENES are made of DNA - the code of life. They are made up of two types of base pair from different number of hydrogen bonds AT, GC which can be turned into instruction. Everyone inherits genes from their parents and passes them on in turn to their children. Every person's genes are different, and the changes in sequence determine the inherited differences between each of us. Some changes, usually in a single gene, may cause serious diseases. Gene therapy is ‘the use of genes as medicine’. It involves the transfer of a therapeutic or working gene copy into specific cells of an individual in order to repair a faulty gene copy. Thus it may be used to replace a faulty gene, or to introduce a new gene whose function is to cure or to favorably modify the clinical course of a condition. It has a promising era in the field of periodontics. Gene therapy has been used as a mode of tissue engineering in periodontics. The tissue engineering approach reconstructs the natural target tissue by combining four elements namely: Scaffold, signaling molecules, cells and blood supply and thus can help in the reconstruction of damaged periodontium including cementum, gingival, periodontal ligament and bone.

Chatterjee, Anirban; Singh, Nidhi; Saluja, Mini

2013-01-01

49

Gene Therapy vs Pharmacotherapy  

Microsoft Academic Search

Recent progress in molecular and cellular biology has developed numerous effective cardiovascular drugs. However, there are\\u000a still number of diseases for which no known effective therapy exists, such as peripheral arterial disease, ischemic heart\\u000a disease, restenosis after angioplasty, vascular bypass graft occlusion, and transplant coronary vasculopathy. Currently, gene\\u000a therapy is emerging as a potential strategy for the treatment of cardiovascular

Ryuichi Morishita

50

Cell and Gene Therapy  

Microsoft Academic Search

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

Robbie Norville

51

Vectors for cancer gene therapy  

Microsoft Academic Search

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

J. Zhang; S. J. Russell

1996-01-01

52

Molecular targets of gene therapy  

Microsoft Academic Search

Ischemic reperfused heart represents a potential target for gene therapy because gene transfer can represent an alternate pharmacological approach to protect the heart from cellular injury. Gene therapy may be particularly useful to deal with previously unapproachable problems. For myocardial preservation, gene therapy could replace those pharmacological interventions when drugs are delivered locally by sustained release with the help of

Dipak K Das; Richard M Engelman; Nilanjana Maulik; John A Rousou; Joseph E Flack; David W Deaton

1999-01-01

53

[Gene therapy in The Netherlands].  

PubMed

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

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

2007-09-01

54

Human Gene Therapy  

Microsoft Academic Search

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.

W. French Anderson

1992-01-01

55

Gene Therapy for Sarcoma  

Microsoft Academic Search

Soft tissue sarcomas are mesenchymal tumors which respond poorly to systemic therapy. Recent studies suggest a higher response rate with an increased doxorubicin dosage. However, this was parallel with a profound hematotoxicity in 75% of patients. Transfer of the human multidrug resistance 1 (MDR1) gene to normal hematopoietic stem cells and transplantation may significantly reduce the hematotoxicity of anthracyclin-based chemotherapy.

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

2002-01-01

56

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

57

Human Gene Therapy. Background Paper.  

National Technical Information Service (NTIS)

The paper focuses on the imminent development of human gene therapy, emphasizing early medical applications. The governmental concerns related to human gene therapy, as for other medical technologies, will include protection of subjects involved in resear...

1984-01-01

58

Homologous Recombination Based Gene Therapy  

Microsoft Academic Search

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

Li-Wen Lai; Yeong-Hau H. Lien

1999-01-01

59

Gene Therapy for Autoimmune Disorders  

Microsoft Academic Search

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

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

2000-01-01

60

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

61

Gene transfer and gene therapy  

Microsoft Academic Search

This book reports the progress in gene transfer that has been made in various species, from Drosophila to higher mammals, including illustrative examples of germline gene transfer and tissue-specific somatic gene regulation in the mouse. Important new information regarding developmental control of gene transcription includes the delineation of distal elements, both cis and trans, controlling specific gene regulation. The book

A. L. Beaudet; R. Mulligan; I. M. Verma

1988-01-01

62

Gene therapy and reproductive medicine  

Microsoft Academic Search

Objective: To review the literature on the principles of gene therapy and its potential application in reproductive medicine.Design: Literature review.Setting: Gene therapy involves transfer of genetic material to target cells using a delivery system, or vector. Attention has primarily focused on viral vectors. Significant problems remain to be overcome including low efficacy of gene transfer, the transient expression of some

John M Stribley; Khurram S Rehman; Hairong Niu; Gregory M Christman

2002-01-01

63

Review: Gene Therapy for Cancer  

Microsoft Academic Search

Gene therapy is a new form of therapeutic intervention with applications in many areas of medical treatment. There are still many technical difficulties to be overcome, but recent advances in the molecular and cellular biology of gene transfer have made it likely that gene therapy will soon start to play an increasing role in clinical practice and particularly in the

Gregory Kouraklis

2000-01-01

64

Imaging the modulation of adenoviral kinetics and biodistribution for cancer gene therapy.  

PubMed

To explore systemic utilization of Epstein-Barr virus (EBV)-specific transcriptionally targeted adenoviruses, three vectors were constructed to examine kinetics, specificity, and biodistribution: adv.oriP.luc, expressing luciferase under EBV-specific control; adv.SV40luc, expressing luciferase constitutively; and adv.oriP.E1A.oriP.luc, a conditionally replicating adenovirus, expressing both luciferase and E1A. Bioluminescence imaging (BLI) was conducted on tumor-bearing severe combined immunodeficient (SCID) mice (C666-1, EBV-positive human nasopharyngeal cancer) treated intravenously (i.v.) with 3 x 10(8) infectious units (ifu) of the adenoviral vectors. At 72 hours, adv.oriPluc demonstrated an 8.4-fold higher tumor signal than adv.SV40luc; adv.oriP.E1A.oriP.luc was 26.7-fold higher; however, a significant liver signal was also observed, necessitating further action to improve biodistribution. Several compounds were examined to this end, including norepinephrine, serotonin, clodronate liposomes, and STI571, to determine whether any of these measures could improve adenoviral biodistribution. Each of these interventions was assessed using BLI in mice i.v. injected with adv.oriP.luc. STI571 achieved the highest increase in tumor-to-liver ratio (TLR; 6.6-fold), which was associated with a 59% reduction in tumor interstitial fluid pressure (IFP) along with a decrease in platelet-derived growth factor-beta receptor (PDGF beta R) activation. This study reports the favorable modulation by STI571 of the biodistribution of adenoviral vectors, providing a potential approach to improving therapeutic outcome. PMID:17356543

Mocanu, Joseph D; Yip, Kenneth W; Alajez, Nehad M; Shi, Wei; Li, Jian-Hua; Lunt, Sarah J; Moriyama, Eduardo H; Wilson, Brian C; Milosevic, Michael; Lo, Kwok-Wai; van Rooijen, Nico; Busson, Pierre; Bastianutto, Carlo; Liu, Fei-Fei

2007-03-13

65

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

66

Gene Therapy Approaches to Immunosuppression  

Microsoft Academic Search

\\u000a Gene therapy is defined as the delivery of genetic material in the form of DNA. Its purpose is to correct a missing or disturbed\\u000a gene function associated with a pathophysiological situation in patients. It is attractive compared to the conventional pharmacological\\u000a therapy, as it can be applied more locally and thus should have fewer side-effects. Somatic gene therapy, the delivery

Reto A. Gadient; Thomas Biihler; Marcel Luyten; N. Rao Movva

67

Local Gene Therapy for Cancer  

Microsoft Academic Search

Cancer is an important problem in public health worldwide. Gene therapy has the potential for improved treatment of cancer\\u000a patients, particularly if used in combination with other, conventional therapies. To date, many strategies of gene therapy\\u000a have been explored, including correction of mutant genes, immunstimulation, prodrug activation, interference of oncogene expression,\\u000a and genetically modified oncolytic viruses. Although the preclinical results

Wolfgang Walther; Ulrike S. Stein; Peter M. Schlag

68

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

69

Gene transfer and gene therapy  

SciTech Connect

This book reports the progress in gene transfer that has been made in various species, from Drosophila to higher mammals, including illustrative examples of germline gene transfer and tissue-specific somatic gene regulation in the mouse. Important new information regarding developmental control of gene transcription includes the delineation of distal elements, both cis and trans, controlling specific gene regulation. The book also offers an overview of vectors for gene transfer, including retroviral vectors and new retroviral packaging cell lines designed to minimize production of replication-competent virus.

Beaudet, A.L.; Mulligan, R.; Verma, I.M.

1988-01-01

70

Hematopoietic Stem Cell Gene Therapy  

Microsoft Academic Search

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

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

2002-01-01

71

Gene therapy for ocular diseases  

PubMed Central

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

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

2011-01-01

72

Gene Therapy in Heart Failure  

Microsoft Academic Search

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

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

2010-01-01

73

Progress in cancer gene therapy  

Microsoft Academic Search

The “First International Symposium on Genetic Anticancer Agents,” which took place in Amsterdam on March 8–9, 2000, served as a forum to review the results of preclinical and clinical gene therapy studies for cancer endeavored to date.Despite the fact that gene therapy was initially conceptualized as an approach for inherited genetic disease, it is currently finding its widest employ for

David T Curiel; Winald R Gerritsen; Mark R L Krul

2000-01-01

74

Gene therapy for lipid disorders  

Microsoft Academic Search

Lipid disorders are associated with atherosclerotic vascular disease, and therapy is associated with a substantial reduction in cardiovascular events. Current approaches to the treatment of lipid disorders are ineffective in a substantial number of patients. New therapies for refractory hypercholesterolemia, severe hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol are needed: somatic gene therapy is one viable approach. The molecular

Masa-aki Kawashiri; Daniel J Rader

2000-01-01

75

Gene therapy for Parkinson's disease  

Microsoft Academic Search

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

Philippe Horellou; Jacques Mallet

1997-01-01

76

Gene therapy--its potential in surgery.  

PubMed Central

Advances in techniques have resulted in practical applications for gene therapy, which is becoming applicable for the treatment of human disease. This review outlines the advantages and disadvantages of the techniques available. Examples of research efforts in the treatment of diseases of relevance to the surgeon (cardiovascular diseases, cancer, wound healing, fracture repair, and in organ transplantation) are presented. Images Figure 1 Figure 2

Gojo, Satoshi; Yamamoto, Shin; Patience, Clive; LeGuern, Christian; Cooper, David K. C.

2002-01-01

77

Prospects for Human Gene Therapy  

Microsoft Academic Search

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

W. French Anderson

1984-01-01

78

Gene therapy in the cornea  

Microsoft Academic Search

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

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

2005-01-01

79

Prospects for Human Gene Therapy.  

National Technical Information Service (NTIS)

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

1994-01-01

80

Bacteria in gene therapy: bactofection versus alternative gene therapy  

Microsoft Academic Search

Recent advances in gene therapy can be attributed to improvements of gene delivery vectors. New viral and nonviral transport vehicles that considerably increase the efficiency of transfection have been prepared. However, these vectors still have many disadvantages that are difficult to overcome, thus, a new approach is needed. The approach of bacterial delivery could in the future be important for

R Pálffy; R Gardlík; J Hodosy; M Behuliak; P Reško; J Radvánský; P Celec

2006-01-01

81

Arthritis gene therapy's first death  

PubMed Central

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

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

2008-01-01

82

Gene therapy of multiple sclerosis  

Microsoft Academic Search

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

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

83

Gene Therapy for Pituitary Tumors  

PubMed Central

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

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

2009-01-01

84

Switching on the Lights for Gene Therapy  

PubMed Central

Strategies for non-invasive and quantitative imaging of gene expression in vivo have been developed over the past decade. Non-invasive assessment of the dynamics of gene regulation is of interest for the detection of endogenous disease-specific biological alterations (e.g., signal transduction) and for monitoring the induction and regulation of therapeutic genes (e.g., gene therapy). To demonstrate that non-invasive imaging of regulated expression of any type of gene after in vivo transduction by versatile vectors is feasible, we generated regulatable herpes simplex virus type 1 (HSV-1) amplicon vectors carrying hormone (mifepristone) or antibiotic (tetracycline) regulated promoters driving the proportional co-expression of two marker genes. Regulated gene expression was monitored by fluorescence microscopy in culture and by positron emission tomography (PET) or bioluminescence (BLI) in vivo. The induction levels evaluated in glioma models varied depending on the dose of inductor. With fluorescence microscopy and BLI being the tools for assessing gene expression in culture and animal models, and with PET being the technology for possible application in humans, the generated vectors may serve to non-invasively monitor the dynamics of any gene of interest which is proportionally co-expressed with the respective imaging marker gene in research applications aiming towards translation into clinical application.

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

2007-01-01

85

Gene therapy of benign gynecological diseases  

Microsoft Academic Search

Gene therapy is the introduction of genetic material into patient's cells to achieve therapeutic benefit. Advances in molecular biology techniques and better understanding of disease pathogenesis have validated the use of a variety of genes as potential molecular targets for gene therapy based approaches. Gene therapy strategies include: mutation compensation of dysregulated genes; replacement of defective tumor-suppressor genes; inactivation of

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

2009-01-01

86

Heat-responsive gene expression for gene therapy  

Microsoft Academic Search

Therapy-inducible vectors are useful for conditional expression of therapeutic genes in gene therapy, which is based on the control of gene expression by conventional treatment modalities. By this approach, combination of chemotherapy, radiation or hyperthermia with gene therapy can result in considerable, additive or synergistic improvement of therapeutic efficacy. This concept has been successfully tested in particular for gene therapy

Wolfgang Walther; Ulrike Stein

2009-01-01

87

GENE THERAPY FOR VENTRICULAR TACHYARRHYTHMIAS  

PubMed Central

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

Donahue, J. Kevin

2013-01-01

88

for Hemophilia B Gene Therapy  

Microsoft Academic Search

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

HENGJUN CHAO; CHRISTOPHER E. WALSH

89

Gene therapy: theoretical and bioethical concepts  

Microsoft Academic Search

Gene therapy holds great promise. Somatic gene therapy has the potential to treat a wide range of disorders, including inherited conditions, cancers, and infectious diseases. Early progress has already been made in the treatment of a range of disorders. Ethical issues surrounding somatic gene therapy are primarily those concerned with safety. Germline gene therapy is theoretically possible but raises serious

Kevin R Smith

2003-01-01

90

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.

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

2008-01-01

91

Gene therapy in status epilepticus.  

PubMed

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

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

2013-09-01

92

Delivery systems for gene therapy  

PubMed Central

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

Mali, Shrikant

2013-01-01

93

Delivery systems for gene therapy.  

PubMed

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

Mali, Shrikant

2013-01-01

94

Gene therapy for atherosclerosis  

Microsoft Academic Search

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

D. J. Rader

1997-01-01

95

Issues in Image Guided Therapy  

Microsoft Academic Search

Medical robotics, Computer Assisted Surgery (CAS), Image-Guided Therapy (IGT) and the like emerged more than 20 years ago and it must be recognized that many advances have been made. Conferences, workshops, have been organized, scientific contributions, position papers and patents have been published, new academic societies have been launched and companies created all over the world to propose methods, devices

Pascal Haigron; Limin Luo; Jean-Louis Coatrieux

2009-01-01

96

Conditional gene targeting for cancer gene therapy  

Microsoft Academic Search

Current treatment of solid tumors is limited by severe adverse effects, resulting in a narrow therapeutic index. Therefore, cancer gene therapy has emerged as a targeted approach that would significantly reduce undesired side effects in normal tissues. This approach requires a clear understanding of the molecular biology of both the malignant clone and the biological vectors that serve as vehicles

Yosef S. Haviv; David T. Curiel

2001-01-01

97

Development and Validation of Non-Integrative, Self-Limited, and Replicating Minicircles for Safe Reporter Gene Imaging of Cell-Based Therapies  

PubMed Central

Reporter gene (RG) imaging of cell-based therapies provides a direct readout of therapeutic efficacy by assessing the fate of implanted cells. To permit long-term cellular imaging, RGs are traditionally required to be integrated into the cellular genome. This poses a potential safety risk and regulatory bottleneck for clinical translation as integration can lead to cellular transformation. To address this issue, we have developed non-integrative, replicating minicircles (MCs) as an alternative platform for safer monitoring of cells in living subjects. We developed both plasmids and minicircles containing the scaffold/matrix attachment regions (S/MAR) of the human interferon-beta gene, driven by the CMV promoter, and expressing the bioluminescence RG firefly luciferase. Constructs were transfected into breast cancer cells, and expanded S/MAR minicircle clones showed luciferase signal for greater than 3 months in culture and minicircles remained as episomes. Importantly, luciferase activity in clonal populations was slowly lost over time and this corresponded to a loss of episome, providing a way to reversibly label cells. To monitor cell proliferation in vivo, 1.5×106 cells carrying the S/MAR minicircle were implanted subcutaneously into mice (n?=?5) and as tumors developed significantly more bioluminescence signal was noted at day 35 and 43 compared to day 7 post-implant (p<0.05). To our knowledge, this is the first work examining the use of episomal, self-limited, replicating minicircles to track the proliferation of cells using non-invasive imaging in living subjects. Continued development of S/MAR minicircles will provide a broadly applicable vector platform amenable with any of the numerous RG technologies available to allow therapeutic cell fate to be assessed in individual patients, and to achieve this without the need to manipulate the cell's genome so that safety concerns are minimized. This will lead to safe tools to assess treatment response at earlier time points and improve the precision of cell-based therapies.

Ronald, John A.; Cusso, Lorena; Chuang, Hui-Yen; Yan, Xinrui; Dragulescu-Andrasi, Anca; Gambhir, Sanjiv Sam

2013-01-01

98

Gene therapy for myositis  

Microsoft Academic Search

\\u000a The inflammatory myopathies, polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM), lead to moderate to\\u000a severe muscle weakness and are characterised by the presence of endomysial inflammation. Each entity has unique clinical,\\u000a immunopathological and histological characteristics which are associated with different responses to therapies and prognosis.\\u000a In DM and PM, first-line treatment options include oral corticosteroids, other immunosuppressant drugs,

Hans H. Jung; Juliane Bremer; Michael Weller

99

Improvements in gene therapy technologies.  

PubMed

We have combined hemagglutinating virus of Japan (HVJ; Sendai virus) with liposomes for efficient in vitro and in vivo fusion-mediated gene delivery. The HVJ-liposome was a highly efficient vehicle for the introduction of oligonucleotides into cells in vivo as well as for the transfer of genes <100 kbp without damaging cells. By coupling the Epstein-Barr (EB) virus replicon apparatus with HVJ-liposomes (virosomes), transgene expression was sustained in vitro and in vivo. When we added cationic lipids, the HVJ-cationic liposomes increased gene delivery 100 to 800 times in vitro compared with the conventional anionic virosomes and were also more useful for gene expression in restricted areas of organs and for gene therapy of disseminated cancers. We further discovered that the use of anionic virosomes with a virus-mimicking lipid composition (artificial viral envelope; AVE type) increased transfection efficiency approximately 10 fold in vivo, especially in the heart, liver, kidney, and muscle. Most animal organs were found to be suitable targets for the fusigenic virosomes, and numerous gene therapy strategies using this system were successful in animals. The combination of suicide gene therapy with radiation was very effective for killing hepatomas in a mouse model. Arteriosclerosis obliterans in animal models was cured by the transfer of hepatocyte growth factor. PMID:11690554

Kaneda, Y

2001-01-01

100

Hypoxia targeting gene expression for breast cancer gene therapy  

Microsoft Academic Search

Gene therapy is a promising strategy to treat various inherited and acquired diseases. However, targeting gene expression to specific tissue is required to minimize side effects of gene therapy. Hypoxia is present in the microenvironment of solid tumors such as breast tumors. A hypoxic tumor targeting gene expression system has been developed for cancer gene therapy. In hypoxic tissues, hypoxia

Minhyung Lee

2009-01-01

101

Gene therapy in clinical medicine  

PubMed Central

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

Selkirk, S

2004-01-01

102

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

103

Gene therapy for arthritis  

Microsoft Academic Search

Rheumatoid arthritis is an autoimmune disease with intra-articular inflammation and synovial hyperplasia that results in progressive degradation of cartilage and bone, in severe cases it causes systemic complications. Recently, biological agents that suppress the activities of proinflammatory cytokines have shown efficacy as antiarthritic drugs, but require frequent administration. Thus, gene transfer approaches are being developed as an alternative approach for

P D Robbins; C H Evans; Y Chernajovsky

2003-01-01

104

Gene therapy for PNET  

Microsoft Academic Search

A new era has been reached in cancer therapeutics in which the techniques of molecular biology can be applied to human brain tumors. Ongoing studies are determining the best vector system with which to deliver genes to cells. Choices include the retroviral, adenoviral, and Herpes simplex virus vector systems. The optimum mode of delivering the vector specifically to the tumor

Corey Raffel

1996-01-01

105

Targeting Cancer Gene Therapy with Magnetic Nanoparticles  

PubMed Central

Recent advances in cancer genomics have opened up unlimited potential for treating cancer by directly targeting culprit genes. However, novel delivery methods are needed in order for this potential to be translated into clinically viable treatments for patients. Magnetic nanoparticle technology offers the potential to achieve selective and efficient delivery of therapeutic genes by using external magnetic fields, and also allows simultaneous imaging to monitor the delivery in vivo. Compared to conventional gene delivery strategies, this technique has been shown to significantly increase gene delivery to human xenograft tumors models, as well as various internal organs (e.g. liver, kidney) and the central nervous system. Magnetic nanoparticle technology, therefore, has the potential to turn the challenge of gene therapy in vivo into a new frontier for cancer treatment.

Li, Charles; Li, Linda; Keates, Andrew C.

2012-01-01

106

Gene therapy for prostate cancer  

Microsoft Academic Search

Basic research continues to unravel the molecular complexity of normal and abnormal biologic processes. The development of\\u000a means to affect the expression level of genes that promote or contribute to cellular transformation, invasion, and metastasis\\u000a has spawned the concept of gene therapy. This relatively new field seeks to reverse or suspend the pathologic progression\\u000a of a variety of diseases including

Jeffrey R. Gingrich; Ravi D. Chauhan; Mitchell S. Steiner

2001-01-01

107

A Comeback for Gene Therapy  

NSDL National Science Digital Library

Cartier et al. report another major advanceâÂÂthe successful first clinical testing of an HIV-derived vector in hematopoietic stem cell (HSC)âÂÂbased gene therapy. The procedure was used to treat a severe neurodegenerative disease, X-linked adrenoleukodystrophy (ALD), and the results indicate stable expression of a therapeutic gene in a substantial fraction of patients' hematopoietic cells, as well as clinical benefits.

Luigi Naldini ("Vita Salute San Raffaele" University;)

2009-11-06

108

Cancer gene therapy: an awkward adolescence  

Microsoft Academic Search

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

Michael M Gottesman

2003-01-01

109

Gene Therapy for Restenosis Are We Ready?  

Microsoft Academic Search

The application of gene therapy techniques to the clinical problem of coronary restenosis has generated tremendous attention and enthusiasm. Use of gene transfer technology to prevent a common intractable illness would represent a watershed event for human gene therapy. However, the time is not yet right to initiate gene therapy trials for restenosis. The biology of restenosis is incompletely understood,

Mary Beth DeYoung; David A. Dichek

2010-01-01

110

Gene therapy for pancreatitis pain  

Microsoft Academic Search

Pancreatic cancer and chronic pancreatitis are clinical syndromes associated with severe pain that is difficult to manage. Thus, seeking additional pain reduction therapies is warranted. Excessive alcohol consumption over an extended period of time is the primary causal agent in pancreatitis. The efficacy of a replication defective Herpes (HSV-1, DPE) viral vector construct encoding the human preproenkephalin gene (HSV-Enk), used

K N Westlund

2009-01-01

111

Ethics of Gene Therapy Debated.  

ERIC Educational Resources Information Center

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

Borman, Stu

1991-01-01

112

Gene therapy for colorectal cancer  

Microsoft Academic Search

Gene therapy has been developed as a potential novel treatment modality for colorectal cancer. The preclinical data have been promising and several clinical trials are under way for colorectal cancer. Data from many phase 1 trials have proven the safety of the reagents, but have not yet demonstrated significant therapeutic benefit. In order to refine this approach, continuing efforts should

Daniel H Palmer; Ming-Jen Chen; David J Kerr

2002-01-01

113

Gene therapy: here to stay.  

PubMed Central

Advances in biotechnology have brought gene therapy to the forefront of medical research. The feasibility of gene transfer was first demonstrated in experiments using tumour viruses. This led to the development of a variety of viral and nonviral methods for the genetic modification of somatic cells. Two main approaches emerged: in-vivo modification, in which gene transfer vehicles are delivered directly into patients, and ex-vivo manipulation, in which cells from the patient are grown in culture, genetically modified and then returned to the patient. In 1990, shortly after the safety of retrovirus-mediated gene transfer was demonstrated in patients with malignant melanoma, the first clinical trial of gene therapy was initiated for adenosine deaminase deficiency. Since then, the number of clinical protocols initiated worldwide has increased exponentially. Although some clinical trials now in progress are concerned with relatively rare inborn errors of metabolism, most are concerned with more commonly encountered cancers and infectious diseases. Preliminary results suggest that by the turn of the century the dream of treating diseases by replacing or supplementing the products of defective genes or introducing novel therapeutic genes will become a reality.

Dube, I D; Cournoyer, D

1995-01-01

114

[Gene therapy for osteoarticular disorders].  

PubMed

Osteoarticular disorders are the major cause of disability in Europe and North America. It is estimated that rheumatoid arthritis affects 1 % of the population and that more than two third of people over age 55 develop osteoarthritis. Because there are no satisfactory treatments, gene therapy offers a new therapeutic approach. The delivery of cDNA encoding anti-arthritic proteins to articular cells has shown therapeutic efficacy in numerous animal models in vivo. Through the development and the experimental progresses that have been made for both rheumatoid arthritis and osteoarthritis, this review discusses the different gene therapy strategies available today and the safety issues with which they may be associated. Among the different vectors available today, adeno-associated virus seems the best candidate for a direct in vivo gene delivery approach for the treatment of joint disorders. PMID:17349293

Gouze, Jean-Noël; Evans, Christopher H; Ghivizzani, Steven C; Gouze, Elvire

2007-03-01

115

Endocrine Aspects of Cancer Gene Therapy  

Microsoft Academic Search

The field of cancer gene therapy is in continuous expansion, and technology is quickly moving ahead as far as gene tar- geting and regulation of gene expression are concerned. This review focuses on the endocrine aspects of gene therapy, in- cluding the possibility to exploit hormone and hormone re- ceptor functions for regulating therapeutic gene expression, the use of endocrine-specific

LUISA BARZON; MARCO BOSCARO; GIORGIO PALU

2010-01-01

116

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

117

Gene therapy in the Cornea: 2005–present  

Microsoft Academic Search

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

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

118

Gene Therapy for Celebral Arterial Diseases  

Microsoft Academic Search

Although there has been steady progress towards cardiovascular gene therapy in humans, gene therapy for cerebrovascular disorders\\u000a is still in its infancy. Several major steps, including gene transfer to cerebral arteries and alteration of gene expression,\\u000a have been taken. There are several promising targets for cerebrovascular gene therapy, such as prevention of cerebral vasospasm\\u000a after subarachnoid hemorrhage, stimulation of formation

Yoshimasa Watanabe; Donald D. Heistad

119

Gene Therapy for Primary Immunodeficiencies  

PubMed Central

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

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

2012-01-01

120

Gene Therapy: Hopes and Problems  

Microsoft Academic Search

\\u000a Gene therapy (GT) is one of the most fascinating consequences of the penetration of molecular biology and genetic engineering\\u000a into medicine. Originally, it was assumed that monogenic genetic diseases will be the main field of its application. However,\\u000a a great majority of the GT-based clinical trials in the last decade have dealt with acquired diseases. Still, its introduction\\u000a into clinical

Vladimír Vonka

121

Molecular imaging of photodynamic therapy  

NASA Astrophysics Data System (ADS)

Recent advances in light sources, detectors and other optical imaging technologies coupled with the development of novel optical contrast agents have enabled real-time, high resolution, in vivo monitoring of molecular targets. Noninvasive monitoring of molecular targets is particularly relevant to photodynamic therapy (PDT), including the delivery of photosensitizer in the treatment site and monitoring of molecular and physiological changes following treatment. Our lab has developed optical imaging technologies to investigate these various aspects of photodynamic therapy (PDT). We used a laser scanning confocal microscope to monitor the pharmacokinetics of various photosensitizers in in vitro as well as ex vivo samples, and developed an intravital fluorescence microscope to monitor photosensitizer delivery in vivo in small animals. A molecular specific contrast agent that targets the vascular endothelial growth factor (VEGF) was developed to monitor the changes in the protein expression following PDT. We were then able to study the physiological changes due to post-treatment VEGF upregulation by quantifying vascular permeability with in vivo imaging.

Chang, Sung K.; Errabelli, Divya; Rizvi, Imran; Solban, Nicolas; O'Riordan, Katherine; Hasan, Tayyaba

2006-02-01

122

Orthopedic Gene Therapy in 2008  

PubMed Central

Orthopedic disorders, although rarely fatal, are the leading cause of morbidity and impose a huge socioeconomic burden. Their prevalence will increase dramatically as populations age and gain weight. Many orthopedic conditions are difficult to treat by conventional means; however, they are good candidates for gene therapy. Clinical trials have already been initiated for arthritis and the aseptic loosening of prosthetic joints, and the development of bone-healing applications is at an advanced, preclinical stage. Other potential uses include the treatment of Mendelian diseases and orthopedic tumors, as well as the repair and regeneration of cartilage, ligaments, and tendons. Many of these goals should be achievable with existing technologies. The main barriers to clinical application are funding and regulatory issues, which in turn reflect major safety concerns and the opinion, in some quarters, that gene therapy should not be applied to nonlethal, nongenetic diseases. For some indications, advances in nongenetic treatments have also diminished enthusiasm. Nevertheless, the preclinical and early clinical data are impressive and provide considerable optimism that gene therapy will provide straightforward, effective solutions to the clinical management of several common debilitating disorders that are otherwise difficult and expensive to treat.

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

2008-01-01

123

Phoenix rising: gene therapy makes a comeback.  

PubMed

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

Limberis, Maria P

2012-05-23

124

Prospects for Gene Therapy in Pediatric Neurosurgery  

Microsoft Academic Search

Gene therapy represents a powerful tool for both the study and potential treatment of pediatric neurological diseases. The majority of strategies for brain gene therapy have focused upon the use of modified viruses as vehicles for efficient delivery of genes into cells of the central nervous system. Retroviruses were originally the most popular vehicles for gene transfer outside the brain;

Michael G. Kaplitt; Borimir Darakchiev

1998-01-01

125

Regulatable Gene Therapy for Prostate Cancer.  

National Technical Information Service (NTIS)

Regulable gene therapy represents a new strategy to control and amplify efficacy of therapeutic gene. By the research efforts during this first period, two new regulators for inducible therapeutic gene expression have been generated, and an adenoviral con...

X. Ye B. W. O'Malley

2003-01-01

126

Gene delivery systems—gene therapy vectors for cystic fibrosis  

Microsoft Academic Search

Gene delivery systems (GDS) play a central role in the development of gene therapy strategies for Cystic Fibrosis (CF). Further, these systems are important tools in studies with cultured cells and in animal models. In this review, we describe the properties of several viral and synthetic gene delivery systems, and evaluate their possible application in gene therapy of CF. While

Daniel Klink; Dirk Schindelhauer; Andreas Laner; Torry Tucker; Zsuzsanna Bebok; Erik M. Schwiebert; A. Christopher Boyd; Bob J. Scholte

2004-01-01

127

Legal and ethical challenges in gene therapy  

Microsoft Academic Search

This paper addresses implications of applying the ethical principle of justice to gene therapy. Regarding somatic cell gene therapy as a treatment of last resort for life-threatening or seriously disabling disorders may be inconsistent with subjecting therapy to the preliminary scientific and ethical scrutiny given to research proposals. Emergency care may justify disregarding legal conditions of care, and be governed

Bernard M. Dickens

1996-01-01

128

In vivo long-term imaging and radioiodine therapy by sodium-iodide symporter gene expression using a lentiviral system containing ubiquitin C promoter.  

PubMed

To establish stable and long-term gene expression in vitro and in vivo, we developed a lentiviral vector system carrying sodium iodide symporter (hNIS) gene under UbC promoter, and transfected this into a colon cancer cell line. The in vitro and in vivo kinetics of radioiodine and [99mTc]-pertechnetate were then investigated, and the therapeutic effect of 1-131 was evaluated in this system. The hNIS gene was transferred into CT26 cells using lentivirus containing UbC promoter. In vitro iodide uptake and efflux were measured in CT26-hNIS cells at various time points. In addition, scintigraphic images were acquired at 30 min after injecting [99mTc]-pertechnetate i.p. into Balb/C mice for 27 days after CT26-hNIS induction. Biodistribution studies were performed at 10 and 30 min and at 1.5, 6 and 24 h after [99mTc]-pertechnetate injections, and the therapeutic effects of radioiodine were investigated by measuring tumor size using a caliper or by quantifying tumor radioactivity levels in scintigraphic images. The iodide uptakes of CT26-hNIS tumors were 10-fold greater than those of CT26 tumors. In addition, iodide uptake was completely blocked by 100 microM potassium perchlorate. The accumulation of [99mTc]-pertechnetate in hNIS expressing tumor cells was found to be positively related to tumor growth. In biodistribution studies, the %ID/g values of CT26-hNIS were 84.0 +/- 4.5 at 1.5 h and 40.8 +/- 3.9 at 24 h and these were approximately 60 times greater than those of CT26 at these time points. Tumor growth in mice treated with 131I was retarded until 46 days post-tumor challenge. The devised lentiviral vector system carrying hNIS controlled by UbC promoter was found to be suitable for the long-term monitoring and radionuclide therapy of cancer in living organism. PMID:17611400

Kim, Hyun Joo; Jeon, Yong Hyun; Kang, Joo Hyun; Lee, Yong Jin; Kim, Kwang Il; Chung, Hye Kyung; Jeong, Jae Min; Lee, Dong Soo; Lee, Myung Chul; Chung, June-Key

2007-07-01

129

Updates on current advances in gene therapy.  

PubMed

Gene therapy is the attempt to treat diseases by means of genetic manipulation. Numerous challenges remain to be overcome before it becomes available as a safe and effective treatment option. Retroviruses and adenoviruses are among the most commonly used viral vectors in trials. The retrovirus introduces the gene it carries into the target cell genome while the adenovirus introduces the gene into the target cell nucleus without incorporating it into the target cell genome. Other viral vectors such as adeno-associated viruses, pseudotyped viruses and herpes simplex viruses, are also gaining popularity. Proposed non-viral methods for gene transfer include physical methods and the employment of chemical vectors (lipoplexes, polyplexes and inorganic nanoparticles). Recent studies have investigated potential applications of gene therapy in correcting genetic diseases, treating malignant disorders and for treatment of other diseases. Trials on gene therapy for SCID and Leber's congenital amaurosis have achieved considerable success, but the widely publicized adverse reaction in X-linked SCID patient receiving gene therapy raised concerns for safety profile of gene therapy. For that, several methods of improving safety and efficacy of gene therapy have been proposed. At present, the three main gene therapy strategies for treatment of cancer are application to oncolytic viruses, suicide-gene therapy and gene-based immunotherapy. Gendicine, the first approved anticancer drugs based on the use of gene therapy principle, is based on the use of oncolytic viruses. More evidence for wider clinical applications of gene therapy are expected as more gene therapy studies progress from the preclinical phase to clinical trial. PMID:21942125

Tani, Jowy; Faustine; Sufian, Jomiany Tani

2011-03-01

130

Gene therapy for childhood immunological diseases  

Microsoft Academic Search

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

D B Kohn

2008-01-01

131

Advances in Duchenne muscular dystrophy gene therapy  

Microsoft Academic Search

Since the initial characterization of the genetic defect for Duchenne muscular dystrophy, much effort has been expended in attempts to develop a therapy for this devastating childhood disease. Gene therapy was the obvious answer but, initially, the dystrophin gene and its product seemed too large and complex for this approach. However, our increasing knowledge of the organization of the gene

Gert-Jan B. van Ommen; Judith C. T. van Deutekom

2003-01-01

132

What has happened to gene therapy?  

Microsoft Academic Search

Trials have demonstrated the feasibility of gene therapy in correcting the gene defect in monogenic disorders such as severe combined immune deficiency and cystic fibrosis, but there are still obstacles and ethical issues to overcome. Conclusion With appropriate research, better delivery strategies and adherence to good standard clinical research and practice, gene therapy research will lead to clinical implementation in

Norman C. Nevin

2000-01-01

133

Gene therapy of neoplastic liver diseases  

Microsoft Academic Search

Since advanced liver cancer lacks effective therapy in most cases, a considerable interest has been drawn towards gene therapy. Natural or chimerical genes can be transferred to the tumour itself, the non-tumoral liver, or even distant tissues using a variety of vectors administered by intratumoral or intravascular routes. The desired selectivity in gene expression can be achieved by increasing the

Bruno Sangro; Maite Herraiz; Jesus Prieto

2003-01-01

134

Microencapsulation — An alternative approach to gene therapy  

Microsoft Academic Search

‘Non-autologous somatic gene therapy’ is a novel approach to gene therapy which does not depend on genetic modification of the patient's own cells. Recombinant cell lines secreting a desired therapeutic gene product can be implanted into different patients requiring the same product replacement. Graft rejection is avoided by enclosing these cells in immuno-isolation devices whose permeability excludes the host's immune

Patricia L. Chang

1996-01-01

135

Targeting Herpetic Keratitis by Gene Therapy  

PubMed Central

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

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

2012-01-01

136

Gene Technology Based Therapies in the Brain  

Microsoft Academic Search

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

T. Wirth; S. Ylä-Herttuala

137

The future of gene therapy for stroke  

Microsoft Academic Search

New diagnostic and treatment strategies are being developed for stroke. Gene therapy has several potential advantages over\\u000a classical pharmacologic therapy. Direct administration of DNA into the brain offers the advantage of producing high concentrations\\u000a of therapeutic agents in a relatively localized environment. Gene transfer also provides longer duration of effect than traditional\\u000a drug therapy. Recent studies indicate that gene transfer

Carol A. Gunnett; Donald D. Heistad

2001-01-01

138

Phacilitate Cell and Gene Therapy Forum  

Center for Biologics Evaluation and Research (CBER)

... Presentations. Transcripts & Minutes (Biologics). -. Phacilitate Cell and Gene Therapy Forum. -. Presentation. FDA Regulation ... More results from www.fda.gov/biologicsbloodvaccines/newsevents/workshopsmeetingsconferences

139

Hemophilia clinical gene therapy: brief review.  

PubMed

Genetic correction of hemophilia A and B was long considered amenable to the available gene transfer technologies. This assumption has come to fruition with the recent results of a phase I/II trial for hemophilia B. Here we review the clinical application of gene therapy for the hemophilia's as a paradigm of the evolution of gene transfer science and technology. This review is not intended as comprehensive but rather to highlight current clinical developments of gene therapy for the hemophilias. PMID:23352600

Walsh, Christopher E; Batt, Katherine M

2013-01-23

140

FUNCTIONAL NANOPARTICLES FOR MOLECULAR IMAGING GUIDED GENE DELIVERY  

PubMed Central

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

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

2010-01-01

141

Magnetic Resonance Reporter Gene Imaging  

PubMed Central

Molecular imaging has undergone an explosive advancement in recent years, due to the tremendous research efforts made to understand and visualize biological processes. Molecular imaging by definition assesses cellular and molecular processes in living subjects, with the targets of following metabolic, genomic, and proteomic events. Furthermore, reporter gene imaging plays a central role in this field. Many different approaches have been used to visualize genetic events in living subjects, such as, optical, radionuclide, and magnetic resonance imaging. Compared with the other techniques, magnetic resonance (MR)-based reporter gene imaging has not occupied center stage, despite its superior three-dimensional depictions of anatomical details. In this article, the authors review the principles and applications of various types of MR reporter gene imaging technologies and discuss their advantages and disadvantages.

Lee, Sheen-Woo; Lee, Sang-Hoon; Biswal, Sandip

2012-01-01

142

Therapy of cancer by cytokines mediated by gene therapy approach  

Microsoft Academic Search

Gene therapy offers a new approach for treatment of cancer. Transfer of genes encoding immunostimulatory cytokines has been used with remarkable success to eliminate cancer in animals. However, clinical trials in patients with this strategy had limited efficacy. Therefore, improvement of gene transfer vector system is necessary. A hybrid viral vector, consisting of SFV replicon with either murine IL-12 or

Cheng Qian; Xin Yuan Liu; Jesus Prieto

2006-01-01

143

Gene Therapy Progress and Prospects: Nonviral vectors  

Microsoft Academic Search

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

T Niidome; L Huang

2002-01-01

144

Republished review: Gene therapy for ocular diseases  

PubMed Central

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

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

2011-01-01

145

Gene Therapy For Ischemic Heart Disease  

PubMed Central

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

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

2010-01-01

146

Regulatory issues in human gene therapy  

Microsoft Academic Search

Protection of human subjects is the ethical and legal responsibility of investigators conducting clinical trials. Public concerns regarding recombinant DNA technology led to additional levels of oversight which are unique to human gene therapy trials. The deaths of a normal volunteer and a gene therapy subject in the late 1990s led to an intensification of oversight with new initiatives that

Kenneth Cornetta

2003-01-01

147

Chromosome engineering: prospects for gene therapy  

Microsoft Academic Search

Recent advances in chromosome engineering and the potential for downstream applications in gene therapy were presented at the Artificial Chromosome Session of Genome Medicine: Gene Therapy for the Millennium in Rome, Italy in September 2001. This session concentrated primarily on the structure and function of human centromeres and the ongoing challenge of equipping human artificial chromosomes (HACs) with centromeres to

B R Grimes; P E Warburton; C J Farr

2002-01-01

148

Engineering targeted viral vectors for gene therapy  

Microsoft Academic Search

To achieve therapeutic success, transfer vehicles for gene therapy must be capable of transducing target cells while avoiding impact on non-target cells. Despite the high transduction efficiency of viral vectors, their tropism frequently does not match the therapeutic need. In the past, this lack of appropriate targeting allowed only partial exploitation of the great potential of gene therapy. Substantial progress

Reinhard Waehler; Stephen J. Russell; David T. Curiel

2007-01-01

149

Physical Principles of Microbubbles for Ultrasound Imaging and Therapy  

Microsoft Academic Search

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

Eleanor Stride

2009-01-01

150

Virus-mediated gene delivery for human gene therapy.  

PubMed

After over 20 years from the first application of gene transfer in humans, gene therapy is now a mature discipline, which has progressively overcome several of the hurdles that prevented clinical success in the early stages of application. So far, the vast majority of gene therapy clinical trials have exploited viral vectors as very efficient nucleic acid delivery vehicles both in vivo and ex vivo. Here we summarize the current status of viral gene transfer for clinical applications, with special emphasis on the molecular properties of the major classes of viral vectors and the information so far obtained from gene therapy clinical trials. PMID:22516095

Giacca, Mauro; Zacchigna, Serena

2012-04-10

151

Antiangiogenic gene therapy of cancer: recent developments  

PubMed Central

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

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

2004-01-01

152

Gene Therapy Techniques for Peripheral Arterial Disease  

Microsoft Academic Search

  Somatic gene therapy is the introduction of new\\u000a genetic material into selective somatic cells with resulting\\u000a therapeutic benefits. Vascular wall and, subsequently, cardiovascular\\u000a diseases have become an interesting target for gene therapy studies.\\u000a Arteries are an attractive target for gene therapy since vascular\\u000a interventions, both open surgical and endovascular, are well suited for\\u000a minimally invasive, easily monitored gene delivery. Promising

Hannu I. Manninen; Kimmo Mäkinen

2002-01-01

153

Cancer gene therapy targeting cellular apoptosis machinery.  

PubMed

The unraveling of cellular apoptosis machinery provides novel targets for cancer treatment, and gene therapy targeting this suicidal system has been corroborated to cause inflammation-free autonomous elimination of neoplastic cells. The apoptotic machinery can be targeted by introduction of a gene encoding an inducer, mediator or executioner of apoptotic cell death or by inhibition of anti-apoptotic gene expression. Strategies targeting cancer cells, which are achieved by selective gene delivery, specific gene expression or secretion of target proteins via genetic modification of autologous cells, dictate the outcome of apoptosis-based cancer gene therapy. Despite so far limited clinical success, gene therapy targeting the apoptotic machinery has great potential to benefit patients with threatening malignancies provided the availability of efficient and specific gene delivery and administration systems. PMID:22800735

Jia, Lin-Tao; Chen, Si-Yi; Yang, An-Gang

2012-07-15

154

Ethical and Social Problems of Gene Therapy  

Microsoft Academic Search

\\u000a Since the early days of gene therapy at the end of the 1980s, both the scientific community and the public have perceived\\u000a the ethical and social problems intrinsic to this discipline. On one hand, the technologies for gene transfer are still largely\\u000a experimental and thus pose important safety issues. On the other hand, the objective of several gene therapy applications

Mauro Giacca

155

Gene therapy for stroke: 2006 overview  

Microsoft Academic Search

Gene therapy is a promising approach for treatment of stroke and other cerebrovascular diseases, although it may take many\\u000a years to realize. Gene therapy could occur prior to a stroke (eg, to stabilize atherosclerotic plaques) and\\/or following a\\u000a stroke (eg, to prevent vasospasm after subarachnoid hemorrhage [SAH] or reduce injury to neurons by ischemic insult). We have\\u000a transferred the gene

Yi Chu; Jordan D. Miller; Donald D. Heistad

2007-01-01

156

Gene Therapy Strategies for Cardiac Electrical Dysfunction  

PubMed Central

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

Greener, Ian; Donahue, J. Kevin

2010-01-01

157

Cytokine-mediated gene therapy for cancer  

Microsoft Academic Search

Background: Significant interest has been generated in the gene therapy of cancer. One strategy involves tumor-directed cytokine gene\\u000a transfer and its effects on tumor immunobiology.\\u000a \\u000a \\u000a Methods: The authors review the current literature pertaining to cytokine gene therapy of cancer and provide a description of gene\\u000a transfer methods currently being evaluated.\\u000a \\u000a \\u000a \\u000a \\u000a Results: Several cytokine gene transfer models have been described involving

Alexander R. Miller; William H. McBride; Kelly Hunt; James S. Economou

1994-01-01

158

Advances in Preclinical Investigation of Prostate Cancer Gene Therapy  

PubMed Central

Treating recurrent prostate cancer poses a great challenge to clinicians. Research efforts in the last decade have shown that adenoviral vector-based gene therapy is a promising approach that could expand the arsenal against prostate cancer. This maturing field is at the stage of being able to translate many preclinical discoveries into clinical practices. At this juncture, it is important to highlight the promising strategies including prostate-targeted gene expression, the use of oncolytic vectors, therapy coupled to reporter gene imaging, and combined treatment modalities. In fact, the early stages of clinical investigation employing combined, multimodal gene therapy focused on loco-regional tumor eradication and showed promising results. Clinicians and scientists should seize the momentum of progress to push forward to improve the therapeutic outcome for the patients.

Figueiredo, Marxa L; Kao, Chinghai; Wu, Lily

2010-01-01

159

Gene Therapy for Chronic Granulomatous Disease  

Microsoft Academic Search

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

W. Scott Goebel; Mary C. Dinauer

2003-01-01

160

Radiolabelled RGD peptides for imaging and therapy.  

PubMed

Imaging of angiogenesis has become increasingly important with the rising use of targeted antiangiogenic therapies like bevacizumab (Avastin). Non-invasive assessment of angiogenic activity is in this respect interesting, e.g. for response assessment of such targeted antiangiogenic therapies. One promising approach of angiogenesis imaging is imaging of specific molecular markers of the angiogenic cascade like the integrin ?(v)?(3). For molecular imaging of integrin expression, the use of radiolabelled peptides is still the only approach that has been successfully translated into the clinic. In this review we will summarize the current data on imaging of ?(v)?(3) expression using radiolabelled RGD peptides with a focus on tracers already in clinical use. A perspective will be presented on the future clinical use of radiolabelled RGD peptides including an outlook on potential applications for radionuclide therapy. PMID:22388629

Gaertner, F C; Kessler, H; Wester, H-J; Schwaiger, M; Beer, A J

2012-02-01

161

Developing particle-mediated gene-transfer technology for research into gene therapy of cancer  

Microsoft Academic Search

Gene therapy aims to (1) introduce specific genes into a host to replace defective ones (replacement therapy); (2) suppress expression of certain undesirable genes (antisense therapy); or (3) provide additional biological activities (supplement therapy). Naked DNA and viral or non-viral vectors containing candidate genes for human gene therapy are being actively pursued by researchers in molecular medicine. New gene transfer

Dennis McCabe; W SUN

1996-01-01

162

Prospects for homologous recombination in human gene therapy  

Microsoft Academic Search

The ideal approach to gene therapy of hereditary diseases or gene correction therapy is considered. The advantages, disadvantages and limits of gene targeting by homologous recombination are discussed with regard to its possible application in gene correction therapy and in comparison with retroviral-mediated gene complementation therapy.

Manuel A. Vega

1991-01-01

163

Gene therapy for cystic fibrosis: an example for lung gene therapy  

Microsoft Academic Search

Gene therapy is currently being evaluated for a wide range of acute and chronic lung diseases. The requirement of gene transfer into the individual cell types of the complex lung structure will very much depend on the target disease. Over the last decade, the gene therapy community has recognized that there is not even one vector that is good for

U Griesenbach; D M Geddes; E W F W Alton

2004-01-01

164

Targeted Gene Therapies: Tools, Applications, Optimization  

PubMed Central

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

Humbert, Olivier; Davis, Luther; Maizels, Nancy

2012-01-01

165

Getting arthritis gene therapy into the clinic  

PubMed Central

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

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

2012-01-01

166

Convergence of gene and cell therapy.  

PubMed

Gene therapy and cell therapy have followed similar roller coaster paths of rising public expectations and disappointment over the past two decades. There is now reason to believe that momentum in the field has reached the point where the successes will be more frequent. The use of gene-modified cells has opened new avenues for engineering desired cell properties, for the use of cells as vehicles for gene delivery, and for tracking cells and controlling cell persistence after transplantation. Some notable recent clinical developments in cellular engineering by gene transfer offer lessons on how the field has emerged, and hint at additional future clinical applications. PMID:23210811

Bersenev, Alexey; Levine, Bruce L

2012-11-01

167

European attitudes to gene therapy and pharmacogenetics.  

PubMed

Views on pharmacogenetics and gene therapy systematically differ across European countries. But despite a complex regulatory regime there is a balance of support, albeit laced with considerable uncertainty. PMID:21745587

Hudson, John; Orviska, Marta

2011-07-02

168

Translational benefits of gene therapy to date  

Microsoft Academic Search

Gene therapy is now a reality with a number of early phase clinical trials having been completed and several currently in\\u000a progress. In spite of some early setbacks substantial progress has been made with treatment of several different diseases\\u000a using a variety of delivery vectors and transgenes. Indeed for some diseases gene therapy is now the treatment of choice,\\u000a in

M. Mary McMenamin

2011-01-01

169

Gene therapy: Sjögren’s syndrome  

Microsoft Academic Search

\\u000a Sjögrens syndrome (SS) is characterized by inflammation and dysfunction of the secretory organs. In the majority of patients\\u000a the salivary and lachrymal glands are predominantly affected, although systemic symptoms are common. The pathogenesis of the\\u000a disease is not well understood and to date there is no universally effective therapy available. The development of gene therapy\\u000a and in particular local gene

Nienke Roescher; Paul Peter Tak; John A. Chiorini

170

Gene Therapy for Leukemia and Lymphoma  

Microsoft Academic Search

\\u000a With the advancement of knowledge in immunology and virology, technological improvement in the transduction efficiency of\\u000a existing viral vectors, and the development of new viral vectors in the past two decades, gene therapy targeting diseases\\u000a at a molecular level has emerged as an exciting and promising strategy for treating hematolymphoid malignancies. Gene therapy\\u000a is aimed to correct disease processes by

Xiaopei Huang; Yiping Yang

171

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

172

Antiangiogenic gene therapy of cancer: recent developments  

Microsoft Academic Search

With the role of angiogenesis in tumor growth and progression firmly established, considerable effort has been directed to antiangiogenic therapy as a new modality to treat human cancers. Antiangiogenic agents have recently received much widespread attention but strategies for their optimal use are still being developed. Gene therapy represents an attractive alternative to recombinant protein administration for several reasons. This

Anita Tandle; Dan G Blazer III; Steven K Libutti

2004-01-01

173

Differentiation, differentiation\\/gene therapy and cancer  

Microsoft Academic Search

“Differentiation, Differentiation\\/Gene Therapy and Cancer” is intended to suggest that an understanding of the cell and molecular biology of cell differentiation should advance the development of new cancer therapies. This article, therefore, reviews four general topics and their relationship to each other: (1) the multistep process of cell differentiation in nontransformed and transformed cells, (2) the use of drugs that

Robert E. Scott

1997-01-01

174

Gene therapy strategies for urological dysfunction  

Microsoft Academic Search

Novel molecular techniques such as conventional and ex vivo gene therapy, and tissue engineering have only recently been introduced to the field of urology. The lower urinary tract is ideally suited for minimally invasive therapy, and also ex vivo approaches would limit the risk of systemic side effects. Muscle-derived stem cells have been used successfully to treat stress incontinence, and

Michael B Chancellor; Naoki Yoshimura; Ryan Pruchnic; Johnny Huard

2001-01-01

175

Gene therapy for primary immunodeficiencies: Part 1.  

PubMed

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

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

2012-09-12

176

Noninvasive Monitoring of Target Gene Expression by Imaging Reporter Gene Expression in Living Animals Using Improved Bicistronic Vectors  

Microsoft Academic Search

Indirect, noninvasive imaging of therapeutic gene expression based on levels of reporter gene expression is a powerful tool to devise improved therapeutic strategies in cancer gene therapy. The use of bicistronic vectors carrying internal ribosome entry sites (IRESs) allows the coexpression of multiple gene products from the same promoter but leads to considerable attenuation of the downstream gene. In this

Yanling Wang; Meera Iyer; Alexander J. Annala; Steve Chappell; Vincent Mauro; Sanjiv S. Gambhir

177

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

2011-11-17

178

Review Article Gene Therapy in Cardiac Arrhythmias  

Microsoft Academic Search

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

Johnson Francis

179

Optimizing Ribozymes for Somatic Cell Gene Therapy  

Microsoft Academic Search

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

Andrea D. Branch; Paul E. Klotman

1998-01-01

180

Gene therapy for cancer, the course ahead  

Microsoft Academic Search

Previous chapters have shown that there are a large number of therapeutic approaches under consideration for the gene therapy of cancer. Many of these have progressed into Phase I clinical trials. However, many of the early results are perceived to be disappointing in terms of low levels of gene transfer and systemic efficacy. In this concluding chapter, possible solutions to

Richard G. Vile

1996-01-01

181

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

182

Cancer gene therapy by IL-12 gene delivery using liposomal bubbles and tumoral ultrasound exposure.  

PubMed

Interleukin-12 (IL-12) gene therapy is expected to be effective against cancers because it primes the immune system for cancer cells. In this therapy, it is important to induce IL-12 gene expression in the tumor tissue. Sonoporation is an attractive technique for developing non-invasive and non-viral gene delivery systems, but simple sonoporation using only ultrasound is not an effective cancer gene therapy because of the low efficiency of gene delivery. We addressed this problem by combining ultrasound and novel ultrasound-sensitive liposomes (Bubble liposomes) which contain the ultrasound imaging gas perfluoropropane. Our previous work showed that this is an effective gene delivery system, and that Bubble liposome collapse (cavitation) is induced by ultrasound exposure. In this study, we assessed the utility of this system in cancer gene therapy using IL-12 corded plasmid DNA. The combination of Bubble liposomes and ultrasound dramatically suppressed tumor growth. This therapeutic effect was T-cell dependent, requiring mainly CD8(+) T lymphocytes in the effector phase, as confirmed by a mouse in vivo depletion assay. In addition, migration of CD8(+) T cells was observed in the mice, indicating that the combination of Bubble liposomes and ultrasound is a good non-viral vector system in IL-12 cancer gene therapy. PMID:19883708

Suzuki, Ryo; Namai, Eisuke; Oda, Yusuke; Nishiie, Norihito; Otake, Shota; Koshima, Risa; Hirata, Keiichi; Taira, Yuichiro; Utoguchi, Naoki; Negishi, Yoichi; Nakagawa, Shinsaku; Maruyama, Kazuo

2009-10-31

183

Transcriptional Targeting in Cancer Gene Therapy  

PubMed Central

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

2003-01-01

184

Gene replacement therapy for hereditary emphysema  

SciTech Connect

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

Skolnick, A.

1989-11-10

185

[Applications of gene therapy in medical genetics].  

PubMed

Over the past three decades, an increasing proportion of genetic research has consisted of molecular studies in medicine. It has resulted in a profound change in the understanding of the pathophysiology of diverse genetic diseases. Gene therapy is the use of nucleic acids as therapeutically useful molecules. Although many genetic discoveries have resulted in better diagnostic tests, the application of molecular technologies to the treatment of genetic diseases is natural and logical. Gene therapy is in a phase of its youth, nevertheless it holds very real promise. In the first 9 years, 396 clinical protocols have been approved worldwide and over 3,000 patients from 22 different countries have carried genetically engineered cells in their body. The conclusion from these trials are that gene therapy has the potential for treating a broad array of human diseases and the procedure appears to carry a very low risk of adverse reactions, but the efficiency of gene transfer and expression in human patients is low. No formal phase III studies to establish clinical efficacy have been completed. Gene therapy is potentially a powerful clinical approach, but it has been restricted by the limited knowledge of vectors and pathophysiology of the diseases to be treated. Better understanding of the disease processes, improvements in vector design, and a great attention to the pharmacological aspects should permit the development of more effective gene therapy. PMID:10835697

Turyk, S

2000-01-01

186

Pathways to gene therapy in rheumatoid arthritis.  

PubMed

Gene therapy offers novel possibilities for the treatment of rheumatoid arthritis. Present research is directed toward harnessing gene transfer technology to deliver genes whose products possess antiarthritic properties; the current emphasis is on transferring genes encoding secreted proteins. Genes may be delivered locally to individual diseased joints or systemically to extra-articular sites where the secreted gene products may enter the circulation. Local delivery is more laborious and unlikely to address systemic components of rheumatoid arthritis but should avoid side effects. Either ex vivo or in vivo strategies may be used to deliver the genes to the target tissues. Ex vivo techniques are more cumbersome but safer, because all genetic manipulations occur outside the body and cells may be extensively screened prior to implantation. A variety of vectors, including retrovirus, adenovirus, herpes simplex virus, and liposomes, as well as naked DNA, have been tested for their ability to deliver genes to joints. At the present stage of vector development, adenovirus seems best suited for in vivo gene delivery to synovium, but several authors have noted an inflammatory response, resulting in loss of gene expression. Ex vivo gene transfer using a retrovirus encoding human interleukin-1 receptor antagonist has succeeded in obtaining high intra-articular transgene expression with promising antiarthritic effects in animal models. Based on these data, the first human gene therapy trial for arthritis has been approved by the US Food and Drug Administration and will begin shortly. PMID:8796983

Evans, C H; Robbins, P D

1996-05-01

187

Lentiviruses in gene therapy clinical research  

Microsoft Academic Search

Gene therapy vectors derived from lentiviruses offer many potentially unique advantages over more conventional retroviral gene delivery systems. Principal amongst these is their ability to provide long-term and stable gene expression and to infect non-dividing cells, such as neurons. However, the use of lentiviral-based vectors in the clinic also raises specific safety and ethical issues. Concerns include the possible generation

J B Connolly

2002-01-01

188

Gene Therapy: Back to the Basics  

Microsoft Academic Search

The concept of gene therapy evolved from the knowledge gained in modern molecular genetics. Following the establishment of\\u000a the “central dogma” of gene expression—that DNA begets RNA begets protein, it was natural to imagine that a human genetic defect could be cured by delivering the correct gene to the affected cells.\\u000a Therefore, it is fair to state that modern molecular

Jim Hu

189

Imaging Cardiac Stem Cell Therapy: Translations to Human Clinical Studies  

PubMed Central

Stem cell therapy promises to open exciting new options in the treatment of cardiovascular diseases. Although feasible and clinically safe, the in vivo behavior and integration of stem cell transplants still remain largely unknown. Thus, the development of innovative non-invasive imaging techniques capable of effectively tracking such therapy in vivo is vital for a more in-depth investigation into future clinical applications. Such imaging modalities will not only generate further insight into the mechanisms behind stem cell-based therapy, but also address some major concerns associated with translational cardiovascular stem cell therapy. In the present review, we summarize the principles underlying three major stem cell tracking methods: (1) radioactive labeling for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging, (2) iron particle labeling for magnetic resonance imaging (MRI), and (3) reporter gene labeling for bioluminescence, fluorescence, MRI, SPECT, and PET imaging. We then discuss recent clinical studies that have utilized these modalities to gain biological insights into stem cell fate.

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

2013-01-01

190

Imaging cardiac stem cell therapy: translations to human clinical studies.  

PubMed

Stem cell therapy promises to open exciting new options in the treatment of cardiovascular diseases. Although feasible and clinically safe, the in vivo behavior and integration of stem cell transplants still remain largely unknown. Thus, the development of innovative non-invasive imaging techniques capable of effectively tracking such therapy in vivo is vital for a more in-depth investigation into future clinical applications. Such imaging modalities will not only generate further insight into the mechanisms behind stem cell-based therapy, but also address some major concerns associated with translational cardiovascular stem cell therapy. In the present review, we summarize the principles underlying three major stem cell tracking methods: (1) radioactive labeling for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging, (2) iron particle labeling for magnetic resonance imaging (MRI), and (3) reporter gene labeling for bioluminescence, fluorescence, MRI, SPECT, and PET imaging. We then discuss recent clinical studies that have utilized these modalities to gain biological insights into stem cell fate. PMID:21538182

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

2011-05-03

191

The case for intrauterine gene therapy.  

PubMed

Single-gene disorders can cause perinatal mortality or severe permanent morbidity. Intrauterine gene therapy seeks to correct the genetic defect in the early stages of pathogenesis through delivery of a vector system expressing the therapeutic transgene to the fetus. Advantages of intrauterine gene therapy include prevention of irreversible organ damage, potentially inducing central tolerance and wider bio-distribution, including the brain after delivery of vector. Already, proof-of-cure has been demonstrated in knockout animal models for several diseases. Long-term outcomes pertaining to efficacy and durability of transgene expression and safety are under investigation in clinically relevant non-human primate models. Bystander effects in the mother from transplacental vector trafficking require further assessment. In this chapter, we discuss the candidate diseases amenable to intrauterine gene therapy, current state-of-the-art evidence, and potential clinical applications. PMID:22819290

Mattar, Citra N; Waddington, Simon N; Biswas, Arijit; Davidoff, Andrew M; Choolani, Mahesh; Chan, Jerry K Y; Nathwani, Amit C

2012-07-20

192

In Vivo Imaging of Gene Expression: MR and Optical Technologies1  

Microsoft Academic Search

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

Christoph Bremer; Ralph Weissleder

193

WU Image-guided Therapy Center (ITC)  

Cancer.gov

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

194

Gene therapy for prostate cancer  

Microsoft Academic Search

Summary The advent of recombinant DNA technology has sparked the age of molecular medicine. The ability to deliberately recombine pieces of DNA and then transfer these specific genes into diseased cells has revolutionized medical research. In fact, the ability to modify these genes in the living person is now possible. Several innovative approaches are being developed to circumvent the limitations

Mitchell S Steiner; Jeffrey R Gingrich

1999-01-01

195

Gene therapy for arterial thrombosis  

Microsoft Academic Search

Conventional antithrombotic treatments with antiplatelet, anticoagulant, or fibrinolytic drugs are not uniformly successful and are associated with hemorrhagic side effects. Thus, new approaches to the prevention and treatment of arterial thrombosis are desirable. The gene transfer approach is particularly attractive because of its unique ability to express an antithrombotic gene at selected sites of the . vessel wall where thrombosis

Giuseppe Vassalli; David A. Dichek

196

442. LV Expressing MR Reporter Genes Allows In Vivo Monitoring of Stem Cell Gene Therapy  

Microsoft Academic Search

Somatic stem cells (SSC) have raised interest because of their therapeutic potential in both cell-based and gene therapy applications. Towards this goal, tracking the fate of either delivered cells or of genetically modified endogenous cells is of utmost importance. Diverse imaging approaches are available for cell tracking and among these MRI shows a greater resolution and allows direct anatomic correlation

Mario Amendola; Letterio S. Politi; Marcello Cadioli; Rossella Galli; Elena Binda; Andrea Falini; Sonia Levi; Giuseppe Scotti; Alessandra Biffi; Luigi Naldini

2006-01-01

197

Antisense oncogene and tumor suppressor gene therapy of cancer  

Microsoft Academic Search

Rapid advances in cancer gene therapy are driven by an explosive development of gene transfer technology and a strong demand for seeking alternatives to unsatisfactory conventional cancer therapies. Discovery of the genetic basis of cancer has indicated that cancer is a disease of genes. Among a variety of approaches to gene therapy of cancer, antisense oncogene and tumor suppressor gene

W.-W. Zhang

1996-01-01

198

Antiprotons for imaging and therapy  

NASA Astrophysics Data System (ADS)

Antiprotons are presently produced and stored at CERN and Fermilab at a rate of about 107 p/s. Efforts are underway to develop transportable storage devices, `bottles', which would store as much as 1012 antiprotons for months, or years and make the antiprotons available anywhere. A workshop held last year at the RAND Corporation assessed the science and technology of antimatter and the enabling tools. The biomedical potential of antiprotons was discussed and appears to be promising at current antimatter collection capabilities. Two applications have been studied using computer simulations: direct 3-D dE/dx imaging and the treatment of tumors with antiprotons. We discuss antiprotonic imaging and make comparisons with X-ray CT scans. The potential of antiprotons for monitoring precise delivery of radiation as well as treatment will also be discussed.

Kalogeropoulos, Theodore E.; Muratore, Robert

1989-04-01

199

Gene Therapy for Parkinson's Disease  

Microsoft Academic Search

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

Kari Andersen

2012-01-01

200

Gene therapy approaches for treating rheumatoid arthritis.  

PubMed

Current gene therapy approaches for treating rheumatoid arthritis have made use of gene transfer technology as an improved delivery system for emerging proteins and other biologicals whose activities may have therapeutic value. Preclinical research has focused on two primary directions, evaluation of methods of gene delivery and identification of gene products with antiarthritic potential. Although there are reports involving systemic gene delivery, the bulk of effort has focused on local, intraarticular administration using ex vivo and in vivo methods. Viral-based vectors, including adenovirus, adeno-associated virus and herpes simplex virus have the greatest efficiency of gene delivery after intraarticular injection and are capable of generating relevant levels of gene products in several animal models of disease. However, there are limitations to existing generations of these systems that currently preclude their clinical application. Those gene products found to be efficacious in animal models of rheumatoid arthritis include proteins that specifically block the activity of the primary inflammatory cytokines, and include interleukin-1 receptor antagonist and soluble receptors for tumor necrosis factor and interleukin-1. Delivery and expression of genes encoding certain cytokines such as interleukins -4, -10, and -13 and viral interleukin-10, that block synthesis of inflammatory mediators and downregulate aspects of cellular and humoral immune pathways have been found beneficial. Although significant progress has been made, leading to Phase I clinical trials, there remain several hurdles to the routine practice of gene therapy for treatment of rheumatoid arthritis. PMID:11039782

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

2000-10-01

201

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

202

Prostate cancer gene therapy clinical trials.  

PubMed

Despite recent advances in early detection and treatment, prostate cancer is still the second leading cause of cancer death in men in the United States, and approximately 27,000 men will die from it this year. Better treatments are needed for aggressive forms of localized disease and hormone-refractory metastatic disease. Recently, several gene therapy strategies have generated provocative results in early-stage clinical trials, raising the possibility that gene therapy may have the potential to affect both localized and metastatic disease. Much work lies ahead. Nevertheless, for the time being, these studies provide hope that gene therapy may someday earn a place in the management of prostate cancer. PMID:17406342

Freytag, Svend O; Stricker, Hans; Movsas, Benjamin; Kim, Jae Ho

2007-04-03

203

Functional chitosan nanocarriers for potential applications in gene therapy  

Microsoft Academic Search

Functional chitosan nanocarriers for suicide gene therapy have been developed. Folic acid conjugated chitosan (FA-chitosan) was used to synthesize zinc sulphide quantum dots (ZnS QDs), which was further converted to chitosan nanocarriers, where the integrated FA acts as targeting, and the embedded QDs as imaging functionalities, respectively. The synthesized nanocarriers were almost spherical with sizes of ~75nm and were nontoxic

Amit Jaiswal; Arun Chattopadhyay; Siddhartha Sankar Ghosh

204

Gene therapy for lung cancer.  

PubMed

The advances that have been made over the past decade in the field of gene transfer as well as in the fields of immunology and the molecular biology of tumorigenesis have brought to reality the possibility of using gene transfer as an anti-cancer treatment modality. The published results of clinical trials using this approach to date have been very limited, and a considerable amount of work still needs to be done in order to make this an effective treatment modality. However the developments that have occurred in the past several years indicate that this modality will become efficacious in the foreseeable future. PMID:10750725

Antonia, S J; Sotomayor, E

2000-03-01

205

Recent gene therapy advancements for neurological diseases.  

PubMed

The past few years have seen rapid advancements in vector-mediated gene transfer to the nervous system and modest successes in human gene therapy trials. The purpose of this review is to describe commonly-used viral gene transfer vectors and recent advancements towards producing meaningful gene-based treatments for central nervous system (CNS) disorders. Gene therapy trials for Canavan disease, Batten disease, adrenoleukodystrophy, and Parkinson's disease are discussed to illustrate the current state of clinical gene transfer to the CNS. Preclinical studies are under way for a number of diseases, primarily lysosomal storage disorders, using a newer generation of vectors and delivery strategies. Relevant studies in animal models are highlighted for Mucopolysaccharidosis IIIB and Krabbe disease to provide a prelude for what can be expected in the coming years for human gene transfer trials, using recent advancements in gene transfer technology. In conclusion, recent improvements in CNS gene transfer technology are expected to significantly increase the degree of disease rescue in future CNS-directed clinical trials, exceeding the modest clinical successes that have been observed so far. PMID:23449113

Nagabhushan Kalburgi, Sahana; Khan, Nadia N; Gray, Steven J

2013-02-01

206

Moving forward: cystic fibrosis gene therapy.  

PubMed

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

Griesenbach, Uta; Alton, Eric W F W

2013-08-04

207

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

208

Gene therapy could begin next month  

SciTech Connect

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

Marwick, C.

1990-09-05

209

Locus control regions and gene therapy  

Microsoft Academic Search

Gene therapy is a procedure in which exogenous genetic material is\\u000aintroduced into the cells of a patient in order to correct an genetic error or\\u000ato provide the cells of the patient with a new functional property.\\u000aCorrection can be achieved by gene targeting via homologous\\u000arecombination, at present achieved with very low efficiency (reviewed in\\u000aYanez and Porter

D. D. Drabek

1999-01-01

210

Current Status of Cardiovascular Gene Therapy  

Microsoft Academic Search

Gene transfer for the therapeutic modulation of cardiovascular diseases is an expanding area of gene therapy. During the last decade several approaches have been designed for the treatment of hyperlipidemias, post-angioplasty restenosis, hypertension, and heart failure, and for protection of vascular by-pass grafts and promotion of therapeutic angiogenesis. Adenoviruses (Ads) and adeno-associated viruses (AAVs) are currently the most efficient vectors

Tuomas T Rissanen; Seppo Ylä-Herttuala

2007-01-01

211

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

212

Immune barriers to successful gene therapy.  

PubMed

Immune responses to viral vectors pose one of the main obstacles to successful human gene replacement therapy, unless gene transfer vectors are applied to immune-privileged sites. Both innate and adaptive immunity work in concert against sustained gene transfer, but the functions of patients' regulatory T cells (Tregs) and tolerogenic dendritic cells (DCs) could potentially be harnessed to reduce these immune responses. Over the last few years, immunologists have gained an ever-increasing knowledge of immunoregulatory pathways, especially those that prevent or dampen adaptive immune responses. The gene therapy community is now in a position to use this expanding knowledge in basic immunology to overcome the so far nearly unsurpassable obstacles posed by the immune system to the long-term replacement of missing or faulty genes by the use of viral vectors. Here, we discuss the current challenges in overcoming immune barriers to gene therapy. In addition, we point out potential strategies that might allow circumvention of cellular or humoral immune responses against the vector or the transgene product. PMID:19101205

Wu, Te-Lang; Ertl, Hildegund C J

2008-12-26

213

ORTHOPAEDIC GENE THERAPY - LOST IN TRANSLATION?  

PubMed Central

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

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

2011-01-01

214

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

PubMed

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

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

2013-05-19

215

MR imaging--guided breast ablative therapy.  

PubMed

The integration of imaging and thermal therapy can provide a minimally invasive or even noninvasive alternative to breast surgery for small tumors. Ongoing trials seek to show safety and efficacy for laser, radiofrequency, microwave, cryoablation, and focused ultrasound surgery. To be successful, these therapies must achieve equivalent or even greater efficacy as surgical outcomes and must demonstrate total ablation of the dominant lesion with negative margins, while sparing normal tissue beyond the target tissue. Procedures have been validated by histopathology subsequent to resection. PMID:15337427

Kacher, Daniel F; Jolesz, Ferenc A

2004-09-01

216

Gene Therapy for Head and Neck Cancer  

Microsoft Academic Search

The mortality associated with head and neck cancer has remained largely unchanged for the past several decades despite advancements in surgery, radiotherapy and chemotherapy. Gene therapy is a novel treatment approach that may potentially advance the treatment of genetic diseases, which include malignancies such as head and neck cancer. Multiple vector systems have been developed that facilitate the introduction of

Waleed M. Abuzeid; Daqing Li; Bert W. O’Malley Jr

2011-01-01

217

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.

Olszko, Miles E.; Trobridge, Grant D.

2013-01-01

218

Human gene therapy and slippery slope arguments  

Microsoft Academic Search

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

T McGleenan

1995-01-01

219

Gene therapy targeting to tumor endothelium  

Microsoft Academic Search

Tumor-associated vasculature is a relatively accessible component of solid cancers that is essential for tumor survival and growth, providing a vulnerable target for cancer gene therapy administered by intravenous injection. Several features of tumor-associated vasculature are different from normal vasculature, including overexpression of receptors for angiogenic growth factors, markers of vasculogenesis, upregulation of coagulation cascades, aberrant expression of adhesion molecules

M Bazan-Peregrino; L W Seymour; A L Harris

2007-01-01

220

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.

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

221

Ribozyme-Mediated Breast Cancer Gene Therapy.  

National Technical Information Service (NTIS)

In our laboratory we have developed lentiviral vectors for use in anti-breast cancer gene therapy. Our specific goal for this project is to evaluate the feasibility of using lentiviral vectors that express anti-HER-2/neu antisense or ribozymes for the tre...

P. M. Pitha-Rowe

2000-01-01

222

Foamy Virus Vectors for HIV Gene Therapy.  

PubMed

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

2013-10-22

223

Gene Therapy and Targeted Toxins for Glioma  

Microsoft Academic Search

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.

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

2005-01-01

224

Ribozyme-Mediated Breast Cancer Gene Therapy.  

National Technical Information Service (NTIS)

In our laboratory we have developed lentiviral vectors for use in anti-breast cancer gene therapy. Our specific goal for this project was to evaluate the feasibility of using lentiviral vectors that express anti-HER-2/neu antisense or ribozymes for the tr...

P. M. Pitha-Rowe L. Dropulic B. Dropulic

2002-01-01

225

Musings on genome medicine: gene therapy  

PubMed Central

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

2009-01-01

226

Using Endothelial Progenitor Cells for Gene Therapy  

Microsoft Academic Search

eaders of Arteriosclerosis, Thrombosis, and Vascular Biology are already well aware of the high level of interest in gene therapy as a potential means of combating cardiac and vascular disease. During the last 10 years or so there have been clear demonstrations in a variety of animal models that it is possible to modulate the progress of atherosclerotic vascular disease,

Jeremy D. Pearson

2010-01-01

227

[Hopes for gene therapy for cardiac failure].  

PubMed

Although the drug therapies developed over the last decades have improved the prognosis of congestive cardiac failure, the condition remains a principal cause of mortality and hospital admission in the industrialised world. The hopes for gene therapy in cardiac failure are based on the possibility of acting on the underlying physiopathological mechanisms by the transfer of genetic material to the failing myocardium. A number of experimental studies targeting the regulation of the calcium ATPase of the sarcoplasmic reticulum, the pathways of beta-adrenergic desensibilisation and the pathways of apoptosis reported encouraging results. Although improvements in the efficacy and safety of techniques of vector construction and methods of delivery to the myocardium incite a certain optimism, the clinical benefits of gene therapy in cardiac failure have yet to be demonstrated. PMID:16479888

Prunier, F; Hajjar, R J

2006-01-01

228

Gene Therapy: Implications for Craniofacial Regeneration  

PubMed Central

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

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

2011-01-01

229

Gene therapy for hemoglobinopathies: progress and challenges  

PubMed Central

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

Dong, Alisa; Rivella, Stefano; Breda, Laura

2013-01-01

230

Cardiac Gene Therapy: Optimization of Gene Delivery Techniques In Vivo  

PubMed Central

Abstract Vector-mediated cardiac gene therapy holds tremendous promise as a translatable platform technology for treating many cardiovascular diseases. The ideal technique is one that is efficient and practical, allowing for global cardiac gene expression, while minimizing collateral expression in other organs. Here we survey the available in vivo vector-mediated cardiac gene delivery methods—including transcutaneous, intravascular, intramuscular, and cardiopulmonary bypass techniques—with consideration of the relative merits and deficiencies of each. Review of available techniques suggests that an optimal method for vector-mediated gene delivery to the large animal myocardium would ideally employ retrograde and/or anterograde transcoronary gene delivery,extended vector residence time in the coronary circulation, an increased myocardial transcapillary gradient using physical methods, increased endothelial permeability with pharmacological agents, minimal collateral gene expression by isolation of the cardiac circulation from the systemic, and have low immunogenicity.

Katz, Michael G.; Swain, JaBaris D.; White, Jennifer D.; Low, David; Stedman, Hansell

2010-01-01

231

Contributions of gene marking to cell and gene therapies.  

PubMed

The first human genetic modification studies used replication-incompetent integrating vector vectors to introduce marker genes into T lymphocytes and subsequently into hematopoietic stem cells. Such studies have provided numerous insights into the biology of hematopoiesis and immune reconstitution and contributed to clinical development of gene and cell therapies. Tracking of hematopoietic reconstitution and analysis of the origin of residual malignant disease after hematopoietic transplantation has been possible via gene marking. Introduction of selectable marker genes has enabled preselection of specific T-cell populations for tumor and viral immunotherapy and reduced the threat of graft-versus-host disease, improving the survival of patients after allogeneic marrow transplantation. Marking studies in humans, murine xenografts, and large animals have helped optimize conditions for gene transfer into CD34(+) hematopoietic progenitors, contributing to the achievement of gene transfer efficiencies sufficient for clinical benefit in several serious genetic diseases such as X-linked severe combined immunodeficiency and adrenoleukodystrophy. When adverse events linked to insertional mutagenesis arose in clinical gene therapy trials for inherited immunodeficiencies, additional animal studies using gene-marking vectors have greatly increased our understanding of genotoxicity. The knowledge gained from these studies is being translated into new vector designs and clinical protocols, which we hope will continue to improve the efficiency, effectiveness and safety of these promising therapeutic approaches. PMID:21261461

Barese, Cecilia N; Dunbar, Cynthia E

2011-05-05

232

Preclinical Studies for Gene Therapy of Duchenne Muscular Dystrophy  

Microsoft Academic Search

The muscular dystrophies are a diverse group of genetic disorders without an effective treatment. Because they are caused by mutations in various genes, the most direct way to treat them involves correcting the underlying gene defect (ie, gene therapy). Such a gene therapy approach involves delivering a therapeutic gene cassette to essentially all the muscles of the body in a

Guy L. Odom; Glen B. Banks; Brian R. Schultz; Paul Gregorevic; Jeffrey S. Chamberlain

2010-01-01

233

2011 Meeting Materials, Cellular, Tissue and Gene Therapies ...  

Center for Biologics Evaluation and Research (CBER)

... 2011 Meeting Materials, Cellular, Tissue and Gene Therapies Advisory Committee. -. ... Committee will discuss cellular and gene therapy products for ... More results from www.fda.gov/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics

234

Gene therapy approaches to regenerating bone  

PubMed Central

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

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

2013-01-01

235

Steps in a Translational Cancer Gene Therapy Trial  

Microsoft Academic Search

This chapter reviews the requisite steps in a translational cancer gene therapy trial. As with all clinical trials, translational\\u000a cancer gene therapy trials require clear concise objectives and endpoints. Several unique factors exist with gene therapy\\u000a trials that must be considered prior to trial development, including the type of vector desired, the delivery mechanism and\\u000a the different gene therapy strategies

Urs W. von Holzen; Stephen G. Swisher

236

Progress in gene targeting and gene therapy for retinitis pigmentosa  

SciTech Connect

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

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

1994-09-01

237

Treatment of peripheral sensorineural hearing loss: gene therapy  

Microsoft Academic Search

Noise, chemicals and genetic defects are all common causes of irreversible hearing loss, which at present have no cure. Gene therapy may soon be utilized in both the protection and the treatment of these exogenous and endogenous sources of hearing loss. Gene therapy technology is rapidly developing and the inner ear is a particularly feasible model for gene therapy. This

M Duan; F Venail; N Spencer; M Mezzina

2004-01-01

238

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

239

Germline alteration by gene therapy: assessing and reducing the risks  

Microsoft Academic Search

Developments in gene therapy are certain to lead to the treatment of an increasing variety of diseases, some of which will affect patients who might wish to have children following their gene therapy treatment. These circumstances raise the concern that germline integration of gene therapy vector DNA could occur. Although our current understanding of reproductive biology and of the biodistribution

Jon W. Gordon

1998-01-01

240

Transcriptionally regulated, prostate-targeted gene therapy for prostate cancer  

Microsoft Academic Search

Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths in American males today. Novel and effective treatment such as gene therapy is greatly desired. The early viral based gene therapy uses tissue-nonspecific promoters, which causes unintended toxicity to other normal tissues. In this chapter, we will review the transcriptionally regulated gene therapy strategy

Yi Lu

2009-01-01

241

Concurrent image and dose reconstruction for image guided radiation therapy  

NASA Astrophysics Data System (ADS)

The importance of knowing the patient actual position is essential for intensity modulated radiation therapy (IMRT). This procedure uses tightened margin and escalated tumor dose. In order to eliminate the uncertainty of the geometry in IMRT, daily imaging is prefered. The imaging dose, limited field of view and the imaging concurrency of the MVCT (mega-voltage computerized tomography) are investigated in this work. By applying partial volume imaging (PVI), imaging dose can be reduced for a region of interest (ROI) imaging. The imaging dose and the image quality are quantitatively balanced with inverse imaging dose planning. With PVI, 72% average imaging dose reduction was observed on a typical prostate patient case. The algebraic reconstruction technique (ART) based projection onto convex sets (POCS) shows higher robustness than filtered back projection when available imaging data is not complete and continuous. However, when the projection is continuous as in the actual delivery, a non-iterative wavelet based multiresolution local tomography (WMLT) is able to achieve 1% accuracy within the ROI. The reduction of imaging dose is dependent on the size of ROI. The improvement of concurrency is also discussed based on the combination of PVI and WMLT. Useful target images were acquired with treatment beams and the temporal resolution can be increased to 20 seconds in tomotherapy. The data truncation problem with the portal imager was also studied. Results show that the image quality is not adversely affected by truncation when WMLT is employed. When the online imaging is available, a perturbation dose calculation (PDC) that estimates the actual delivered dose is proposed. Corrected from the Fano's theorem, PDC counts the first order term in the density variation to calculate the internal and external anatomy change. Although change in the dose distribution that is caused by the internal organ motion is less than 1% for 6 MV beams, the external anatomy change has substantial impact on the dose distribution. A 5% change in the dose volume histogram is observed in phantom study. The influence of the external contour change on dose distribution can be calculated by PDC within 10 seconds.

Sheng, Ke

242

Approval expected for prelude to gene therapy  

SciTech Connect

Authorization to insert a gene into humans is imminent. It only remains for James B. Wyngaarden, MD, National Institutes of Health (NIH) director, and Frank E. Young, MD, Food and Drug Administration (FDA) commissioner, to give approval, which they are expected to do this month. The numerous reviews are an indication of the care with which this proposal was considered. Even though it does not constitute gene therapy per se, it must be regarded as a prelude to such experiments, Wyngaarden has noted. The work involves placing the gene for neomycin resistance into tumor-infiltrating lymphocytes as a marker for following the fate of these cells when they are injected into cancer patients. The use of the gene is not directly therapeutic, although the goal is an improved antitumor regimen.

Marwick, C.

1989-01-27

243

Targeted Gene Therapy of Cancer: Second Amendment toward Holistic Therapy  

PubMed Central

It seems solid tumors are developing smart organs with specialized cells creating specified bio-territory, the so called “tumor microenvironment (TME)”, in which there is reciprocal crosstalk among cancer cells, immune system cells and stromal cells. TME as an intricate milieu also consists of cancer stem cells (CSCs) that can resist against chemotherapies. In solid tumors, metabolism and vascularization appears to be aberrant and tumor interstitial fluid (TIF) functions as physiologic barrier. Thus, chemotherapy, immunotherapy and gene therapy often fail to provide cogent clinical outcomes. It looms that it is the time to accept the fact that initiation of cancer could be generation of another form of life that involves a cluster of thousands of genes, while we have failed to observe all aspects of it. Hence, the current treatment modalities need to be re-visited to cover all key aspects of disease using combination therapy based on the condition of patients. Perhaps personalized cluster of genes need to be simultaneously targeted.

Barar, Jaleh; Omidi, Yadollah

2013-01-01

244

Targeted cancer gene therapy: the flexibility of adenoviral gene therapy vectors  

Microsoft Academic Search

Recombinant adenoviral vectors are promising reagents for therapeutic interventions in humans, including gene therapy for biologically complex diseases like cancer and cardiovascular diseases. In this regard, the major advantage of adenoviral vectors is their superior in vivo gene transfer efficiency on a wide spectrum of both dividing and non-dividing cell types. However, this broad tropism at the same time represents

M. G. Rots; D. T. Curiel; W. R. Gerritsen; H. J. Haisma

2003-01-01

245

Gene therapy targeting to tumor endothelium.  

PubMed

Tumor-associated vasculature is a relatively accessible component of solid cancers that is essential for tumor survival and growth, providing a vulnerable target for cancer gene therapy administered by intravenous injection. Several features of tumor-associated vasculature are different from normal vasculature, including overexpression of receptors for angiogenic growth factors, markers of vasculogenesis, upregulation of coagulation cascades, aberrant expression of adhesion molecules and molecular consequences of hypoxia. Many of these differences provide candidate targets for tumor-selective 'transductional targeting' of genetically- or chemically modified vectors and upregulated gene expression can also enable 'transcriptional targeting', regulating tumor endothelia-selective expression of transgenes following nonspecific gene delivery. Tumor vasculature also represents an important site of therapeutic action by the secreted products of antiangiogenic gene therapies that are expressed in non-endothelial cells. In this review we assess the challenges faced and the vectors that may be suitable for gene delivery to exploit these targets. We also overview some of the strategies that have been developed to date and highlight the most promising areas of research. PMID:17096029

Bazan-Peregrino, M; Seymour, L W; Harris, A L

2006-11-10

246

Gene expression: Biomarker of antidepressant therapy?  

PubMed

Abstract While antidepressant therapy is an essential treatment of major depression, a substantial group of treated patients do not respond to therapy, or suffer from severe side effects. Moreover, the time of onset of the clinical improvement is often delayed. Antidepressants as currently available usually enhance serotonergic, noradrenergic and dopaminergic neurotransmission and may contribute to the inadequate remission rates for major depression. Therefore biomarkers enabling the identification of subgroups of patients and also finding unprecedented targets would provide the basis for personalized medication and thus improve treatment efficacy and reduce side effects. Several pharmacogenetic studies on antidepressant treatment response using single nucleotide polymorphism (SNPs) mapping have been performed but provided only modest findings. Therefore the analysis of gene expression to integrate genomic activity and environmental effects promises a new approach to cope with the complexity of factors influencing antidepressant treatment. Here gene expression studies focusing on candidate genes and genome-wide approaches using RNA derived from peripheral blood cells are reviewed. The most promising findings exist for hypothalamic-pituitary-adrenal (HPA) axis, inflammation and neuroplasticity related genes. However, straightforward translation into tailored treatment is still unlikely. Contradictory results limit the clinical use of the findings. Future studies are necessary, which could include functional analysis and consider gene-environment interactions. PMID:24151803

Menke, Andreas

2013-10-01

247

Cocaine hydrolase gene therapy for cocaine abuse  

PubMed Central

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

Brimijoin, Stephen; Gao, Yang

2013-01-01

248

Glucagon-Like Peptide-1 Gene Therapy  

PubMed Central

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

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

2011-01-01

249

Interactive Fly: Early Zygotic Gene Expression Images  

NSDL National Science Digital Library

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

PhD Thomas B Brody (NIH Laboratory of Neurochemistry)

2006-12-12

250

Gene Therapy to Prevent Organophosphate Intoxication  

Microsoft Academic Search

The specific hydrolytic activity of PON1 paraoxonase\\/arylesterase enzymes in liver and blood provides a natural barrier against the entry of organophosphate toxins into the central and peripheral nervous systems. Inherited differences in PON1 enzyme concentrations may determine levels of susceptibility to organophosphate injury in humans. To test whether boosting serum levels of PON1 enzymes by gene therapy might provide increased

J. Cowan; C. M. Sinton; A. W. Varley; F. H. Wians; R. W. Haley; R. S. Munford

2001-01-01

251

Creating a cardiac pacemaker by gene therapy  

Microsoft Academic Search

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

Traian M. Anghel; Steven M. Pogwizd

2007-01-01

252

Adrenergic Receptor Signaling Components in Gene Therapy  

Microsoft Academic Search

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

Andrea D. Eckhart; Walter J. Koch

253

Creating a Cardiac Pacemaker by Gene Therapy  

Microsoft Academic Search

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

Traian M. Anghel; Steven M. Pogwizd

254

Gene Therapy in Thalassemia and Hemoglobinopathies  

PubMed Central

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

Breda, Laura; Gambari, Roberto; Rivella, Stefano

2009-01-01

255

An overview of current delivery systems in cancer gene therapy  

Microsoft Academic Search

The main objective in gene therapy is the development of efficient, non-toxic gene carriers that can encapsulate and deliver foreign genetic materials into specific cell types such as cancerous cells. During the past two decades, enormous research in the area of gene delivery has been conducted worldwide, in particular for cancer gene therapy application. Viral vectors are biological systems derived

Anas El-Aneed

2004-01-01

256

Gene Transfer Therapy for Heritable Disease: Cell and Expression Targeting  

Microsoft Academic Search

Gene therapy is defined as the delivery of a functional gene for expression in somatic tissues with the intent to cure a disease. Different gene transfer strategies may be required to target different tissues. Adenosine deaminase (ADA) deficiency is a good gene therapy model for targeting a rare population of pluripotent hematopoietic stem cells capable of self-renewal. We present evidence

Kohnoske Mitani; Paula R. Clemens; Annemarie B. Moseley; C. Thomas Caskey

1993-01-01

257

Development of engineered cells for implantation in gene therapy  

Microsoft Academic Search

Human gene therapy is based on the technology of genetic engineering of cells, either through ex vivo or in vivo methods of gene transfer. Many autologous cell types have been successfully modified to deliver recombinant gene products. An alternate form of gene therapy based on genetic modification of non-autologous cells is described. Protection within immuno-isolating devices would allow implantation of

Patricia L. Chang; Kelly MacMillan Bowie

1998-01-01

258

Nanoparticle PEGylation for imaging and therapy  

PubMed Central

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

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

2011-01-01

259

Concepts in Gene Therapy for Cartilage Repair  

PubMed Central

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

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

2009-01-01

260

Photoacoustic imaging and temperature measurement for photothermal cancer therapy  

Microsoft Academic Search

Photothermal therapy is a noninvasive, targeted, laser- based technique for cancer treatment. During photothermal therapy, light energy is converted to heat by tumor-specific photoabsorbers. The corresponding temperature rise causes localized cancer destruc- tion. For effective treatment, however, the presence of photoabsorbers in the tumor must be ascertained before therapy and thermal imaging must be performed during therapy. This study investigates

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

2008-01-01

261

Synchronization of HIFU therapy system with an arbitrary ultrasound imager  

Microsoft Academic Search

Synchronization for image guided therapy using high intensity focused ultrasound (HIFU) and imaging ultrasound is achieved with a new technique that uses the focused transducer as a receiver that can detect the acoustic pulses created by the imaging probe. Without synchronization, interference from the high intensity source occludes the imager's display unpredictably, degrading the quality of the system. An imaging

Neil Owen; Michael Bailey; James Hossack; Lawrence Crum

2003-01-01

262

A New Acycloguanosine-Specific Supermutant of Herpes Simplex Virus Type 1 Thymidine Kinase Suitable for PET Imaging and Suicide Gene Therapy for Potential Use in Patients Treated with Pyrimidine-Based Cytotoxic Drugs  

PubMed Central

The herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene is widely used as a suicide gene in combination with ganciclovir (GCV) and as a nuclear imaging reporter gene with an appropriate reporter probe. Wild-type HSV1-tk recognizes a variety of pyrimidine and acycloguanosine nucleoside analogs, including clinically used antiviral drugs. PET of HSV1-tk reporter gene expression will be compromised in patients receiving nucleoside-based antiviral treatment. With the use of an acycloguanosine-specific mutant of the enzyme, PET of HSV1-tk reporter gene expression can be successfully performed with acycloguanosine-based radiotracers without interference from pyrimidine-based antiviral drugs. Methods: The levels of expression of wild-type HSV1-tk and HSV1-A167Ytk, HSV1-sr39tk, and HSV1-A167Ysr39tk mutants fused with green fluorescent protein (GFP) and transduced into U87 cells were normalized to the mean fluorescence of GFP measured by fluorescence-activated cell sorting. The levels of enzymatic activities of wild-type HSV1-tk and its mutants were compared by 2-h in vitro radiotracer uptake assays with 3H-2?-fluoro-2?-deoxy-1-?-d-arabinofuranosyl-5-ethyluracil (3H-FEAU), 3H-pencyclovir (3H-PCV), and 3H-GCV and by drug sensitivity assays. PET with 18F-FEAU and 18F-9-[4-fluoro-3-(hydroxymethyl)butyl]guanine (18F-FHBG) was performed in mice with established subcutaneous tumors, expressing wild-type HSV1-tk and its mutants, followed by tissue sampling. Results: FEAU accumulation was not detected in HSV1-A167Ysr39tk–expressing cells and xenografts. Lack of conversion of pyrimidine derivatives by the HSV1-A167Ysr39tk supermutant was also confirmed by a drug sensitivity assay, in which the 50% inhibitory concentrations for thymine 1-?-d-arabinofuranoside and bromovinyldeoxyuridine were found to be similar to those in nontransduced cells. In contrast, we found that HSV1-A167Ysr39tk could readily phosphorylate 3H-GCV at levels similar to those of wild-type HSV1-tk and HSV1-A167Ytk but showed enhanced activity with 3H-PCV in vitro and with 18F-FHBG in vivo. Conclusion: We developed a new reporter gene, HSV1-A167Ysr39tk, which exhibits specificity and high phosphorylation activity for acycloguanosine derivatives. The resulting supermutant can be used for PET with 18F-FHBG and suicidal gene therapy protocols with GCV in patients treated with pyrimidine-based cytotoxic drugs.

Likar, Yury; Dobrenkov, Konstantin; Olszewska, Malgorzata; Vider, Elena; Shenker, Larissa; Cai, Shangde; Pillarsetty, Nagavarakishore; Hricak, Hedvig; Ponomarev, Vladimir

2009-01-01

263

Gene therapy for primary adaptive immune deficiencies.  

PubMed

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

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

2011-06-01

264

Image-guided therapy: evolution and breakthrough.  

PubMed

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

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

265

Gene therapy for the regeneration of bone  

PubMed Central

Gene transfer technologies offer the prospect of enhancing bone regeneration by delivering osteogenic gene products locally to osseous defects. In most cases the gene product will be a protein, which will be synthesized endogenously within and around the lesion in a sustained fashion. It will have undergone authentic post-translational processing and lack the alterations that occur when recombinant proteins are synthesized in bioreactors and stored. Several different ex vivo and in vivo gene delivery strategies have been developed for this purpose, using viral and non-viral vectors. Proof of principle has been established in small animal models using a variety of different transgenes, including those encoding morphogens, growth factors, angiogenic factors, and transcription factors. A small number of studies demonstrate efficacy in large animal models. Developing these promising findings into clinical trials will be a long process, constrained by economic, regulatory and practical considerations. Nevertheless, the overall climate for gene therapy is improving, permitting optimism that applications in bone regeneration will eventually become available.

Evans, Christopher

2011-01-01

266

Gene therapy for carcinoma of the breast: Genetic toxins  

PubMed Central

Abstract Gene therapy was initially envisaged as a potential treatment for genetically inherited, monogenic disorders. The applications of gene therapy have now become wider, however, and include cardiovascular diseases, vaccination and cancers in which conventional therapies have failed. With regard to oncology, various gene therapy approaches have been developed. Among them, the use of genetic toxins to kill cancer cells selectively is emerging. Two different types of genetic toxins have been developed so far: the metabolic toxins and the dominant-negative class of toxins. This review describes these two different approaches, and discusses their potential applications in cancer gene therapy.

Vassaux, Georges; Lemoine, Nick R

2000-01-01

267

Image registration in adaptive radiation therapy  

NASA Astrophysics Data System (ADS)

This thesis focuses on the development, validation and application of image registration software in adaptive radiation therapy. The contents can be divided into three components: deformable image registration validation, rigid registration based daily patient positioning and deformable image registration for dose accumulation. In the first component, a protocol was developed for the validation of commercial deformable registration systems, applicable to a wide range of applications. The protocol was used to assess the capabilities of a commercial system and results suggest that deformable registration could potentially be optimized by treating applications separately instead of using one algorithm for all applications. The use of rigid registration for daily positioning of helical tomotherapy prostate patients was investigated in the second component. We quantified alignment discrepancies between daily treatment MVCT images and their corresponding planning CT images resulting from different automated rigid registration schemes. Based on alignments, errors in prostate positioning that would occur if patient repositioning was based on mutual information optimization of entire images or simply bony anatomy were evaluated, with the latter having a 20% decreased average prostate misplacement. The dosimetric implications of performing patient positioning based on either bony anatomy matching or prostate matching in treatment and planning images were also investigated. Prostate doses were fairly insensitive, however, doses to the radiation sensitive bladder and rectum varied with not only positioning strategy, but also the direction of daily prostate motion. The third component of this thesis involves the use of deformable registration and dose accumulation in the comparison of treatment and planning doses. Using correlation coefficient optimization and assuming B-spline parameterized deformations, we demonstrated that deformable registration can be improved by performing separate registrations over each clinically relevant region on interest. Our deformable model was incorporated into a dose accumulation framework and cumulative treatment doses were compared to those that were planned. In addition, cumulative doses that would have been delivered had patient positioning been based on bone matching and prostate matching were also evaluated. These studies may suggest that daily anatomical variations play a greater role in treatment dosimetry than does the selection of registration based image guidance procedure.

Rivest, Ryan Chad

268

Facile synthesis of carbon-11-labeled cholesterol-based cationic lipids as new potential PET probes for imaging of gene delivery in cancer  

Microsoft Academic Search

Gene therapy based on gene delivery is a promising strategy for the treatment of various human diseases such as cancer. Cationic lipids represent one of the important synthetic gene delivery systems. There is a great interest in imaging of gene therapy using the biomedical imaging technique positron emission tomography (PET). Carbon-11-labeled cholesterol-based cationic lipids were first designed and synthesized as

Mingzhang Gao; Min Wang; Kathy D. Miller; George W. Sledge; Gary D. Hutchins; Qi-Huang Zheng

2010-01-01

269

969. Development of Non-Invasive Imaging Strategies to Assess the Impact of Gene Therapy: Phenotypic Assessment of the Neurodegenerative CNS Disorder Late Infantile Neuronal Ceroid Lipofuscinosis Using Magnetic Resonance Spectroscopy  

Microsoft Academic Search

Several animal models of neurodegenerative lysosomal storage disease have been successfully treated by intracranial gene transfer. Among the most challenging aspects of moving these strategies to the clinic is to identify objective outcome parameters to measure the success of gene therapy. Classical phenotyping with measurement of neurological functional parameters and\\/or survival will take years of observation, it is not ethical

Neil R. Hackett; Dolan Sondhi; Stephen M. Kaminsky; Stefan Worgall; Lisa A. Arkin; Charleen A. Hollmann; Dikoma C. Shungu; Xiangling Mao; Jonathan P. Dyke; Linda Heier; Mark Souweidane; Michael Kaplitt; Ronald G. Crystal

2005-01-01

270

Gene therapy of primary T cell immunodeficiencies.  

PubMed

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

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

2013-04-10

271

Gene therapy: Into the home stretch  

SciTech Connect

Tumors cannot live without blood. Shut off the blood vessels that feed a tumor and the tumor will turn black and shrivel away. That simple idea lies behind the first attempt to cure a disease by gene therapy, expected to take place at the National Cancer Institute in the next few weeks. When it does, it will test a technique that worked like a charm in mice. When a potent natural killer called tumor necrosis factor, or TNF, is injected into the bloodstream of mice, it begins to shrink tumors within hours, sometimes even minutes. But so far, attempts to recreate that miracle in people with cancer have not fared as well. TNF has been given intravenously to more than 35 patients in experiments that were a failure. Researchers hope to deliver TNF in much larger doses directly to a tumor by packaging the gene for TNF inside special lymphocytes that have a natural affinity for cancer.

Culliton, B.J.

1990-08-31

272

Gene therapy: progress in childhood disease.  

PubMed

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

Ginn, Samantha L; Alexander, Ian E

2011-10-21

273

Corneal gene therapy: basic science and translational perspective.  

PubMed

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 the 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

2013-02-13

274

Cystic Fibrosis Gene Therapy: Key Questions and Prospects  

Microsoft Academic Search

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

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

2006-01-01

275

Gene Therapy for Cancer Treatment: Past, Present and Future  

Microsoft Academic Search

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

Deanna Cross; James K. Burmester

2006-01-01

276

Gene therapy in epilepsy: The focus on NPY  

Microsoft Academic Search

Gene therapy represents an innovative and promising alternative for the treatment of epileptic patients who are resistant to conventional antiepileptic drugs. Among the various approaches for the application of gene therapy in the treatment of CNS disorders, recombinant viral vectors have been most widely used so far. Several gene targets could be used to correct the compromized balance between inhibitory

Francesco Noe’; Jari Nissinen; Asla Pitkänen; Marco Gobbi; Gunther Sperk; Annamaria Vezzani

2007-01-01

277

Stem Cell-Based Gene Therapy.  

PubMed

Many researchers and clinicians wonder if gene therapy remains a way to treat genetic or acquired life-threatening diseases. For the last few years, many experimental, pre-clinical, and clinical data have been published showing that it is possible to transfer with relatively high efficiency new genetic information (transgene) in many cells or tissues including both hematopoietic progenitor cells and differentiated cells. Based on experimental works, addition of the normal gene to cells with deletions, mutations, or alterations of the corresponding endogenous one has been shown to reverse the phenotype and to restore (in some case) the functional defect. In spite of very attractive preliminary results, however, suggesting the feasibility and safety of this process, therapeutically efficient gene transfer and expression in targeted cells or tissues must be proven. In this review, we will focus primarily on the attempts to use gene transfer in hematopoietic stem cells as a model for more general genetic manipulations of stem cells. Hematopoietic stem cells are included in a subset of bone marrow, cord blood, or peripheral blood cells identified by the expression of the CD34 antigen on their membrane. PMID:10388049

Bagnis; Mannoni

1997-01-01

278

Gene therapy progress and prospects: gene therapy of lysosomal storage disorders  

Microsoft Academic Search

Despite disappointments with early clinical studies, there is continued interest in the development of gene therapy for the group of metabolic diseases referred to as lysosomal storage disorders (LSDs). The LSDs are monogenic and several small and large, representative animal models of the human diseases are available. Further, the successful reconstitution of only low and unregulated tissue levels of the

S H Cheng; A E Smith

2003-01-01

279

A Novel Cell-Based Therapy for Contusion Spinal Cord Injury Using GDNF-Delivering NIH3T3 Cells with Dual Reporter Genes Monitored by Molecular Imaging  

Microsoft Academic Search

This aim of our study was to evaluate a novel cell-based therapy for contusion spinal cord injury (SCI) using embryonic-derived NIH3T3 cells, which endogenously express glial cell line-derived neurotrophic factor (GDNF).Methods: Proliferation and differen- tiation of transplanted NIH3T3 cells and their anti-apoptotic ef- fects were examined after their engraftment into the spinal cords of Long-Evans rats subjected to acute SCI

Wen-Cheng Lo; Chung-Huei Hsu; Alexander T. H. Wu; Liang-Yo Yang; Wei-Hong Chen; Wen-Ta Chiu; Wen-Fu Lai; Chih-Hsiung Wu; Juri G. Gelovani; Win-Ping Deng

280

Photoacoustic imaging and temperature measurement for photothermal cancer therapy  

PubMed Central

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

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

2009-01-01

281

1018. Stem Cell Gene Therapy: Toward a Universal Platform Relying on Custom Endonuclease-Boosted Gene Targeting, Cybridization, Transient Regenerative\\/Epigenetic Gene Therapy and Synergistic Combinations  

Microsoft Academic Search

A platform has been devised in which autologous stem cells are the targets of both long-term and transient gene therapy culminating in synergistic combinations. Gene targeting and cybridization drive long-term gene therapy: they mediate gene repair\\/alteration or targeted transgene integration, and mitochondrial (mt)DNA transfer, respectively. Transient regenerative gene therapy drives regenerative medicine sensu stricto (aging\\/degenerative pathologies) and synergizes long-term gene

Roger Bertolotti

2006-01-01

282

Cancer gene therapy utilized ultrasound (US)-sensitive liposome as non-viral vector  

NASA Astrophysics Data System (ADS)

Sonoporation is an attractive technique to develop non-invasive and non-viral gene delivery system. However, simple sonoporation using only ultrasound (US) is not enough to establish effective cancer gene therapy because of low efficiency of gene delivery. Therefore, we improved this problem by the combination of US and novel US-sensitive liposome (Bubble liposome) which was a liposome containing US imaging gas (perfluoropropane). This was an effective gene delivery system with collapse (cavitation) that was induced by US exposure to Bubble liposome. In this study, we assessed the ability of this system in cancer gene therapy using IL-12 cording plasmid DNA. The combination of Bubble liposomes and ultrasound was dramatically suppressed tumor growth. Therefore, we concluded that the combination of Bubble liposomes and ultrasound would be a good non-viral vector system in IL-12 cancer gene therapy.

Suzuki, Ryo; Oda, Yusuke; Namai, Eisuke; Nishiie, Norihito; Hirata, Keiichi; Taira, Yuichiro; Utoguchi, Naoki; Negichi, Yoichi; Maruyama, Kazuo

2010-03-01

283

Radiolabeled antibodies for cancer imaging and therapy.  

PubMed

Radiolabeled antibodies were studied first for tumor detection by single-photon imaging, but FDG PET stopped these developments. In the meantime, radiolabeled antibodies were shown to be effective in the treatment of lymphoma. Radiolabeling techniques are well established and radiolabeled antibodies are a clinical and commercial reality that deserves further studies to advance their application in earlier phase of the diseases and to test combination and adjuvant therapies including radiolabeled antibodies in hematological diseases. In solid tumors, more resistant to radiations and less accessible to large molecules such as antibodies, clinical efficacy remains limited. However, radiolabeled antibodies used in minimal or small-size metastatic disease have shown promising clinical efficacy. In the adjuvant setting, ongoing clinical trials show impressive increase in survival in otherwise unmanageable tumors. New technologies are being developed over the years: recombinant antibodies and pretargeting approaches have shown potential in increasing the therapeutic index of radiolabeled antibodies. In several cases, clinical trials have confirmed preclinical studies. Finally, new radionuclides, such as lutetium-177, with better physical properties will further improve the safety of radioimmunotherapy. Alpha particle and Auger electron emitters offer the theoretical possibility to kill isolated tumor cells and microscopic clusters of tumor cells, opening the perspective of killing the last tumor cell, which is the ultimate challenge in cancer therapy. Preliminary preclinical and preliminary clinical results confirm the feasibility of this approach. PMID:22907380

Barbet, Jacques; Bardiès, Manuel; Bourgeois, Mickael; Chatal, Jean-François; Chérel, Michel; Davodeau, François; Faivre-Chauvet, Alain; Gestin, Jean-François; Kraeber-Bodéré, Françoise

2012-01-01

284

Chimeric RNA\\/DNA oligonucleotide-based gene therapy  

Microsoft Academic Search

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

Li-Wen Lai; Yeong-Hau H. Lien

2002-01-01

285

Progress and prospects: hurdles to cardiovascular gene therapy clinical trials  

Microsoft Academic Search

Several gene therapy approaches have been designed for the treatment of cardiovascular diseases. A positive finding is that the safety of cardiovascular gene therapy has been excellent even in long-term follow-up. However, several hurdles to this field are still present. A major disappointing feature of the trials is that while preclinical and uncontrolled phase-I gene therapy trials have been positive,

M Hedman; J Hartikainen; S Ylä-Herttuala

2011-01-01

286

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

Microsoft Academic Search

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

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

2011-01-01

287

Genes involved in the control of tumor progression and their possible use for gene therapy  

Microsoft Academic Search

Summary Three major groups of genes may be used for cancer gene therapy: (i ) oncogenes and tumor suppressor genes; ( ii ) genes involved in the control of tumor progression and metastasis; and ( iii ) genes encoding proteins protecting the organism from tumor cells. Each group contains numerous genes, and the discovery of new important genes is an

Georgii P. Georgiev; Sergei L. Kiselev; Evgenii M. Lukanidin

288

Gene therapy for disorders of the central nervous system.  

PubMed

Though heavily hyped in the early 1990s as the answer to many genetic diseases, gene therapy has largely failed to live up to its promises up to now. The scientific challenges of conveying replacement genes into the brain have prevented it from having an impact on more than a handful of conditions. In addition, gene therapy has been beset by safety problems. During the last 5 years, new vectors and techniques have started to resolve not only safety issues that once held gene therapy back but also markedly to improve efficient gene delivery within the brain and even the spinal cord. Brain gene therapy will not be suitable for every neurological disease, but considerable progress made in the field means we can now envisage that CNS gene therapy will be able to treat many neurological conditions that are not obviously treatable in any other way. PMID:23622409

Aubourg, Patrick

2013-01-01

289

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

PubMed

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

Okada, Takashi

2010-11-01

290

Dendritic cell-based cancer gene therapy.  

PubMed

In view of their potent antigen-presenting capacity and ability to induce effective immune responses, dendritic cells (DCs) have become an attractive target for therapeutic manipulation of the immune system. The application of tumor-associated antigen (TAA)-expressing DCs for cancer therapy has been the subject of intensive translational investigation. Previous clinical trials demonstrated tumor-specific immune responses without any significant toxicity. However, the clinical success has been modest, because only a limited number of immunized patients demonstrated cancer regression. Considerable progress has been made in the knowledge of DC biology, which opens new avenues for the development of optimized clinical protocols. One such promising approach that might carve its place in the future of DC-based therapy is the use of gene-modified DCs. DCs engineered to express TAAs allow multiepitope presentation by both major histocompatibility complex (MHC) class I and II molecules of full-length TAAs independent of the patient's HLA constitution, as opposed to peptide vaccination strategies. Besides transgene TAA expression, DCs can be genetically modified (1) to express a variety of immune-potentiating molecules (e.g., costimulatory molecules, cytokines, and chemokines) or (2) to downregulate negative modulators of DC functioning, all allowing an enhancement of their immunogenic potential. In the present review, gene delivery systems for DCs are discussed, as well as the various transgenes used for genetic modification of DCs. Moreover, a detailed review of the already published trials using gene-modified DCs is presented and future DC-based strategies targeting multiple layers of the complex cellular immune response are highlighted. PMID:19656053

Smits, Evelien L J M; Anguille, Sébastien; Cools, Nathalie; Berneman, Zwi N; Van Tendeloo, Viggo F I

2009-10-01

291

Successful Gene Therapy in Utero for Lethal Murine Hypophosphatasia  

PubMed Central

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

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

2011-01-01

292

Cancer gene therapy utilized ultrasound (US)-sensitive liposome as non-viral vector  

Microsoft Academic Search

Sonoporation is an attractive technique to develop non-invasive and non-viral gene delivery system. However, simple sonoporation using only ultrasound (US) is not enough to establish effective cancer gene therapy because of low efficiency of gene delivery. Therefore, we improved this problem by the combination of US and novel US-sensitive liposome (Bubble liposome) which was a liposome containing US imaging gas

Ryo Suzuki; Yusuke Oda; Eisuke Namai; Norihito Nishiie; Keiichi Hirata; Yuichiro Taira; Naoki Utoguchi; Yoichi Negichi; Kazuo Maruyama

2010-01-01

293

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

PubMed

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

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

2013-08-01

294

September 23, 2011: Cellular, Tissue and Gene Therapies ...  

Center for Biologics Evaluation and Research (CBER)

... September 23, 2011: Cellular, Tissue and Gene Therapies Advisory ... Staff: Humanitarian Device Exemption (HDE) Regulation: Questions and ... More results from www.fda.gov/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics

295

October 9, 2009: Cellular, Tissue and Gene Therapies ...  

Center for Biologics Evaluation and Research (CBER)

... October 9, 2009: Cellular, Tissue and Gene Therapies Advisory Committee Meeting Announcement Waivers for Conflicts of Interest. -. ... More results from www.fda.gov/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics

296

Charter of the Cellular, Tissue and Gene Therapies Advisory ...  

Center for Biologics Evaluation and Research (CBER)

... virology, molecular biology, cell biology, developmental biology, tumor biology, biochemistry, rDNA technology, nuclear medicine, gene therapy ... More results from www.fda.gov/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics

297

February 10, 2012: Cellular, Tissue and Gene Therapies ...  

Center for Biologics Evaluation and Research (CBER)

... February 10, 2012: Cellular, Tissue and Gene Therapies Advisory Committee Meeting: Waivers for Conflicts of Interest. ... More results from www.fda.gov/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics

298

Nuclear medicine imaging and therapy of neuroendocrine tumours  

Microsoft Academic Search

Radiolabelled peptides are used for specific targeting of receptors (over-)expressed by tumour cells. Dependent on the kind of labelling and the radionuclide used, these compounds may be utilised for imaging or for therapy. A concise overview is provided on basic principles of designing and developing radiopeptides for these applications. Furthermore, clinical application of these compounds for imaging and therapy is

Martin Gotthardt; I. Dijkgraaf; O. C. Boerman; W. J. G. Oyen

2006-01-01

299

November 29, 2012: Cellular, Tissue and Gene Therapies ...  

Center for Biologics Evaluation and Research (CBER)

... Graeme Price, Ph.D. Staff Fellow Gene Transfer and Immunogenicity Branch Division of Cellular and Gene Therapies Office of Cellular, Tissue and ... More results from www.fda.gov/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics

300

Cognitive–Behavioral Body Image Therapy for Body Dysmorphic Disorder  

Microsoft Academic Search

Body dysmorphic disorder (BDD) is a distressing body image disorder that involves excessive preoccupation 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 therapy

James C. Rosen; Jeff Reiter; Pam Orosan

1995-01-01

301

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.

Thumann, Gabriele

2012-01-01

302

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.

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

2009-01-01

303

Deciphering Development: Quantifying Gene Expression through Imaging  

NSDL National Science Digital Library

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

Melissa Lee Philips (;)

2007-08-01

304

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

305

206. Intracellular Signal-Responsive Gene Carrier for Cell-Specific Gene Therapy  

Microsoft Academic Search

Cell specificity is one of the most important but unsolved issues for gene therapy. In fact, some serious side effects in gene therapy have been reported due to nonspecific gene expression in untargeted cells. Thus, many targeting strategies have been investigated in various drug and gene delivery systems. These strategies often utilize the interaction between a molecular marker on the

Yoshiki Katayama; Jeong Hun Kang; Kota Kodama; Jun Oishi; Takuro Niidome

2005-01-01

306

Tumor therapy by gene regulation system responding to cellular signal  

Microsoft Academic Search

For safe and efficient gene therapy, the development of gene delivery systems to specifically target tumor cells is one of the most important issues regarding present gene delivery methodologies. Recently, we have developed a novel drug or gene delivery system responding to cellular signals (D-RECS) that can activate transgenes in response to hyperactivated cellular signals. Especially, a protein kinase C

Tetsuro Tomiyama; Riki Toita; Jeong-Hun Kang; Daisuke Asai; Shujiro Shiosaki; Takeshi Mori; Takuro Niidome; Yoshiki Katayama

2010-01-01

307

Prospects of chimeric RNA-DNA oligonucleotides in gene therapy  

Microsoft Academic Search

A strategy called targeted gene repair was developed to facilitate the process of gene therapy using a chimeric RNA-DNA oligonucleotide. Experiments demonstrated the feasibility of using the chimeric oligonucleotide to introduce point conversion in genes in vitro and in vivo. However, barriers exist in the low and\\/or inconstant frequency of gene repair. To overcome this difficulty, three main aspects should

Xue-Song Wu; De-Pei Liu; Chih-Chuan Liang

2001-01-01

308

Gene therapy for breast cancer. — review of clinical gene therapy trials for breast cancer and mdr1 gene therapy trial in cancer institute hospital  

Microsoft Academic Search

Gene therapy for advanced breast cancer is anticipated to be a useful therapeutic approach. Strategies in ongoing clinical\\u000a protocols can be divided into four groups: (1) suppression of oncogenes or transfer of tumor-suppressor genes; (2) enhancement\\u000a of immunological response; (3) transfer of suicide genes; (4) protection of bone marrow using drug resistance genes. We have\\u000a started a clinical study of

Shunji Takahashi; Yoshinori Ito; Kiyohiko Hatake; Yoshikazu Sugimoto

2006-01-01

309

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

PubMed Central

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

2003-01-01

310

Gene Therapy and Informed Consent Decision Making: Nursing Research Directions  

Microsoft Academic Search

Recent gene therapy clinical trials have demonstrated significant promise for treating a number of genetic neuromuscular disorders. Although nurses are experienced in educating patients and families about the benefits and risks of conventional therapeutics, there are significant challenges for guiding patients through the decision-making phase of gene therapy clinical trial participation. The first part of this review provides an overview

Rita W. Kaspar; Celia E. Wills; Brian K. Kaspar

2009-01-01

311

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

312

Prospects for Gene Therapy in the Fragile X Syndrome  

ERIC Educational Resources Information Center

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

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

2004-01-01

313

Averting abnormal inheritance: potential of gene therapy and preimplantation diagnosis  

Microsoft Academic Search

Serious inherited disease in children can be averted by preimplantation genetic diagnosis (PGD) and potentially by gene therapy in addition to prenatal diagnosis. PGD is now well established and provides a secure, if expensive and complex form of care. Gene therapy has been practised only in animals, although its success in alleviating various conditions in adults and newborns, together with

Adrian J. Thrasher; Robert G Edward

2004-01-01

314

Large animal models of hematopoietic stem cell gene therapy  

Microsoft Academic Search

Large animal models have been instrumental in advancing hematopoietic stem cell (HSC) gene therapy. Here we review the advantages of large animal models, their contributions to the field of HSC gene therapy and recent progress in this field. Several properties of human HSCs including their purification, their cell-cycle characteristics, their response to cytokines and the proliferative demands placed on them

G D Trobridge; H-P Kiem

2010-01-01

315

What nurse practitioners should know about gene therapy.  

PubMed

: The application of gene therapy to human patients has grown tremendously in recent years. Study findings have allowed scientists to develop newer genomic approaches to managing patients with chronic diseases. Nurse practitioners must be prepared to collaborate with the medical community to provide patients support and essential education about gene therapy treatment. PMID:24096549

Smith, Sarah E; Reeder, Sara J

2013-11-10

316

Angiogenic gene therapy in the treatment of ischemic cardiovascular diseases  

Microsoft Academic Search

Summary Encouraging preliminary data suggest that gene therapy may soon be an option for the treatment of patients with advanced coronary artery disease that is not amenable to conventional treatment. A critical consideration in developing cardiovascular gene transfer as a therapy is the ability to deliver the vector, viral or plasmid, to the desired tissue in a safe fashion. Attempts

Tamer A. Malik; Cesario Bianchi; Frank W. Sellke

2004-01-01

317

Recent advances in the pharmacology of neurological gene therapy  

Microsoft Academic Search

The choice of vectors, transgenes, regulatory elements, delivery approaches and the capacity to transduce the appropriate target cell type all influence the effectiveness of gene therapy for neurological diseases. Furthermore, even if many strategies are sound and effective in experimental animals, issues relating to side effects of gene therapy, longevity of therapeutic transgene expression and diffusion throughout the brain can

Pedro Ricardo Lowenstein; Maria Graciela Castro

2004-01-01

318

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

Microsoft Academic Search

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

Dajing Xia; Terence Moyana; Jim Xiang

2006-01-01

319

Advances in Cardiovascular Molecular Imaging for Tracking Stem Cell Therapy  

PubMed Central

The high mortality rate associated with cardiovascular disease is partially due to the lack of proliferative cells in the heart. Without adequate repair following myocardial infarction, progressive dilation can lead to heart failure. Stem cell therapies present one promising option for treating cardiovascular disease, though the specific mechanisms by which they benefit the heart remain unclear. Before stem cell therapies can be used safely in human populations, their biology must be investigated using innovative technologies such as multi-modality molecular imaging. The present review will discuss the basic principles, labeling techniques, clinical applications, and drawbacks associated with four major modalities: radionuclide imaging, magnetic resonance imaging, bioluminescence imaging, and fluorescence imaging.

Ransohoff, Katherine J.; Wu, Joseph C.

2010-01-01

320

Translational Applications of Molecular Imaging and Radionuclide Therapy  

SciTech Connect

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

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

2005-06-17

321

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.

2013-01-01

322

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

PubMed

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

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

2007-10-01

323

Development of Viral Vectors for Gene Therapy for Chronic Pain  

PubMed Central

Chronic pain is a major health concern that affects millions of people. There are no adequate long-term therapies for chronic pain sufferers, leading to significant cost for both society and the individual. The most commonly used therapy for chronic pain is the application of opioid analgesics and nonsteroidal anti-inflammatory drugs, but these drugs can lead to addiction and may cause side effects. Further studies of the mechanisms of chronic pain have opened the way for development of new treatment strategies, one of which is gene therapy. The key to gene therapy is selecting safe and highly efficient gene delivery systems that can deliver therapeutic genes to overexpress or suppress relevant targets in specific cell types. Here we review several promising viral vectors that could be applied in gene transfer for the treatment of chronic pain and further discuss the possible mechanisms of genes of interest that could be delivered with viral vectors for the treatment of chronic pain.

Huang, Yu; Liu, Xin; Dong, Lanlan; Liu, Zhongchun; He, Xiaohua; Liu, Wanhong

2011-01-01

324

Site-specific gene therapy for cardiovascular disease  

PubMed Central

Gene therapy holds considerable promise for the treatment of cardiovascular disease and may provide novel therapeutic solutions for both genetic disorders and acquired pathophysiologies such as arteriosclerosis, heart failure and arrhythmias. Recombinant DNA technology and the sequencing of the human genome have made a plethora of candidate therapeutic genes available for cardiovascular diseases. However, progress in the field of gene therapy for cardiovascular disease has been modest; one of the key reasons for this limited progress is the lack of gene delivery systems for localizing gene therapy to specific sites to optimize transgene expression and efficacy. This review summarizes progress made toward the site-specific delivery of cardiovascular gene therapy and highlights selected promising novel approaches.

Fishbein, Ilia; Chorny, Michael; Levy, Robert J

2010-01-01

325

Neural stem cell-based gene therapy for brain tumors.  

PubMed

Advances in gene-based medicine since 1990s have ushered in new therapeutic strategy of gene therapy for inborn error genetic diseases and cancer. Malignant brain tumors such as glioblastoma multiforme and medulloblastoma remain virtually untreatable and lethal. Currently available treatment for brain tumors including radical surgical resection followed by radiation and chemotherapy, have substantially improved the survival rate in patients suffering from these brain tumors; however, it remains incurable in large proportion of patients. Therefore, there is substantial need for effective, low-toxicity therapies for patients with malignant brain tumors, and gene therapy targeting brain tumors should fulfill this requirement. Gene therapy for brain tumors includes many therapeutic strategies and these strategies can be grouped in two major categories: molecular and immunologic. The widely used molecular gene therapy approach is suicide gene therapy based on the conversion of non-toxic prodrugs into active anticancer agents via introduction of enzymes and genetic immunotherapy involves the gene transfer of immune-stimulating cytokines including IL-4, IL-12 and TRAIL. For both molecular and immune gene therapy, neural stem cells (NSCs) can be used as delivery vehicle of therapeutic genes. NSCs possess an inherent tumor tropism that supports their use as a reliable delivery vehicle to target therapeutic gene products to primary brain tumors and metastatic cancers throughout the brain. Significance of the NSC-based gene therapy for brain tumor is that it is possible to exploit the tumor-tropic property of NSCs to mediate effective, tumor-selective therapy for primary and metastatic cancers in the brain and outside, for which no tolerated curative treatments are currently available. PMID:20521177

Kim, Seung U

2011-03-01

326

Gene Therapy Progress and Prospects: Bringing gene therapy into medical practice: the evolution of international ethics and the regulatory environment  

Microsoft Academic Search

The concept and application of ethical principles in the context of medical research is changing rapidly. This is especially true for fast moving fields such as gene therapy, a relatively new but rapidly maturing field offering opportunities to influence health at a fundamental level, which may become a cornerstone of medicine. By 2004, over 700 gene therapy clinical protocols had

J Spink; D Geddes

2004-01-01

327

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

328

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

329

Translational Approaches towards Cancer Gene Therapy: Hurdles and Hopes  

PubMed Central

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

Barar, Jaleh; Omidi, Yadollah

2012-01-01

330

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

331

Gene therapy progress and prospects: transcription regulatory systems  

Microsoft Academic Search

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

C Toniatti; H Bujard; R Cortese; G Ciliberto

2004-01-01

332

[31] Ligand-inducible transgene regulation for gene therapy  

Microsoft Academic Search

A synthetic ligand regulable system for gene transfer and expression has been developed in our laboratory based on mechanistic studies pf steriod hormone receptor and transcriptional regulation. This gene switch system possesses most of the important features that are required for application of the system in biological research and clinical gene therapy in the future. As the primary ligand tested

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

2002-01-01

333

Gene therapy for liver cancer: clinical experience and future prospects.  

PubMed

In contrast to the large quantity of preclinical evidence for efficacy, few gene therapy agents have reached clinical development for the treatment of primary and secondary liver cancer. This review discusses the published clinical trials that have explored the feasibility, safety and efficacy of gene therapy strategies for the treatment of liver cancer. Strategies include restoration of tumor suppressor genes, genetic prodrug-activating therapy, genetic immunotherapy and oncolytic virotherapy. In these trials, transgene expression of varying degrees has been detected. Globally, gene therapy has proven to be safe, with none of the agents tested reaching the MTD. Although none of the phase II trials provided significant response rates, objective remissions have occasionally been observed and proof-of-concept for the ability of gene therapy to produce significant tumor cell killing has been determined. Insufficient delivery following intravascular administration and short-lived transgene expression are likely to be the cause of this limited antitumor efficacy. The development of new gene therapy vectors with improved characteristics will increase the probability of success of gene therapy for the treatment of liver cancer. PMID:20886388

Sangro, Bruno; Prieto, Jesus

2010-10-01

334

[Development of the image registration program for portal and DRR images in radiation therapy].  

PubMed

In this article, the authors propose an image registration program of portal images and digitally reconstructed radiography (DRR) images used as simulation images for external beam radiation therapy planning. First, the center of the radiation field in a portal image taken using a computed radiograhy cassette is matched to the center of the portal image. Then scale points projected on a DRR image and the portal image are deleted, and the portal image with the radiation field is extracted. Registration of the DRR and portal images is performed using mutual information as the registration criterion. It was found that the absolute displacement misregistrations in two directions (x, y) were 1.2 +/- 0.7mm and 0.5 +/- 0.3 mm, respectively, and rotation disagreement about the z axis 0.3 +/- 0.3 degrees. It was concluded the proposed method was applicable to image registration of portal and DRR images in radiation therapy. PMID:23002480

Watanabe, Hiroyuki; Ito, Takeshi; Nakazeko, Kazuma; Tachibana, Atsuhi; Hashimoto, Takeyuki; Shinohara, Hiroyuki

2012-01-01

335

Nitric Oxide Gene Therapy for Prostate Cancer.  

National Technical Information Service (NTIS)

Traditional therapies for advanced prostate cancer are unable to cure a majority of patients. One approach to therapy is over-production of inducible nitric oxide synthase (iNOS) within the tumor by injecting replication defective adenovirus containing th...

E. Armour

1999-01-01

336

Nitric Oxide Gene Therapy for Prostate Cancer.  

National Technical Information Service (NTIS)

Traditional therapies for advanced prostate cancer are unable to cure a majority of patients. An approach to therapy we have tested involves production of nitric oxide (NO) by introduction of replication defective adenovirus containing the DNA sequences f...

E. P. Armour

2001-01-01

337

Monitoring Murine Skeletal Muscle Function for Muscle Gene Therapy  

PubMed Central

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

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

2011-01-01

338

Imaging and profiling of absorbed dose in neutron capture therapy  

Microsoft Academic Search

Imaging and profiling of the absorbed dose in tissue-equivalent gel phantoms exposed to thermal neutrons were performed at the TAPIRO fast reactor (ENEA, Italy). The proposed method, aimed at supporting the planning of neutron capture therapy, allows measurement of three-dimensional distributions of the therapy dose not only in tumors but also in normal tissue. This feature is very important, because

G. Gambarini; S. Agosteo; U. Danesi; F. Garbellini; B. Lietti; M. Mauri; G. Rosi

2001-01-01

339

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

340

Gene therapy to the kidney using viral vectors  

PubMed Central

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

Akbulut, Talha; Park, Frank

2009-01-01

341

Non-viral delivery of ribozymes for cancer gene therapy.  

PubMed

Ribozymes are RNA molecules with the capacity to effect sequence-specific cleavage of other transcripts. Since their initial discovery, there has been considerable interest in the development of ribozymes and other RNA therapeutics for gene therapy, particularly in the realm of cancer. However, as with other gene therapy applications, the delivery of ribozyme-based therapeutics to the target tissues of interest has represented a significant obstacle to the maturation of this technology to the clinical arena. This review will discuss the progress made so far in the use of non-viral methods for the systemic delivery of ribozymes for cancer gene therapy. PMID:15500403

Kashani-Sabet, Mohammed

2004-11-01

342

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.

Huang, Xiaopei; Yang, Yiping

2011-01-01

343

Overview of image-guided radiation therapy  

Microsoft Academic Search

Radiation therapy has gone through a series of revolutions in the last few decades and it is now possible to produce highly conformal radiation dose distribution by using techniques such as intensity-modulated radiation therapy (IMRT). The improved dose conformity and steep dose gradients have necessitated enhanced patient localization and beam targeting techniques for radiotherapy treatments. Components affecting the reproducibility of

Lei Xing; Brian Thorndyke; Eduard Schreibmann; Yong Yang; Tian-Fang Li; Gwe-Ya Kim; Gary Luxton; Albert Koong

2006-01-01

344

Gene Therapy from the perspective of Systems Biology  

PubMed Central

Gene therapy research has expanded from its original concept of replacing absent or defective DNA with functional DNA for transcription. Genetic material may be delivered via multiple vectors, including naked plasmid DNA, viruses and even cells with the goal of increasing gene expression; and the targeting of specific tissues or cell types is aimed at decreasing risks of systemic or side effects. As with the development of any drug, there is an amount of empiricism in the choice of gene target, route of administration, dosing and in particular the scaling-up from pre-clinical models to clinical trials. Systems Biology, whose arsenal includes high-throughput experimental and computational studies that account for the complexities of host-disease-therapy interactions, holds significant promise in aiding the development and optimization of gene therapies, including personalized therapies and the identification of biomarkers for success of these strategies. In this review we describe some of the obstacles and successes in gene therapy, using the specific example of growth factor gene delivery to promote angiogenesis and blood vessel remodeling in ischemic diseases; we also make references to anti-angiogenic gene therapy in cancer. The opportunities for Systems Biology and in silico modeling to improve on current outcomes are highlighted.

Mac Gabhann, Feilim; Annex, Brian H.

2010-01-01

345

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

PubMed Central

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

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

2011-01-01

346

Percutaneous gene therapy heals cranial defects.  

PubMed

Nonhealing bone defects are difficult to treat. As the bone morphogenic protein and transforming growth factor beta pathways have been implicated in bone healing, we hypothesized that percutaneous Smad7 silencing would enhance signaling through both pathways and improve bone formation. Critical sized parietal trephine defects were created and animals received percutaneous injection of: agarose alone or agarose containing nonsense or Smad7 small interfering RNA (siRNA). At 12 weeks, SMADs1, 2, 3, 5, 7 and 8 levels were assessed. Smad1/5/8 osteogenic target, Dlx5, and SMAD2/3 angiogenic target, plasminogen activator inhibitor-1 (Pai1), transcription levels were measured. Noncanonical signaling through TGF? activated kinase-1 (Tak1) and target, runt-related transcription factor 2 (Runx2) and collagen1?1 (Col1?1), transcription were also measured. Micro-computed tomography and Gomori trichome staining were used to assess healing. Percutaneous injection of Smad7 siRNA significantly knocked down Smad7 mRNA (86.3±2.5%) and protein levels (46.3±3.1%). The SMAD7 knockdown resulted in a significant increase in receptor-regulated SMADs (R-SMAD) (Smad 1/5/8 and Smad2/3) nuclear translocation. R-SMAD nuclear translocation increased Dlx5 and Pai1 transcription. Additionally, noncanonical signaling through Tak1 increased Runx2 and Col1?1 target transcription. Compared with animals treated with agarose alone (33.9±2.8% healing) and nonsense siRNA (31.5±11.8% healing), animals treated Smad7 siRNA had significantly great (91.2±3.8%) healing. Percutaneous Smad7 silencing increases signal transduction through canonical and noncanonical pathways resulting in significant bone formation. Minimally invasive gene therapies may prove effective in the treatment of nonhealing bone defects. PMID:23594990

Layliev, J; Sagebin, F; Weinstein, A; Marchac, A; Szpalski, C; Saadeh, P B; Warren, S M

2013-04-18

347

Prospects for gene therapy of insulin-dependent diabetes mellitus  

Microsoft Academic Search

Summary   The application of gene therapy to Type I (insulin-dependent) diabetes mellitus awaits improvements in gene transfer technologies\\u000a and the development of better tools for accurate diagnosis of pre-diabetic people. Identification of the most promising candidate\\u000a genes for gene transfer requires further elucidation of the molecular events involved in beta-cell autoimmune destruction,\\u000a islet ontogeny and differentiation, and beta-cell function. This

S. Efrat

1998-01-01

348

Targeted vectors for gene therapy of cancer and retroviral infections  

Microsoft Academic Search

Gene therapy has developed to a technology which rapidly moved from the laboratory bench to the bedside in the clinic. This\\u000a implies safe, efficient and targeted gene transfer systems for suitable application to the patient. Beside the development\\u000a of such gene transfer vectors of viral or nonviral origin, improvement of cell type specific and inducible gene expression\\u000a is pivotal for

Wolfgang Walther; Ulrike Stein

1996-01-01

349

Dear Gene Therapy IND or Master File Sponsor Letter  

Center for Biologics Evaluation and Research (CBER)

... for potential use in non-clinical or clinical studies of human gene therapy. ... Please confirm that all animal safety information has been submitted as ... More results from www.fda.gov/biologicsbloodvaccines/safetyavailability

350

Section 9150: Office of Cellular, Tissue and Gene Therapies  

Center for Biologics Evaluation and Research (CBER)

... SOPP 9150.1: Notification of National Institutes of Health (NIH) / Office of Biotechnology Activities (OBA) of Changes in a Gene Therapy Protocol ... More results from www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/proceduressopps

351

October 9, 2009: Cellular, Tissue and Gene Therapies ...  

Center for Biologics Evaluation and Research (CBER)

... Terrig Thomas, PhD, Agnes Lim, MD and Shiowjen Lee, PhD. -. -. ... Tissue and Gene Therapies Advisory Committee Meeting: Post Approval Safety ... More results from www.fda.gov/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics

352

Public Workshop on Cell and Gene Therapy Clinical Trials in ...  

Center for Biologics Evaluation and Research (CBER)

... Workshop on Cell and Gene therapy Clinical Trials in Pediatric Populations Video. -. -. ... D (PPT - 1.1MB) [ARCHIVED] Robert M. Nelson, MD, Ph.D. ... More results from www.fda.gov/biologicsbloodvaccines/newsevents/workshopsmeetingsconferences

353

December 14, 2010: Cellular, Tissue and Gene Therapies ...  

Center for Biologics Evaluation and Research (CBER)

... DVM, Ph.D. DACVS Assistant Professor Department of Large Animal Clinical Sciences ... Division of Cell and Gene Therapy University of ... More results from www.fda.gov/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics

354

Molecular Genetic and Gene Therapy Studies of the Musculoskeletal System.  

National Technical Information Service (NTIS)

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

S. Mohan

2009-01-01

355

Molecular Genetic and Gene Therapy Studies of the Musculoskeletal System.  

National Technical Information Service (NTIS)

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

S. Mohan

2007-01-01

356

Cardiovascular gene therapy: current status and therapeutic potential  

PubMed Central

Gene therapy is emerging as a potential treatment option in patients suffering from a wide spectrum of cardiovascular diseases including coronary artery disease, peripheral vascular disease, vein graft failure and in-stent restenosis. Thus far preclinical studies have shown promise for a wide variety of genes, in particular the delivery of genes encoding growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) to treat ischaemic vascular disease both peripherally and in coronary artery disease. VEGF as well as other genes such as TIMPs have been used to target the development of neointimal hyperplasia to successfully prevent vein graft failure and in-stent restenosis in animal models. Subsequent phase I trials to examine safety of these therapies have been successful with low levels of serious adverse effects, and albeit in the absence of a placebo group some suggestion of efficacy. Phase 2 studies, which have incorporated a placebo group, have not confirmed this early promise of efficacy. In the next generation of clinical gene therapy trials for cardiovascular disease, many parameters will need to be adjusted in the search for an effective therapy, including the identification of a suitable vector, appropriate gene or genes and an effective vector delivery system for a specific disease target. Here we review the current status of cardiovascular gene therapy and the potential for this approach to become a viable treatment option.

Gaffney, M M; Hynes, S O; Barry, F; O'Brien, T

2007-01-01

357

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

2011-10-28

358

Two Treatment Strategies Using a Therapy / Imaging Rotating Transducer  

NASA Astrophysics Data System (ADS)

Deep-seated tumours can be treated by high intensity interstitial ultrasound using a miniature transducer brought in contact with the target. A dual mode transducer was designed for performing simultaneous imaging. Two therapeutic strategies are envisaged in this study. First, the transducer can be rotated step-by-step and therapy interrupted periodically for acquiring echo lines. In a second approach, fast rotation of the transducer allows 2D-imaging and therapy is applied transiently over a small angular sector. Simultaneous imaging and therapy were performed in vitro with the designed transducer (2.5×7.5mm2, cylindrically focused at 10mm, 11MHz) following these two approaches. Up to 10mm deep lesions were obtained with the immobile transducer emitting an intensity of 17W/cm2 for 120s. M-mode images were constructed on-line during treatment. For the second strategy, the transducer rotated at a 7 rotations per second pace. Each turn, imaging was interrupted for ~0.02s in order to perform therapy at instantaneous intensity of 240W/cm2. Up to 8mm deep lesions were obtained for a 240s treatment. On M-mode images obtained with the motionless transducer, changes in the speckle pattern could be related to the formation of the lesion. But these images were difficult to read, lesion depths were not always assessable. Furthermore this imaging mode can not be used to position the probe. The second approach allowed real time guidance but the transducer was more solicited in therapy. The feasibility of interstitial ultrasound thermal therapy and imaging using a single miniature transducer was demonstrated and two therapeutic approaches were proposed.

Bouchoux, Guillaume; Lafon, Cyril; Berriet, Rémi; Fleury, Gérard; Cathignol, Dominique

2007-05-01

359

Cancer gene therapy by IL12 gene delivery using liposomal bubbles and tumoral ultrasound exposure  

Microsoft Academic Search

Interleukin-12 (IL-12) gene therapy is expected to be effective against cancers because it primes the immune system for cancer cells. In this therapy, it is important to induce IL-12 gene expression in the tumor tissue. Sonoporation is an attractive technique for developing non-invasive and non-viral gene delivery systems, but simple sonoporation using only ultrasound is not an effective cancer gene

Ryo Suzuki; Eisuke Namai; Yusuke Oda; Norihito Nishiie; Shota Otake; Risa Koshima; Keiichi Hirata; Yuichiro Taira; Naoki Utoguchi; Yoichi Negishi; Shinsaku Nakagawa; Kazuo Maruyama

2010-01-01

360

Image-Guided Photodynamic Cancer Therapy  

Microsoft Academic Search

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

Zheng-Rong Lu; Anagha Vaidya

361

Targeted Gene Delivery to Accomplish Gene Therapy for Breast Cancer.  

National Technical Information Service (NTIS)

We are developing methods to derive gene transfer vectors capable of accomplishing targeted gene delivery to metastatic breast cancer cells. In this regard, strategies have been explored to modify adenoviral vectors by altering their binding tropism. Gene...

D. T. Curiel

1998-01-01

362

Gene therapy for adenosine-deaminase-deficient severe combined immunodeficiency  

Microsoft Academic Search

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

Alessandro Aiuti

2004-01-01

363

Progress and prospects: gene therapy for inherited immunodeficiencies  

Microsoft Academic Search

Haematopoietic stem cell transplantation (HSCT) is now widely used to treat primary immunodeficiencies (PID). For patients with specific disorders (severe combined immunodeficiency (SCID)-X1, adenosine deaminase deficiency (ADA)–SCID, X-chronic granulomatous disease (CGD) and Wiskott–Aldrich Syndrome (WAS)) who lack a suitable human leukocyte antigen (HLA)-matched donor, gene therapy has offered an important alternative treatment option. The success of gene therapy can be

W Qasim; H B Gaspar; A J Thrasher

2009-01-01

364

The Potential for Gene Therapy of Neurodegenerative Disorders  

Microsoft Academic Search

Gene therapy has been in the medical spotlight for over a decade now and its enormous potential offers hope to many sufferers\\u000a of diseases involving a genetic component. Although progress has been made, clinical gene therapy is still quite a remote\\u000a possibility especially in the relatively new field of targeting the central nervous system (CNS). The treatment of CNS disorders

Alice Andreu; Andrew D. Miller

365

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

366

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

Microsoft Academic Search

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

IA McNeish; SJ Bell; NR Lemoine

2004-01-01

367

Progress and prospects: gene therapy for performance and appearance enhancement  

Microsoft Academic Search

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

M Kiuru; R G Crystal

2008-01-01

368

Cytokine Immuno-Gene Therapy for Treatment of Brain Tumors  

Microsoft Academic Search

The prognosis for patients with an intracerebral (i.c.) neoplasm is poor. Conventional treatments such as surgery, radiation therapy and chemotherapy have done little to affect long-term survival, and new methods of treatment are urgently needed. In this report approaches involving cytokine gene therapy in treatment of malignant brain tumors are reviewed and contrasted to a strategy developed in this laboratory

Terry Lichtor; Roberta P. Glick

2003-01-01

369

MR imaging of therapy-induced changes of bone marrow  

Microsoft Academic Search

MR imaging of bone marrow infiltration by hematologic malignancies provides non-invasive assays of bone marrow cellularity\\u000a and vascularity to supplement the information provided by bone marrow biopsies. This article will review the MR imaging findings\\u000a of bone marrow infiltration by hematologic malignancies with special focus on treatment effects. MR imaging findings of the\\u000a bone marrow after radiation therapy and chemotherapy

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

2007-01-01

370

Optical imaging-guided cancer therapy with fluorescent nanoparticles  

PubMed Central

The diagnosis and treatment of cancer have been greatly improved with the recent developments in nanotechnology. One of the promising nanoscale tools for cancer diagnosis is fluorescent nanoparticles (NPs), such as organic dye-doped NPs, quantum dots and upconversion NPs that enable highly sensitive optical imaging of cancer at cellular and animal level. Furthermore, the emerging development of novel multi-functional NPs, which can be conjugated with several functional molecules simultaneously including targeting moieties, therapeutic agents and imaging probes, provides new potentials for clinical therapies and diagnostics and undoubtedly will play a critical role in cancer therapy. In this article, we review the types and characteristics of fluorescent NPs, in vitro and in vivo imaging of cancer using fluorescent NPs and multi-functional NPs for imaging-guided cancer therapy.

Jiang, Shan; Gnanasammandhan, Muthu Kumara; Zhang, Yong

2010-01-01

371

RNA repair: a novel approach to gene therapy.  

PubMed

Treatment of genetic disorders by gene therapy has conventionally been attempted through the transfer of a wild type version of a gene to the cells of a patient harboring defective copies of a disease associated gene. Despite significant advances using this paradigm, several technical hurdles must still be overcome before this 'gene replacement' approach will become useful in the treatment of a variety of genetic maladies. Such limitations have led a number of researchers to begin to investigate alternative strategies to genetic therapy. Repair of mutant genetic instructions represents a fundamentally different approach to genetic therapy that may have significant advantages over gene replacement. Herein, we will discuss recent advances using repair of mutant RNAs as a novel means to correct genetic deficiencies. PMID:11072109

Watanabe, T; Sullenger, B A

2000-11-15

372

Hypoxia as a target for tissue specific gene therapy.  

PubMed

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

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

2013-06-03

373

Inorganic nanoparticles for cancer imaging and therapy  

Microsoft Academic Search

Inorganic nanoparticles have received increased attention in the recent past as potential diagnostic and therapeutic systems in the field of oncology. Inorganic nanoparticles have demonstrated successes in imaging and treatment of tumors both ex vivo and in vivo, with some promise towards clinical trials. This review primarily discusses progress in applications of inorganic nanoparticles for cancer imaging and treatment, with

Huang-Chiao Huang; Sutapa Barua; Gaurav Sharma; Sandwip K. Dey; Kaushal Rege

2011-01-01

374

Inorganic nanoparticles for cancer imaging and therapy  

Microsoft Academic Search

Inorganic nanoparticles have received increased attention in the recent past as potential diagnostic and therapeutic systems in the field of oncology. Inorganic nanoparticles have demonstrated successes in imaging and treatment of tumors both ex vivo and in vivo, with some promise towards clinical trials. This review primarily discusses progress in applications of inorganic nanoparticles for cancer imaging and treatment, with

Huang-Chiao Huang; Sutapa Barua; Gaurav Sharma; Sandwip K. Dey; Kaushal Rege

375

Potential cancer gene therapy by baculoviral transduction.  

PubMed

Many different types of therapeutic genes, ranging from suicide genes, tumor suppressor genes, to genes encoding tumor-specific antigens, have been successfully delivered by insect baculoviral vectors to treat tumours in animal models. These encouraging results observed to date underscore the potential for using the non-human baculovirus to combat human cancer. The present review outlines the advances in this area and highlights the challenges behind translating the findings from research with baculoviral vectors into clinical practice. PMID:20402653

Wang, Shu; Balasundaram, Ghayathri

2010-06-01

376

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

377

Peripheral blood stem cell and gene therapy  

Microsoft Academic Search

Mobilized peripheral blood stem cells characterized by sustained re-populating ability could be optimal target cells for ex-vivo gene transfer. In spite of very attractive preliminary results obtained in the murine studies, therapeutically efficient gene transfer and expression in human targeted cells must be proven. In recent years, effort has been spent on the identification of factors limiting gene transfer efficiency

Marina Cavazzana-Calvo; Claude Bagnis; Patrice Mannoni; Alain Fischer

1999-01-01

378

Modalities and future prospects of gene therapy in heart transplantation.  

PubMed

Heart transplantation is the treatment of choice for many patients with end-stage heart failure. Its success, however, is limited by organ shortage, side effects of immunosuppressive drugs, and chronic rejection. Gene therapy is conceptually appealing for applications in transplantation, as the donor organ is genetically manipulated ex vivo before transplantation. Localised expression of immunomodulatory genes aims to create a state of immune privilege within the graft, which could eliminate the need for systemic immunosuppression. In this review, recent advances in the development of gene therapy in heart transplantation are discussed. Studies in animal models have demonstrated that genetic modification of the donor heart with immunomodulatory genes attenuates ischaemia-reperfusion injury and rejection. Alternatively, bone marrow-derived cells genetically engineered with donor-type major histocompatibility complex (MHC) class I or II promote donor-specific hyporesponsiveness. Genetic engineering of naïve T cells or dendritic cells may induce regulatory T cells and regulatory dendritic cells. Despite encouraging results in animal models, however, clinical gene therapy trials in heart transplantation have not yet been started. The best vector and gene to be delivered remain to be identified. Pre-clinical studies in non-human primates are needed. Nonetheless, the potential of gene therapy as an adjunct therapy in transplantation is essentially intact. PMID:19318274

Vassalli, Giuseppe; Roehrich, Marc-Estienne; Vogt, Pierre; Pedrazzini, Giovanni B; Siclari, Francesco; Moccetti, Tiziano; von Segesser, Ludwig K

2009-03-21

379

Synchronization of HIFU therapy system with an arbitrary ultrasound imager  

NASA Astrophysics Data System (ADS)

Synchronization for image guided therapy using high intensity focused ultrasound (HIFU) and imaging ultrasound is achieved with a new technique that uses the focused transducer as a receiver that can detect the acoustic pulses created by the imaging probe. Without synchronization, interference from the high intensity source occludes the imager's display unpredictably, degrading the quality of the system. An imaging probe (Sonosite 180) is registered with a HIFU transducer (d=33 mm, roc=55 mm, f=3.5 MHz) such that the scan line bisects the single element focus. When acoustically coupled through a scattering medium, imaging pulses are passively detected with the HIFU transducer and electronically conditioned into a TTL level trigger. A LabVIEW program uses the trigger to create a pulse width modulated signal that controls the timing of HIFU excitation during treatment. Detection takes less than 1% of the time between displayed images when the imager is running at 20 frames per second. HIFU excitations are programmed to occur such that the single element focus is free of interference when viewed with the imager during treatment. With no electrical connections for this new, simple technique, an arbitrary imager can be selected for synchronized image guided therapy. [Work supported by NSBRI.

Owen, Neil; Bailey, Michael; Hossack, James; Crum, Lawrence

2003-10-01

380

A triple suicide gene strategy that improves therapeutic effects and incorporates multimodality molecular imaging for monitoring gene functions.  

PubMed

Gene-directed enzyme prodrug therapy (GDEPT), or suicide gene therapy, has shown promise in clinical trials. In this preclinical study using stable cell lines and xenograft tumor models, we show that a triple-suicide-gene GDEPT approach produce enhanced therapeutic efficacy over previous methods. Importantly, all the three genes (thymidine kinase, cytosine deaminase and uracil phosphoribosyltransferase) function simultaneously as effectors for GDEPT and markers for multimodality molecular imaging (MMI), using positron emission tomography, magnetic resonance spectroscopy and optical (fluorescent and bioluminescent) techniques. It was demonstrated that MMI can evaluate the distribution and function/activity of the triple suicide gene. The concomitant expression of these genes significantly enhances prodrug cytotoxicity and radiosensitivity in vitro and in vivo. PMID:23722591

Xing, L; Sun, X; Deng, X; Kotedia, K; Zanzonico, P B; Ackerstaff, E; Koutcher, J A; Ling, C C; Li, G C

2013-05-31

381

[Injection therapy of the spine without imaging].  

PubMed

Nerve root blocks and epidural perineural injections are main part in the conservative treatment of degenerative spine diseases. These injections should be done without imaging because degenerative spine diseases - discogenic oder spinal stenotic - tend to recurrence and danger arises from too many imaging with cumulative ionizing radiation over the years, especially in younger people. After certain training it is possible to perform spinal injections without imaging only considering topographic anatomical landmarks like in any other local anesthesia for surgical reasons. Repetitive periradicular injections desensitize the nerve root by local anesthetics and reduce its inflammatory swelling by steroids. The decompensated symptomatic deformity turns back into an asymptomatic compensated status. PMID:17171383

Theodoridis, T

2007-01-01

382

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

ERIC Educational Resources Information Center

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

Hinz, Lisa D.

2013-01-01

383

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

384

Perspectives in vector development for systemic cancer gene therapy  

Microsoft Academic Search

Summary Gene therapy is perceived as a revolutionary technology with the promise to cure almost any disease, provided that we understand its genetic basis. However, enthusiasm has rapidly abated as multiple clinical trials have failed to show efficacy. The limiting factor seems to be the lack of a suitable delivery system to carry the therapeutic genes to the target tissue

Arash Hatefi; Brenda F. Canine

2009-01-01

385

Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency  

Microsoft Academic Search

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

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

2009-01-01

386

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

387

Gene therapy in the treatment of intestinal inflammation  

Microsoft Academic Search

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

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

2004-01-01

388

Gene therapy: Regulations, ethics and its practicalities in liver disease  

Microsoft Academic Search

Gene therapy is a new and promising approach which opens a new door to the treatment of human diseases. By direct transfer of genetic materials to the target cells, it could exert functions on the level of genes and molecules. It is hoped to be widely used in the treatment of liver disease, especially hepatic tumors by using different vectors

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

2008-01-01

389

Problems and potential for gene therapy in Duchenne muscular dystrophy  

Microsoft Academic Search

Hopes ran high that a cure for Duchenne muscular dystrophy (DMD) would quickly follow the discovery of dystrophin by Lou Kunkel and his group in the 1980's. Myoblast transplantation, the favoured method of gene `complementation', unfortunately did not progress beyond the experimental stage. A more sober approach to gene therapy followed using a variety of transfection or direct methods to

B. A Kakulas

1997-01-01

390

GENE THERAPY FOR PROSTATE CANCER: WHERE ARE WE NOW?  

Microsoft Academic Search

Purpose: The ability to recombine specifically and alter DNA sequences followed by techniques to transfer these sequences or even whole genes into normal and diseased cells has revolutionized medical research and ushered the clinicians of today into the age of gene therapy. We provide urologists a review of relevant background information, outline current treatment strategies and clinical trials, and delineate

MITCHELL S. STEINER; JEFFREY R. GINGRICH

2000-01-01

391

Prospects for gene therapy using haemopoietic stem cells  

Microsoft Academic Search

Gene therapy has thus far promised much and delivered little. Much of this has been due to deficiencies in the reagents and methodologies employed in early clinical trials. Recent technological advances in vectors and haemopoietic stem cell manipulation, coupled with improved pre-clinical assays of gene transfer and expression in re-populating stem cells give cause for greater optimism. Here we review

Leslie J Fairbairn; Joanne C Ewing

2001-01-01

392

MRI reporter genes: applications for imaging of cell survival, proliferation, migration and differentiation.  

PubMed

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 with 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 nevertheless be detected, although indirectly, using reporter gene 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 and bioluminescent proteins and the reaction product of expressed enzymes and exogenous substrates were examined using in vitro histological methods and in vivo whole body imaging methods. Recent advances in MRI reporter gene methods raised 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 was by monitoring gene expression patterns in gene therapy and in vivo imaging of the survival, proliferation, migration and differentiation of pluripotent and multipotent cells used in cell-based regenerative therapies for cancer, myocardial infarction and neural degeneration. In this review, we characterized a variety of MRI reporter gene methods based on their applicability to report cell survival/proliferation, migration and differentiation. In particular, we discussed which methods were best suited for translation to clinical use in regenerative therapies. PMID:23225197

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

2012-12-06

393

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.

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

2011-01-01

394

Current perspectives on imaging cardiac stem cell therapy.  

PubMed

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

2010-04-15

395

Cellular, Tissue and Gene Therapies Advisory Committee ...  

Center for Biologics Evaluation and Research (CBER)

Text Version... fibroblasts within Restylane for soft tissue augmentation ... therapy • Pregnant or lactating women • Facial surgery in the lower 2/3 of the face or semi ... More results from www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials

396

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

397

New strategy for monitoring targeted therapy: molecular imaging  

PubMed Central

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

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

2013-01-01

398

Development of Viral Vectors for Use in Cardiovascular Gene Therapy  

PubMed Central

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

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

2010-01-01

399

Prospects for gene therapy in corneal disease  

Microsoft Academic Search

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

A S Jun; D F P Larkin; DFP Larkin

2003-01-01

400

Gene therapy of skin adhesion disorders (mini review).  

PubMed

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

Cavazza, Alessia; Mavilio, Fulvio

2012-08-01

401

Imaging: Guiding the Clinical Translation of Cardiac Stem Cell Therapy  

PubMed Central

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

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

2011-01-01

402

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

2013-04-03

403

Imaging: guiding the clinical translation of cardiac stem cell therapy.  

PubMed

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

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

2011-09-30

404

Light-induced adenovirus gene transfer, an efficient and specific gene delivery technology for cancer gene therapy  

Microsoft Academic Search

A main issue for further clinical progress of cancer gene therapy is to develop technologies for efficient and specific delivery of therapeutic genes to tumor cells. In this work, we describe a photochemical treatment that substantially improves gene delivery by adenovirus, one of the most efficient gene delivery vectors known. Transduction of two different cell lines was studied by microscopy,

Anders Høgset; Birgit Øvstebø Engesæter; Lina Prasmickaite; Kristian Berg; Øystein Fodstad; Gunhild Mari Mælandsmo

2002-01-01

405

Dose imaging and profiling for boron neutron capture therapy planning  

Microsoft Academic Search

Imaging and profiling of the absorbed dose in tissue-equivalent gel-phantoms exposed to thermal neutrons were performed at the TAPIRO fast reactor (ENEA, Italy). The proposed method, aimed at supporting the planning of Neutron Capture Therapy (NCT), allows to measure 3D distributions of the therapy dose not only in tumors, but also in the healthy tissue. This feature is very important,

G. Gambarini; S. Agosteo; U. Danesi; F. Garbellini; B. Lietti; M. Mauri; E. Nava; G. Rosi; R. Tinti

2000-01-01

406

Imaging Cardiac Stem Cell Therapy: Translations to Human Clinical Studies  

Microsoft Academic Search

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

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

407

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

PubMed Central

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

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

2010-01-01

408

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

PubMed Central

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

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

2012-01-01

409

Geometric accuracy in radiation therapy: Dosimetric, imaging and economic considerations  

NASA Astrophysics Data System (ADS)

In 2007 in Canada, 159,900 men and women will be diagnosed with cancer. Radiation Therapy (RT) is the treatment of cancer by irradiating malignant tissue with ionizing radiation and it is used on up to 50% of all cancers. The objective of radiation therapy is to deliver a lethal dose of radiation to the tumour while sparing the surrounding healthy tissues and organs at risks (OARs). Thus, the accuracy with which the radiation therapy process must be carried out is critical. The presence of setup errors and uncertainties throughout the RT process impacts the dose received by the tumour and OARs and can compromise the outcome for the patient. This thesis focuses on the study of the limiting geometrical accuracy imposed by factors present in radiation therapy process (such as setup errors and uncertainties or the spatial resolution of the imaging systems that we use) and its consequences for the patient. The consequences are quantified through the use of a physical outcome surrogate, the Equivalent Uniform Dose (EUD), which numerically describes the dose distribution received by the target and normal structures surrounding it. A cost-outcome analysis is presented in which the incremental cost of radiation therapy is directly related to the patients outcome (using the EUD) for using various imaging modalities and correction protocols in Image Guided Adaptive Radiation Therapy (IGART).

Ploquin, Nicolas P.

410

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

411

Fetal gene therapy of ?-thalassemia in a mouse model  

PubMed Central

Fetuses with homozygous ?-thalassemia usually die at the third trimester of pregnancy or soon after birth. Hence, the disease could potentially be a target for fetal gene therapy. We have previously established a mouse model of ?-thalassemia. These mice mimic the human ?-thalassemic conditions and can be used as preclinical models for fetal gene therapy. We tested a lentiviral vector containing the HS 2, 3, and 4 of the ?-LCR, a central polypurine tract element, and the ?-globin gene promoter directing either the EGFP or the human ?-globin gene. We showed that the GFP expression was erythroid-specific and detected in BFU-E colonies and the erythroid progenies of CFU-GEMM. For in utero gene delivery, we did yolk sac vessel injection at midgestation of mouse embryos. The recipient mice were analyzed after birth for human ?-globin gene expression. In the newborn, human ?-globin gene expression was detected in the liver, spleen, and peripheral blood. The human ?-globin gene expression was at the peak at 3–4 months, when it reached 20% in some recipients. However, the expression declined at 7 months. Colony-forming assays in these mice showed low abundance of the transduced human ?-globin gene in their BFU-E and CFU-GEMM and the lack of its transcript. Thus, lentiviral vectors can be an effective vehicle for delivering the human ?-globin gene into erythroid cells in utero, but, in the mouse model, delivery at late midgestation could not transduce hematopoietic stem cells adequately to sustain gene expression.

Han, Xiao-Dong; Lin, Chin; Chang, Judy; Sadelain, Michel; Kan, Y. W.

2007-01-01

412

Potential of Gene Therapy for the Treatment of Pituitary Tumors  

PubMed Central

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

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

2010-01-01

413

Gene Expression Analysis of Human Prostate Carcinoma during Hormonal Therapy Identifies Androgen-Responsive Genes and Mechanisms of Therapy Resistance  

PubMed Central

The androgen-signaling pathway is critical to the development and progression of prostate cancer and androgen ablation is a mainstay of therapy for this disease. We performed a genome-wide expression analysis of human prostate cancer during androgen ablation therapy to identify genes regulated by androgen and genes differentially expressed after the development of resistance. Six hundred and fifty-four of 63,175 probe sets detected significant expression changes after 3 months of treatment with goserelin and flutamide. This included 149 genes that were also differentially expressed 36 hours after androgen withdrawal in LNCaP cells. These genes reflect the physiological changes that occur in treated tumors and include potential direct targets of the androgen receptor. Expression profiles of androgen ablation-resistant tumors demonstrated that many of the gene expression changes detected during therapy were no longer present suggesting a reactivation of the androgen response pathway in the absence of exogenous hormone. Therapy resistance was associated with differential expression of a unique set of genes that reflect potential mechanisms of reactivation. Specifically an up-regulation of the androgen receptor and key enzymes for steroid biosynthesis suggest that resistant tumors have increased sensitivity to and endogenous synthesis of androgenic hormones. The specific pathways of reactivation provide opportunities for classification of resistant tumors and targeted therapies.

Holzbeierlein, Jeff; Lal, Priti; LaTulippe, Eva; Smith, Alex; Satagopan, Jaya; Zhang, Liying; Ryan, Charles; Smith, Steve; Scher, Howard; Scardino, Peter; Reuter, Victor; Gerald, William L.

2004-01-01

414

Cancer Imaging and Therapy with Bispecific Antibody Pretargeting  

PubMed Central

This article reviews recent preclinical and clinical advances in the use of pretargeting methods for the radioimmunodetection and radioimmunotherapy of cancer. Whereas directly-labeled antibodies, fragments, and subfragments (minibodies and other constructs) have shown promise in both imaging and therapy applications over the past 25 years, their clinical adoption has not fulfilled the original expectations due to either poor image resolution and contrast in scanning or insufficient radiation doses delivered selectively to tumors for therapy. Pretargeting involves the separation of the localization of tumor with an anticancer antibody from the subsequent delivery of the imaging or therapeutic radionuclide. This has shown improvements in both imaging and therapy by overcoming the limitations of conventional, or 1-step, radioimmunodetection or radioimmunotherapy. We focus herein on the use of bispecific antibodies followed by radiolabeled peptide haptens as a new modality of selective delivery of radionuclides for the imaging and therapy of cancer. Our particular emphasis in pretargeting is the use of bispecific trimeric (3 Fab’s) recombinant constructs made by a modular method of antibody and protein engineering of fusion molecules called Dock and Lock (DNL).

Goldenberg, David M.; Chatal, Jean-Francois; Barbet, Jacques; Boerman, Otto; Sharkey, Robert M.

2007-01-01

415

Dual-mode transducers for ultrasound imaging and thermal therapy.  

PubMed

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

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

2009-08-18

416

Transcriptional targeting of tumor endothelial cells for gene therapy  

PubMed Central

It is well known that angiogenesis plays a critical role in the pathobiology of tumors. Recent clinical trials have shown that inhibition of angiogenesis can be an effective therapeutic strategy for patients with cancer. However, one of the outstanding issues in anti-angiogenic treatment for cancer is the development of toxicities related to off-target effects of drugs. Transcriptional targeting of tumor endothelial cells involves the use of specific promoters for selective expression of therapeutic genes in the endothelial cells lining the blood vessels of tumors. Recently, several genes that are expressed specifically in tumor-associated endothelial cells have been identified and characterized. These discoveries have enhanced the prospectus of transcriptionaly targeting tumor endothelial cells for cancer gene therapy. In this manuscript, we review the promoters, vectors, and therapeutic genes that have been used for transcriptional targeting of tumor endothelial cells, and discuss the prospects of such approaches for cancer gene therapy.

Dong, Zhihong; Nor, Jacques E.

2009-01-01

417

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

418

Fetal gene therapy: Opportunities and risks  

Microsoft Academic Search

Advances in human prenatal medicine and molecular genetics have allowed the diagnosis of many genetic diseases early in gestation. In-utero transplantation of allogeneic hematopoietic stem cells (HSC) has been successfully used as a therapy in different animal models and recently also in human fetuses. Unfortunately, clinical success of this novel treatment is limited by the lack of donor cell engraftment

Anna M. Wagner; Andreina Schoeberlein; Daniel Surbek

2009-01-01

419

Gene Therapy for Advanced Parkinson's Shows Promise  

MedlinePLUS

... 2011 An experimental surgical treatment for Parkinson’s disease (PD) – which involves inserting the human gene known as ... brain was a safe approach in people with PD. Investigators at seven US research centers led by ...

420

Gene therapy clinical trials worldwide to 2012 - an update.  

PubMed

To date, over 1800 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical trials from official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our June 2012 update, we have entries on 1843 trials undertaken in 31 countries. We have analysed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our searchable database are available on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical. We also provide an overview of the progress being made in clinical trials of gene therapy approaches around the world and discuss the prospects for the future. PMID:23355455

Ginn, Samantha L; Alexander, Ian E; Edelstein, Michael L; Abedi, Mohammad R; Wixon, Jo

2013-02-01

421

Advances in adenovirus-mediated p53 cancer gene therapy.  

PubMed

Introduction: The tumor suppressor p53 gene regulates diverse cellular processes, such as cell-cycle arrest, senescence, apoptosis and autophagy, and it is frequently inactivated by genetic alterations in ? 50% of all types of human cancers. To restore wild-type p53 function in p53-inactivated tumors, adenovirus-mediated p53 gene therapy has been developed as a promising antitumor strategy in preclinical experiments and clinical studies. Areas covered: This review focuses on the clinical relevance of replication-deficient adenovirus vectors that carry the wild-type p53 gene (Ad-p53; Advexin, Gendicine and SCH-58500) in clinical studies of patients with various cancers and the future perspectives regarding conditionally replicating adenovirus vectors expressing the wild-type p53 gene (CRAd-p53; AdDelta24-p53, SG600-p53, OBP-702) in preclinical experiments. Moreover, the recent advances in our understanding of the molecular basis for the p53-mediated tumor suppression network induced by Ad-p53 and CRAd-p53 vectors and the combination therapies for promoting the therapeutic potential of adenovirus-mediated p53 gene therapy are discussed. Expert opinion: Exploration of the molecular mechanism underlying the p53-mediated tumor suppression network and the effective strategy for enhancing the p53-mediated cell death signaling pathway would provide novel insights into the improvement of clinical outcome in p53-based cancer gene therapy. PMID:24107178

Tazawa, Hiroshi; Kagawa, Shunsuke; Fujiwara, Toshiyoshi

2013-11-01

422

Retroviral integration profiles: their determinants and implications for gene therapy.  

PubMed

Retroviruses have often been used for gene therapy because of their capacity for the long-term expression of transgenes via stable integration into the host genome. However, retroviral integration can also result in the transformation of normal cells into cancer cells, as demonstrated by the incidence of leukemia in a recent retroviral gene therapy trial in Europe. This unfortunate outcome has led to the rapid initiation of studies examining various biological and pathological aspects of retroviral integration. This review summarizes recent findings from these studies, including the global integration patterns of various types of retroviruses, viral and cellular determinants of integration, implications of integration for gene therapy and retrovirus-mediated infectious diseases, and strategies to shift integration to safe host genomic loci. A more comprehensive and mechanistic understanding of retroviral integration processes will eventually make it possible to generate safer retroviral vector platforms in the near future. PMID:22531129

Lim, Kwang-il

2012-04-01

423

GENE THERAPY FOR THE TREATMENT OF PITUITARY TUMORS  

PubMed Central

Pituitary adenomas constitute the most frequent neuroendocrine pathology in humans. Current therapies include surgery, radiotherapy and pharmacological approaches. Although useful, none of them offers a permanent cure. Current research efforts to implement gene therapy in pituitary tumors include the treatment of experimental adenomas with adenoviral vector-mediated transfer of the suicide gene for thymidine kinase, which converts the prodrug ganciclovir into a toxic metabolite. In some cases, the suicide transgene has been placed under the control of pituitary cell-type specific promoters. Also, regulatable adenoviral vector systems are being assessed in gene therapy approaches for experimental pituitary tumors. Although the efficiency and safety of current viral vectors must be optimized before clinical use, they remain as highly promising therapeutic tools.

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

2010-01-01

424

Large Animal Models of Neurological Disorders for Gene Therapy  

PubMed Central

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

Gagliardi, Christine; Bunnell, Bruce A.

2009-01-01

425

Gene therapy approaches for the selective killing of cancer cells.  

PubMed

This review describes gene therapy strategies that take advantage of defective signal transduction pathways to selectively kill cancer cells without adversely affecting normal cells. The distinctive features of cancer cells currently exploited by gene therapy include mitosis, cell permissiveness to infection, specific protease activity, and the activity of the p53, Rb/E2F and wnt/catenin signal transduction pathways. In most cases, proof of concept has been obtained in vitro and in vivo, but only a few approaches made it to the clinic. Overall, the clinical success rate has been disappointing and it is concluded that the gene therapy of cancer requires more innovation and hard work before its potential can be fully realized. PMID:12171540

Westphal, Eva Maria; Melchner Hv, Harald von

2002-01-01

426

Gene Therapy Using Gene Fusions for Genetic or Acquired Disorders.  

National Technical Information Service (NTIS)

The invention is related generally to the construction of fusion genes. More particularly, it is related to the construction of a fusion gene comprising a coding sequence for a selectable marker linked by fusion to another coding sequence, the product of ...

I. Pastan M. Gottesman

1988-01-01

427

Targeted adenoviral vectors for cancer gene therapy.  

PubMed

The delineation of the molecular basis of cancer allows for the possibility of specific intervention at the molecular level for therapeutic purposes. To this end, viral and nonviral vectors have been designed for delivery and expression of genes into target malignant and non-malignant cells. Gene transfer by available vectors, applied both in the ex vivo and in in vivo contexts, has resulted frequently in the desired cellular phenotypical changes. In this regard, recombinant adenoviruses have been particularly efficient for in vivo gene transfer. Importantly, numerous human clinical protocols using adenoviruses have rapidly entered Phase I clinical trials. However, major vector-related problems remain to be solved before the transfer of therapeutic genes by adenoviruses can become an effective and common place strategy for cancer. An overriding obstacle is the basic ability to deliver therapeutic genes specifically into tumor cells. Here we review a diverse number of advances in adenoviral vectors being developed for overcoming this obstacle. As vector technology fulfills these requirements for obtaining the "targetable-injectable" vector, it is anticipated that promising results already observed in pre-clinical studies will translate quickly into the clinic. PMID:10026898

Bilbao, G; Gómez-Navarro, J; Curiel, D T

1998-01-01

428

Gene- and Viral-Based Therapies for Brain Tumors  

PubMed Central

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

Asadi-Moghaddam, Kaveh; Chiocca, E. Antonio

2011-01-01

429

Technology evaluation: VEGF165 gene therapy, Valentis Inc.  

PubMed

Valentis Inc, formerly GeneMedicine, is developing a vascular endothelial growth factor (VEGF165) non-viral gene therapy using its proprietary PINC polymer for plasmid condensation. Two physician-initiated phase II angioplasty trials are ongoing, one for treating peripheral vascular disease and one for treating coronary artery disease [281714], [347153]. In February 2000, the trials were expected to be completed in the fourth quarter of 2000 [356225]; however, in October 2000, it was reported that the trial for peripheral vascular disease would be completed in the first quarter of 2001 [385232]. In March 2000, Valentis initiated a trial incorporating Valentis's DOTMA-based cationic lipid gene delivery system and the VEGF165 gene with Eurogene's local collar-reservoir delivery device. The trial is designed to demonstrate that the VEGF165 gene, delivered locally to the outside surface of a blood vessel, will transfect and express in the smooth muscle cells of the vessel wall [360683]. In March 1999, Valentis was awarded with a Phase II SBIR grant of $686,260. The aim of grant was to advance the development of non-viral gene therapies for ischemia. Specifically, Valentis intended to select an optimal promoter to be used with the VEGF expression plasmid. Valentis also intended to evaluate the gene therapy system in a rabbit ischemia model and complete the necessary preclinical studies for submission of an IND [318137]. PMID:11249737

Morse, M A

2001-02-01

430

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

Microsoft Academic Search

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

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

2009-01-01

431

Hematopoietic stem cell-based gene therapy for HIV disease  

PubMed Central

Although combination antiretroviral therapy can dramatically reduce the circulating viral load in those infected with HIV, replication-competent virus persists. To eliminate the need for indefinite treatment, there is growing interest in creating a functional HIV-resistant immune system through the use of gene-modified hematopoietic stem cells (HSC). Proof-of-concept for this approach has been provided in the instance of an HIV-infected adult transplanted with allogeneic stem cells from a donor lacking the HIV co-receptor, CCR5. Here, we review this and other strategies for HSC-based gene therapy for HIV disease.

Kiem, Hans-Peter; Jerome, Keith R.; Deeks, Steven G.; McCune, Joseph M.

2012-01-01

432

Strategy of gene therapy for liver cirrhosis and hepatocellular carcinoma  

Microsoft Academic Search

Background\\/Purpose. Liver cirrhosis and hepatocellular carcinoma (HCC) are major causes of morbidity and mortality worldwide, without effective\\u000a therapies. Our aim was to establish a novel approach for the diseases utilizing in-vivo gene therapy.\\u000a \\u000a \\u000a Methods. To achieve effective gene expression in vivo, we employed a well-established transfection method, hemagglutinating virus\\u000a of Japan (HVJ)-liposome. Liver cirrhosis, characterized by parenchymal collapse, was induced

Yuji Iimuro; Jiro Fujimoto

2003-01-01

433

Hematopoietic-stem-cell-based gene therapy for HIV disease.  

PubMed

Although combination antiretroviral therapy can dramatically reduce the circulating viral load in those infected with HIV, replication-competent virus persists. To eliminate the need for indefinite treatment, there is growing interest in creating a functional HIV-resistant immune system through the use of gene-modified hematopoietic stem cells (HSCs). Proof of concept for this approach has been provided in the instance of an HIV-infected adult transplanted with allogeneic stem cells from a donor lacking the HIV coreceptor, CCR5. Here, we review this and other strategies for HSC-based gene therapy for HIV disease. PMID:22305563

Kiem, Hans-Peter; Jerome, Keith R; Deeks, Steven G; McCune, Joseph M

2012-02-01

434

Current targeting strategies for adenovirus vectors in cancer gene therapy.  

PubMed

Adenovirus vectors (Adv) are the most frequently used vectors in gene therapy research, especially in cancer gene therapy. However, despite encouraging preclinical and early clinical results, the successful clinical utility of gene therapy has not yet been fully realized. Challenges to clinical trial success for targeted Adv include inefficient Adv-mediated gene transfer (because many tumor cells lack Adv receptors), poor transduction in tumor tissues after systemic administration, accumulation and undesirable transgene expression in the liver. This review summarizes current targeting strategies for Adv to overcome these obstacles. Strategies include transductional selectivity through genetic modification of viral coat proteins, transcriptional selectivity by means of tumor-specific promoters, and selective biodistribution from conjugation with targeting ligands or polymers such as polyethylene glycol (PEG). Furthermore, combining selective biodistribution and active targeting ligands such as proteins, antibodies and peptides is an intriguing and promising approach that will also be covered in this review. These studies have provided new insights into our understanding of the utility of Adv in cancer gene therapy. PMID:21762081

Yao, X-L; Nakagawa, S; Gao, J-Q

2011-09-01

435

Two-dimensional ultrasound image matching system for photodynamic therapy  

NASA Astrophysics Data System (ADS)

Two-dimensional (2D) ultrasound imaging is commonly used for diagnosis in a variety of medical fields. However, there are several drawbacks of conventional 2D-ultrasound imaging. These include prostate or transducer movement that produces sets of different images that are difficult to interpret. Also during patient's reexamination correspondence between sets of images before reexamination and after is difficult to establish. This can be described as a problem of correlation between two sets of images: the first created before distortion or examination, the second one after. We propose a method to register 2D ultrasound volumes based on external markers introduced in the prostate. The metal balls are inserted in the prostate at three distinct locations in the prostate. These appear as bright dots in the ultrasound field, serve as reference points, are then outlined through a user-interactive program from two sets of images. Then, the computer program rotates and translates till they match respectively, and displays the mapped points with their corresponding location. Based on this idea we developed an image-guided system for PDT that require high-precision placement of implants. In the planning stage, the system performs an automatic acquisition of 2D transrectal ultrasound images that will ultimately be used to construct the treatment plan. At the time of the therapy, new sets of ultrasound images are acquired and a match is established between the virtual world and the patient's real world with the aid of manually introduced markers and image matching algorithms.

Zaim, Amjad; Keck, Rick W.; Selman, Steven H.; Jankun, Jerzy

2001-05-01

436

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

437

Gene Therapy for Lysosomal Storage Diseases  

Microsoft Academic Search

Lysosomal storage diseases (LSDs) comprise a diverse group of monogenetic disorders with complex clinical phenotypes that include both systemic and central nervous system pathologies. In recent years, the identification or development of mouse models recapitulating the clinical course of the LSDs has been instrumental in evaluating therapeutic strategies. Here, we review the various gene replacement strategies for target organs affected

Mark S. Sands; Beverly L. Davidson

2006-01-01

438

Paroxysmal nocturnal haemoglobinuria: Nature's gene therapy?  

PubMed Central

The development of paroxysmal nocturnal haemoglobinuria (PNH) requires two coincident factors: somatic mutation of the PIG-A gene in one or more haemopoietic stem cells and an abnormal, hypoplastic bone marrow environment. When both of these conditions are met, the fledgling PNH clone may flourish. This review will discuss the pathophysiology of this disease, which has recently been elucidated in some detail.

Johnson, R J; Hillmen, P

2002-01-01

439

Gene Therapy for Diseases and Genetic Disorders  

MedlinePLUS

... at least two years. Hemophilia Patients born with Hemophilia are not able to induce blood clots and suffer from external and internal bleeding that can be life threatening. In a clinical trial conducted in the United States , the therapeutic gene was introduced into the liver of patients, ...

440

Papillomaviruses as targets for cancer gene therapy  

Microsoft Academic Search

The human papillomaviruses (HPVs) are a diverse group of infectious agents, some of which are a causative agent of human cancers. Cervical cancer and oral cancer are closely associated with specific types of HPV, and the tumors grow only if there is continual expression of the viral E6 and E7 genes. Evidence from in vitro studies shows that when expression

E J Shillitoe

2006-01-01

441

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

2013-07-10

442

Gold nanocages for cancer imaging and therapy.  

PubMed

Gold nanocages are hollow nanostructures with porous walls that can be simply prepared via the galvanic replacement reaction between silver nanocubes and chloroauric acid. Their optical resonance peaks can be precisely tuned into the near-infrared region, in which the adsorption caused by blood or soft tissue is essentially negligible. Significantly, the strong absorption of gold nanocages makes them attractive as a novel class of contrast enhancement and photothermal agents for cancer detection and treatment. The well-established chemistry for gold also allows them to target specific cells by functionalizing their surface with various moieties such as antibodies, peptides, and DNAs. In this chapter, we focus on their use as a photothermal agent for the ablation of cancer cells and as a contrast agent for the in vivo noninvasive photoacoustic imaging of blood vessels and the sentinel lymph nodes in rats. PMID:20217590

Au, Leslie; Chen, Jingyi; Wang, Lihong V; Xia, Younan

2010-01-01

443

Combined radiation and gene therapy for brain tumors with adenovirus-mediated transfer of cytosine deaminase and uracil phosphoribosyltransferase genes  

Microsoft Academic Search

Radiation therapy is an established modality for the treatment of malignant gliomas. Several reports have shown the advantage of additional radiation in combination with gene therapy. In this study, we investigated the ability of radiation therapy to enhance 5-fluorocytosine (5-FC)\\/cytosine deaminase (CD) plus uracil phosphoribosyltransferase (UPRT) gene therapy in malignant gliomas. In vitro study suggested evidence of a significant cytotoxic

Hirokazu Kambara; Takashi Tamiya; Yasuhiro Ono; Shinji Ohtsuka; Kinya Terada; Yoshiaki Adachi; Tomotsugu Ichikawa; Hirofumi Hamada; Takashi Ohmoto

2002-01-01

444

[Is there a place for gene therapy in organ transplantation?].  

PubMed

The major research objectives in organ transplantation are to palliate the lack of organs, to decrease the adverse effects of chronic immunosuppression and to improve medium-term and long-term graft survival. Xenotransplantation and induction of a permanent and specific tolerance to an allograft therefore represent two main lines of research which could partly resolve the problems of organ transplantation. The objective of this article is to evaluate the possible role of gene therapy in the development of xenotransplantation and induction of allograft tolerance. They review the various gene vectors currently available as well as the routes of administration of these vectors specific to transplantation. The place of gene therapy is then evaluated in the context of allo- and xenotransplantation. In allotransplantation, transfection of certain genes of interest into the transplant organ before implantation or into the recipient's immune system is considered. Transfection into the transplant organ of genes coding for immunomodulating cytokines (TGF-beta, IL-4, IL-10, etc.), molecules which block the second signal (CTLA4-Ig) or molecules responsible for apoptosis (Fas/FasL) is discussed. The value of gene therapy in the recipient's immune system consists of transfection onto the recipient's bone marrow cells of genes coding for major histocompatibility system molecules (HLA-DR, DQ, etc.). In xenotransplantation, gene therapy will certainly play a major role in the development of transgenic pigs expressing, on the surface endothelium of their organs, certain human molecules which regulate the activity of complement (CD55, CD59, etc.) or which modify the expression of glycosylated xenoantigens (alpha-galactosyl) recognized by performed antibodies. PMID:9406456

Gianello, P

1997-01-01

445

Angiogenic Gene Therapy for the Treatment of Retinopathies  

Microsoft Academic Search

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

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

446

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

447

Purine and Pyrimidine-Based Analogs and Suicide Gene Therapy  

Microsoft Academic Search

Nucleobase and nucleoside analogs are widely used chemotherapeutic agents in the treatment of cancer and viral diseases. These\\u000a compounds inhibit or disrupt DNA synthesis, and as tumor cells usually divide more rapidly than normal cells, there is a narrow\\u000a therapeutic window to be exploited. Suicide gene therapy delivers genes to the cancer cells, enabling them to convert relatively\\u000a nontoxic prodrugs

Zoran Gojkovic; Anna Karlsson

448

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

449

Gene therapy of epithelial ovarian cancer using adenoviral vectors  

Microsoft Academic Search

Ovarian cancer is the fourth most common cause of death in women. Gene therapy using the herpes simplex virus thymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) treatment has been successfully applied in the treatment of different cancers in experimental animals and in humans. In a recent report, we have demonstrated that the HSV-tk\\/GCV system can be used efficiently to

Ayman Al-Hendy

1998-01-01

450

Artificial and engineered chromosomes: developments and prospects for gene therapy  

Microsoft Academic Search

At the gene therapy session of the ICCXV Chromosome Conference (2004), recent advances in the construction of engineered chromosomes\\u000a and de novo human artificial chromosomes were presented. The long-term aims of these studies are to develop vectors as tools\\u000a for studying genome and chromosome function and for delivering genes into cells for therapeutic applications. There are two\\u000a primary advantages of

Brenda R. Grimes; Zoia Larin Monaco

2005-01-01

451

Problems and potential for gene therapy in Duchenne muscular dystrophy.  

PubMed

Hopes ran high that a cure for Duchenne muscular dystrophy (DMD) would quickly follow the discovery of dystrophin by Lou Kunkel and his group in the 1980's. Myoblast transplantation, the favoured method of gene 'complementation', unfortunately did not progress beyond the experimental stage. A more sober approach to gene therapy followed using a variety of transfection or direct methods to introduce the normal gene. In view of these advances it is timely for the potential of gene therapy for DMD to be considered in the light of the disease process. It may be assumed that if dystrophin is replaced muscle fibre necrosis will cease. For this purpose expression of the gene should be continuous and expressed throughout the body well before there are irreversible changes. It would seem that gene therapy would not be particularly helpful if this occurs when the muscle lesions are near the end stage. If our objective is to retain ambulation dystrophin must be replaced well before the end stage. It should be kept in mind that even when the disorder first becomes clinically apparent at the age of about 5 years, muscle lesions are very advanced in the limb girdle groups. Therefore, the best that may be hoped to achieve by gene therapy at the age of 5 years would be to arrest the process at that stage of involvement with the patient having permanent but static weakness. Cardiac lesions are probably minimal at this time. To improve life expectancy, the respiratory muscles would need to be preserved. The enormous size of the gene is another difficulty so that some thought has been given to the introduction of a 'minigene' converting the clinical phenotype from DMD to the more benign Becker phenotype with improved life expectancy. PMID:9267845

Kakulas, B A

1997-07-01

452

Problems, Side Effects, and Disappointments in Clinical Cancer Gene Therapy  

Microsoft Academic Search

Genetic therapeutic agents have been tested in cancer patients for over 10 yr. Five major approaches have been tested in clinical\\u000a trials: tumor suppressor gene replacement, prodrug-activating enzyme delivery, oncolytic virotherapy, antisense oligonucleotide\\u000a delivery, and cytokine immuno-gene therapy. Proof-of-principle demonstrations of transgene expression, as well as certain\\u000a biological activities, have been shown; serious toxicity has been rare. However, the field

Ta-Chiang Liu; David H. Kirn

453

Glaucoma: genes, phenotypes, and new directions for therapy  

PubMed Central

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

Fan, Bao Jian; Wiggs, Janey L.

2010-01-01

454

Development and application of adenoviral vectors for gene therapy of cancer  

Microsoft Academic Search

For successful gene vaccination and therapy of cancer, it is essential to develop gene delivery vectors that can meet clinical and social requirements. The need for improved vectors was clearly manifested during the peak of the first wave of gene therapy. Adenoviral (Ad) vectors have recently drawn the attention of many of those involved in the field of gene therapy

Wei-Wei Zhang

1999-01-01

455

Ligand-inducible transgene regulation for gene therapy.  

PubMed

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

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

2002-01-01

456

Barriers for Retinal Gene Therapy: Separating Fact from Fiction  

PubMed Central

The majority of recent preclinical gene therapy studies targeting the retina have used adeno-associated virus (AAV) as the gene transfer vector. However, AAV has several limitations including the ability to generate innate inflammatory responses, the ability to cause insertional mutagenesis at a frequency of up to 56% in some tissues and a limited cloning capacity of 4.8Kb. Furthermore, AAV is known to generate limiting immune responses in humans despite the absence of similar immune responses in preclinical canine and murine studies. Three clinical trials to treat Leber’s congenital amaurosis using AAV are under way. A clinical trial to treat Stargardt’s using lentivirus vectors has also been recently announced. However, very limited evidence currently exists that lentivirus vectors can efficiently transduce photoreceptor cells. In contrast, very few preclinical ocular gene therapy studies have utilized adenovirus as the gene therapy vector. Nonetheless, the only two ocular gene therapy clinical trials performed to date have each used adenovirus as the vector and more significantly, in these published trials there has been no observed serious adverse event. These trials appear to be poised for Phase II/III status. Activation of cytotoxic T lymphocytes limits duration of transgene expression in the retina from first generation adenovirus vectors. However, an advanced class of adenovirus vectors referred to as Helper-dependent Adenovirus (Hd-Ad) have recently been shown to be capable of expressing transgenes in ocular tissues for more than one year. Hd-Ad vectors have many properties that potentially warrant their inclusion in the retinal gene therapy toolbox for the treatment of retinal degenerative diseases.

Kumar-Singh, Rajendra

2008-01-01

457

Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy.  

PubMed

X-linked adrenoleukodystrophy (X-ALD) is a severe genetic demyelinating disease caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. When performed at an early stage of the disease, allogeneic hematopoietic stem cell transplantation (HCT) can arrest the progression of cerebral demyelinating lesions. To overcome the limitations of allogeneic HCT, hematopoietic stem cell (HSC) gene therapy strategy aiming to perform autologous transplantation of lentivirally corrected cells was developed. We demonstrated the preclinical feasibility of HSC gene therapy for ALD based on the correction of CD34+ cells from X-ALD patients using an HIV1-derived lentiviral vector. These results prompted us to initiate an HSC gene therapy trial in two X-ALD patients who had developed progressive cerebral demyelination, were candidates for allogeneic HCT, but had no HLA-matched donors or cord blood. Autologous CD34+ cells were purified from the peripheral blood after G-CSF stimulation, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1 cDNA, and then reinfused into the patients after they had received full myeloablative conditioning. Over 3 years of follow-up, the hematopoiesis remained polyclonal in the two patients treated with 7-14% of granulocytes, monocytes, and T and B lymphocytes expressing the lentivirally encoded ALD protein. There was no evidence of clonal dominance or skewing based on the retrieval of lentiviral insertion repertoire in different hematopoietic lineages by deep sequencing. Cerebral demyelination was arrested 14 and 16months, respectively, in the two treated patients, without further progression up to the last follow-up, a clinical outcome that is comparable to that observed after allogeneic HCT. Longer follow-up of these two treated patients and HSC gene therapy performed in additional ALD patients are however needed to evaluate the safety and efficacy of lentiviral HSC gene therapy in cerebral forms of X-ALD. PMID:22365775

Cartier, Nathalie; Hacein-Bey-Abina, Salima; Bartholomae, Cynthia C; Bougnères, Pierre; Schmidt, Manfred; Kalle, Christof Von; Fischer, Alain; Cavazzana-Calvo, Marina; Aubourg, Patrick

2012-01-01

458

Bio-LDH nanohybrid for gene therapy  

Microsoft Academic Search

Nano-sized inorganic clay, such as layered double hydroxide (LDH), has been demonstrated as delivery carrier for genes and drugs by hybridizing with DNA and c-antisense oligonucleotide (As-myc). Upon intercalating biomolecules into hydroxide layers, the basal spacing of LDH increases from 8.7 Å (for NO3?) to 23.9 Å (DNA) and 17.1 Å (As-myc), respectively. A strong suppression of cell growth (65%)

Seo-Young Kwak; Yong-Joo Jeong; Jong-Sang Park; Jin-Ho Choy

2002-01-01

459

The EIIAPA Chimeric Promoter for Tumor Specific Gene Therapy of Hepatoma  

Microsoft Academic Search

Purpose  For targeted imaging and therapy of hepatocellular carcinoma (HCC), we established a chimeric promoter (EIIAPA) containing\\u000a alpha-fetoprotein (AFP) promoter and hepatitis B virus enhancer II (EIIA) to control downstream expression of reporter and\\u000a therapeutic genes.\\u000a \\u000a \\u000a \\u000a \\u000a Procedures  We combined AFP promoter and EIIA to establish a chimeric EIIAPA promoter, then developed a bi-cistronic plasmid vector containing\\u000a HSV1-tk and luciferase genes controlled by

Ya-Ju Hsieh; Fu-Du Chen; Chien-Chih Ke; Hsin-Ell Wang; Chih-Jen Huang; Ming-Feng Hou; Kang-Ping Lin; Juri G. Gelovani; Ren-Shyan Liu

460

Development of hybrid viral vectors for gene therapy.  

PubMed

Adenoviral, retroviral/lentiviral, adeno-associated viral, and herpesviral vectors are the major viral vectors used in gene therapy. Compared with non-viral methods, viruses are highly-evolved, natural delivery agents for genetic materials. Despite their remarkable transduction efficiency, both clinical trials and laboratory experiments have suggested that viral vectors have inherent shortcomings for gene therapy, including limited loading capacity, immunogenicity, genotoxicity, and failure to support long-term adequate transgenic expression. One of the key issues in viral gene therapy is the state of the delivered genetic material in transduced cells. To address genotoxicity and improve the therapeutic transgene expression profile, construction of hybrid vectors have recently been developed. By adding new abilities or replacing certain undesirable elements, novel hybrid viral vectors are expected to outperform their conventional counterparts with improved safety and enhanced therapeutic efficacy. This review provides a comprehensive summary of current achievements in hybrid viral vector development and their impact on the field of gene therapy. PMID:23070017

Huang, Shuohao; Kamihira, Masamichi

2012-10-13