Both acquired disorders, like AIDS and cancer, as well as inherited disorders like hemophilia, cystic fibrosis, mental retardation, and many others will prove amenable to treatment by gene therapy. The approach is both rational and highly likely to achieve dramatic results. The human genome project and the work of many groups across various disciplines are helping to rapidly identify and clone the required genes for such an approach. However, the promise of gene therapy for the treatment of human inherited and acquired disorders will not be fully realized until the issue of delivery is satisfactorily resolved. Thus, there is an urgent need for safe, efficient and targetable vectors to permit the delivery of genes being discovered in the course of studying the human genome. In this grant we document the generation of the first truly targetable vector system for gene delivery. Our studies today have established a method for production of targetable high-titered virus vectors capable of achieving complete tumor regression in an animal model. This system embodies all the attributes of safety, high efficiency of transduction and expression, and ease of engineering and production that are necessary for successful gene therapy. Through this application we seek funding to perfect the system, to resolve some issues of fundamental importance not only to our vector system but also for the field of apoptosis in general. We also seek to develop vectors and therapeutic approaches that have a high probability of helping to treat a broad variety of diseases and disorders.
Our specific aims are: 1. To develop at least three highly apoptotic Sindbis-virus based vectors that would be able to target growing human tumor cells. 2. To test the above vectors in experimental animal protocols to establish safety, pharmacokinetics, biodistribution, and optimal dosing schedules for successful therapy of tumors. 3. To identify and study the mechanism of action of a major gene conferring resistance/susceptibility to apoptosis. The approach is based on the observation that mammalian cells are fully susceptible to Sindbis virus mediated apoptosis, while insect cells are completely resistant. These novel studies, in combination with ongoing efforts to investigate viral-induced apoptosis, will expand the range of diseases that can be approached with Sindbis and other viral vectors, as well as contribute important new knowledge to the field of apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068498-07
Application #
6512778
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Yovandich, Jason L
Project Start
1995-09-30
Project End
2005-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
7
Fiscal Year
2002
Total Cost
$273,900
Indirect Cost
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
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Hurtado, Alicia; Tseng, Jen-Chieh; Boivin, Christopher et al. (2005) Identification of amino acids of Sindbis virus E2 protein involved in targeting tumor metastases in vivo. Mol Ther 12:813-23
Tseng, Jen-Chieh; Hurtado, Alicia; Yee, Herman et al. (2004) Using sindbis viral vectors for specific detection and suppression of advanced ovarian cancer in animal models. Cancer Res 64:6684-92
Tseng, Jen-Chieh; Levin, Brandi; Hurtado, Alicia et al. (2004) Systemic tumor targeting and killing by Sindbis viral vectors. Nat Biotechnol 22:70-7

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