Successful application of gene therapy for treatment of human disease requires the efficient and safe delivery of therapeutic genes to the desired sites of expression. The most effective approach would be to develop vectors that home to and transduce specific cells and tissues through an intravenous route. Towards this end, we made significant progress in developing oncoretroviral and lentiviral vectors, in combination with pseudotypes of Sindbis virus envelope, for stable transduction of genes delivered via the bloodstream.The central hypothesis of this proposal is that efficient targeting vectors with high selectivity can be developed based upon oncoretroviral and lentiviral vectors. Numerous previous efforts have been made to develop retroviral vectors that can target specific cells and tissues. Typically, this involved modification of the native envelope and/or pseudotyping with other viral envelopes. These approaches have not been generally applicable because modifications in native envelope lead to large reductions in viral titer and pseudotypes with other viral envelopes are not generally applicable to targeting of many different types of cells and tissues. In 2001 we reported the use of a modified Sindbis virus envelope bearing the Fc binding domain of protein A to pseudotype retroviral vectors and redirect their specificity with monoclonal antibodies. Recently, we reported further modifications to enable the targeting to cells and tissues in living animals through intravenous injection. We propose to further characterize the properties of this vector in regards to its virological properties and utilize such information for further development of vector specificity and efficiency of targeting in living animals. Given our long-standing interest in retroviral biology, recent development of gene therapy vectors and studies in mice and non-human primates, we feel that we are well positioned to address the questions posed in this application.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI069350-05
Application #
7787471
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Park, Eun-Chung
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$337,610
Indirect Cost
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Morizono, Kouki; Xie, Yiming; Helguera, Gustavo et al. (2009) A versatile targeting system with lentiviral vectors bearing the biotin-adaptor peptide. J Gene Med 11:655-63
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Morizono, Kouki; Pariente, Nonia; Xie, Yiming et al. (2009) Redirecting lentiviral vectors by insertion of integrin-tageting peptides into envelope proteins. J Gene Med 11:549-58

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