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 #
1R01AI069350-01
Application #
7084950
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
2006-04-01
Budget End
2007-03-31
Support Year
1
Fiscal Year
2006
Total Cost
$347,625
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; Olafsen, Tove et al. (2011) The soluble serum protein Gas6 bridges virion envelope phosphatidylserine to the TAM receptor tyrosine kinase Axl to mediate viral entry. Cell Host Microbe 9:286-98
Onyango-Makumbi, Carolyne; Omer, Saad B; Mubiru, Michael et al. (2011) Safety and efficacy of HIV hyperimmune globulin for prevention of mother-to-child HIV transmission in HIV-1-infected pregnant women and their infants in Kampala, Uganda (HIVIGLOB/NVP STUDY). J Acquir Immune Defic Syndr 58:399-407
Onyango-Makumbi, Carolyne; Bagenda, Danstan; Mwatha, Antony et al. (2010) Early weaning of HIV-exposed uninfected infants and risk of serious gastroenteritis: Findings from two perinatal HIV prevention trials in Kampala, Uganda. J Acquir Immune Defic Syndr 53:20-7
Kamata, Masakazu; Liu, Shirley; Liang, Min et al. (2010) Generation of human induced pluripotent stem cells bearing an anti-HIV transgene by a lentiviral vector carrying an internal murine leukemia virus promoter. Hum Gene Ther 21:1555-67
Morizono, Kouki; Ku, Amy; Xie, Yiming et al. (2010) Redirecting lentiviral vectors pseudotyped with Sindbis virus-derived envelope proteins to DC-SIGN by modification of N-linked glycans of envelope proteins. J Virol 84:6923-34
Kamata, Masakazu; Liang, Min; Liu, Shirley et al. (2010) Live cell monitoring of hiPSC generation and differentiation using differential expression of endogenous microRNAs. PLoS One 5:e11834
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
Liang, Min; Morizono, Kouki; Pariente, Nonia et al. (2009) Targeted transduction via CD4 by a lentiviral vector uses a clathrin-mediated entry pathway. J Virol 83:13026-31
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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