The long-term goals of this project are to develop methods for improved and generically based therapy of disorders of the central nervous system. We wish to continue our studies on the design and preparation of virus vectors to express foreign genes in cells of the CNS, either through direct introduction of the transducing vector or through the implantation of genetically modified cells into the brain. We will continue to use the Lesch-Nyhan syndrome as the principal disease model for these studies, but we will extend the approach to other disorders, including the particularly useful model of GM1 gangliosidosis. We shall use retrovirus vectors derived from Moloney Murine Leukemia Virus (MoMLV) and herpes simplex type 1 (HSV-1) to express reporter genes and HPRT and mammalian beta-galactosidases in target cells in vitro and in vivo and to test two approaches to gene therapy; one involving direct introduction of transducing vector into the CNS, and the other involving implantation into the CNS of genetically modified cells.
The specific aims of this proposal are: 1.to characterize the effect of HPRT deficiency in mice. 2.to develop retroviruses capable of efficient tissue-specific infection and site specific integration. 3.to develop HSV-based vectors capable of stably transducing foreign genes into neurons and other post-mitatic cells. 4 to develop methods for direct vector delivery in vivo. 5.to test gene transfer approaches to the phenotypic correction of HPRT-deficient mice. 6 to examine the potential for gene therapy of GM1 gangliosidosis and other disorders, including defects of the hepatocyte.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD020034-09
Application #
3317834
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1985-04-01
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
9
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Iida, A; Chen, S T; Friedmann, T et al. (1996) Inducible gene expression by retrovirus-mediated transfer of a modified tetracycline-regulated system. J Virol 70:6054-9
Chen, S T; Iida, A; Guo, L et al. (1996) Generation of packaging cell lines for pseudotyped retroviral vectors of the G protein of vesicular stomatitis virus by using a modified tetracycline inducible system. Proc Natl Acad Sci U S A 93:10057-62
Douar, A M; Themis, M; Sandig, V et al. (1996) Effect of amniotic fluid on cationic lipid mediated transfection and retroviral infection. Gene Ther 3:789-96
Wang, M J; Friedmann, T; Johnson, P A (1995) Differentiation of PC12 cells by infection with an HSV-1 vector expressing nerve growth factor. Gene Ther 2:323-35
Miyanohara, A; Yee, J K; Bouic, K et al. (1995) Efficient in vivo transduction of the neonatal mouse liver with pseudotyped retroviral vectors. Gene Ther 2:138-42
Roemer, K; Johnson, P A; Friedmann, T (1995) Transduction of foreign regulatory sequences by a replication-defective herpes simplex virus type 1: the rat neuron-specific enolase promoter. Virus Res 35:81-9
Friedmann, T; Yee, J K (1995) Pseudotyped retroviral vectors for studies of human gene therapy. Nat Med 1:275-7
Lin, S; Gaiano, N; Culp, P et al. (1994) Integration and germ-line transmission of a pseudotyped retroviral vector in zebrafish. Science 265:666-9
Runnebaum, I B; Yee, J K; Kieback, D G et al. (1994) Wild-type p53 suppresses the malignant phenotype in breast cancer cells containing mutant p53 alleles. Anticancer Res 14:1137-44
Jinnah, H A; Wojcik, B E; Hunt, M et al. (1994) Dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease. J Neurosci 14:1164-75

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