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.