GROWTH FACTOR ENHANCED RETROVIRAL GENE TRANSFER TO CNS

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DESCRIPTION: (Adapted from the Applicant's Abstract) While retroviral vectors could potentially be incorporated as a tool for delivering genetic material into the CNS, the use of these vectors has been limited in the brain and spinal cord because of the lack of robust cell division. The applicant speculated that this inherent limitation of MLV based viral vectors could potentially be overcome by utilizing the known mitogenic effect of several different growth factors on cells of the CNS. Different growth factors effect cell division in different cell types. Using this information the PI has hypothesized that an in vivo application of growth factor could enhance MLV based gene transfer to the adult brain. The goal of the present application is to examine further this technical approach of gene transfer to the brain, a region with poor numbers of dividing cells even after injury or during disease states. In aim one, the applicant proposes to determine the dose response curves for growth factor (eg., FGF,PDGF, EGF) induced mitogenesis. These studies will help establish the concentration of growth factor required to optimize cell division in vivo. Aim 2 will identify and quantify the particular cell types transduced in animals first primed with a specific growth factor and subsequently given an injection of MLV based vectors expressing a marker gene. These experiments will allow the applicant to determine if the administration of a growth factor enables one to target specific cell types for gene delivery to the CNS. In aim 3, animals treated with growth factor and MLV vectors will be allowed to survive for up to 6 months. The cell types transduced in these animals will be determined and quantified so as to allow the assessment of longevity of the transgene for each of the cell populations that can be targeted. Aim 4 will test the therapeutic potential of the gene transfer approach in the rat model of Parkinson's disease. In this model the biochemical and behavioral changes associated with this treatment will be analyzed. It is hoped that these proposed experiments will lead to a new generation of studies designed to broaden the application of MLV vectors to include other neurodegenerative disease models of the CNS.