The long term goal of this Project is to develop gene therapy methods for the treatment of neural disorders. Two types of neurological dysfunction will he investigated: spinal cord lesions and autosomal dominant retinitis pigmentosa (ADRP). The first is a complex problem likely to require multiple therapeutic strategies. It is expected that gene therapy of spinal cord lesions will the introduction of multiple genes using vectors that can promote tissue specific transgene expression. This Program will assess the effect of two classes of gene in rat spinal cord lesion models. The neurotrophic factors GDNF and NT-3 will be tested both in vivo and ex vivo in conjunction with spinal cord grafts to determine if they can promote neuronal rescue. The second disease (ADRP) was chosen for this Program because it is a well characterized single gene defect which presents inherently simpler therapeutic problems. Ribozymes capable of downregulating the dominant mutation will be tested in newly developed rat models of retinitis pigmentosa to determine if clinically relevant improvement can he achieved in the course of the disease. Finally, all of the projects will focus on the use of one kind of viral vector, adeno-associated virus (AAV). AAV was chosen because the preliminary data assembled by the Project members suggests that AAV is likely to be successful in directing expression of transgenes in the terminally differentiated tissues of the retina and spinal cord for extended time periods and because it holds the promise of tissue specific gene expression. However, the Program recognizes the fact that AAV still has significant technical difficulties associated with it and these are also addressed. In addition, the Program has established a Vector Core Laboratory which will supply vectors of uniform and reproducible quality to all subprojects, construct modified versions of existing marker genes and genes of potential therapeutic value, and develop better purification methods. The Vector Core also will serve as mechanism to insure rapid exchange of information among all subprojects.
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