Neurodegenerative diseases constitute a major human health problem. In three of these conditions, i.e. Alzheimer's disease and age-related retinal degeneration, specific neuronal populations die, and they have been shown to respond to neurotrophic factors other gene products. Major difficulties concerned with the use of these molecules are the methods of delivery. To promote e restoration of normal function within neural circuits, the methods should supply the products in the physiologic context (i.e., by the appropriate cells) and 2) provide the products for extended periods with minimal pathologic consequences. The technologies employed to date do not meet these standards. To deliver relevant genes, we have developed latent, nonpathogenic Herpes simplex virus vectors. These vectors are designed to express foreign proteins for extended periods, and they neither replicate nor reactivate from the latent state. With a prototype agent, we have demonstrated stable, long-term expression of a foreign gene m neurons of intact animal. We now propose to express those genes whose products have either been shown or strongly considered to alter progression of the diseases just mentioned. In the case of Alzheimer's disease, we will use vectors expressing NGF, BDNF and NT-3 and assess role of these factors in the regulation of central cholinergic circuits, their potential role in the pathogenesis of AD and their possible therapeutic role in two models of cholinergic deficiency, the fimbria-fornix lesion and the senile age rat. Virus will be inoculated into the hippocampus and basal forebrain, expression of the growth factors verified by in situ hybridization and, where possible, by immuno- cytochemistry. Then, the cholinergic response will be determined by immunostaining for NGF receptor, choline acetyltranferase and, in the case of the senile rat model, by behavioral studies. For Parkinson's disease, viruses encoding similar trophic factors and tyrosine hydroxylase (TH) will be introduced into the substantia nigra and corpus striatum of intact and chemically lesioned animals. The effect of the factors be assayed by staining for dopamine and TH, by microdialysis for extracellular dopamine, and by quantitation of apomorphine-induced rotation. For degeneration, vectors expressing basic fibroblast growth factor and the """"""""retinal degeneration slow gene"""""""" will be injected Into retinae of animals with inherited and light-induced retinal degeneration, and the response will be monitored by direct observation of the retinal nuclear layer. These experiments will result in the development of powerful new tools for study of the nervous system and characterize the potential therapeutic role of growth factors and related molecules in neurodegenerative disorders.
