Inhibition of neuronal cell death in Parkinson's disease by transduction of neurotrophic factor gene.

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Pigment epithelium-derived factor (PEDF), a neurotrophic agents first identified in conditioned medium from cultured human retinal pigment epithelial cells, induces neuronal differentiation with neuritic outgrowth in Y-79 retinoblastoma cells and has a neurotrophic survival effect on cerebellar granule cells in culture. PEDF also have protective effect against glutamate toxicity and induction of apoptotic cell death of cultured granular cells. In this project, first we investigated the effects of human recombinant PEDF (hrPEDF) on proliferation of cultured nigral neurones. To do this experiments, we used cultures of nigral neurones isolated from the fetal rat brains. The number of nigral neurones, which identified by immunohistochemistry for tyrosine hydroxilase, is larger in the presence of PEDF than that of controls. The effect of PEDF showed a dose-response relationship. In second studies, we have performed the transduction of PEDF gene to the striatum and nigra of mice. To this purpose, we used recombinent adeno-associated (AAV) vectors which are sufficient for packaging and integration. AAV containing cDNA encoding PEDF and GFP were injected to the striatum of the mice by streotaxic operation. GFP-positive cells were observed in the striatum and the substantia nigra, which were transported through strionigral pathway. We are now conducting immunohistochemistry for PEDF on these sections to confirm the expression of the PEDF.Our study suggest the possibility of PEDF gene transfer to the striatum and nigra and effect of survival of niral neurones, and furthermore potential role for the gene therapy of Parkinson's disease