EX VIVO ANGIOGENIC GENE TRANSFER IN NEURAL TRANSPLANTS

DESCRIPTION: It is well known in humans that Parkinson's disease results from the specific degeneration of dopaminergic neurons in the pars compacta of the substantia nigra of the mesencephalon. The relatively new strategy of neuronal transplantation has provided encouraging results for Parkinson's disease patients, but unfortunately the survival of dopaminergic neurons in these transplants is extremely poor. We propose to increase neuronal survival in neural transplants by focal stimulation of angiogenesis. Using a replication-deficient herpes simplex viral vector containing the cDNA for human vascular endothelial growth factor(VEGF), we propose to increase expression of VEGF in dopaminergic cultures of embryonic rat mesencephalon, and examine whether steriotactic transplantation of these cells into adult rat striatum increases parameters of angiogenesis and neuronal survival within the transplant, such as blood vessel number, total cell number and the number of tyrosine hydroxylase-immunoreactive cells. Using a chemically lesioned rat model which creates a specific dopaminergic deficit similar to that seen in Parkinson's disease, we will test the efficacy and long term survival of these transplants using behavioral tests such as drug-induced stereotypic rotations. The implications of these results could have an immediate impact on current clinical transplantation strategies for Parkinson's disease, and furthermore have general implications for improving cell survival in other neural transplantation paradigms.