Recombinant adeno-associated viral vector-mediated glial cell line-derivedneurotrophic factor gene transfer protects nigral dopamine neurons after onset of progressive degeneration in a rat model of Parkinson's disease

Previous work has demonstrated that viral vector mediated gene transfer of glial cell line-derived neurotrophic factor (GDNF), when administered prior to a striatal injection of the specific neurotoxin, 6-hydroxy-dopamine (6- OHDA), can protect nigral dopamine (DA) neurons from cell death. When consi dering gene therapy for Parkinson's disease (PD), vector delivery prior to the onset of neuropathology is not possible and chronic delivery will likel y be necessary in a GDNF based PD therapy. The present study was undertaken to determine if GDNF delivered via a recombinant adenoassociated viral vec tor (rAAV) could affect nigral DA cell survival when initiated just after t he administration of striatal 6-OHDA. The onset of rAAV-mediated GDNF trans gene expression near the substantia nigra was determined to bean somewhere between 1 and 7 days after the 6-OHDA injection and subsequent vector admin istration. The cell survival data indicate that rAAV-GDNF delivery results in a highly significant sparing of nigral DA neurons, These data indicate t hat a single delivery of rAAV encoding GDNF is efficacious when delivered a fter the onset of progressive degeneration in a rat model of PD. (C) 1999 A cademic Press.