Long-term rAAV-mediated gene transfer of GDNF in the rat parkinson's model: Intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system

Previous studies have used recombinant adeno-associated viral (rAAV) vector s to deliver glial cell line-derived neurotrophic factor (GDNF) in the subs tantia nigra to protect the nigral dopamine (DA) neurons from 6-hydroxydopa mine-induced damage. However, no regeneration or functional recovery was ob served in these experiments. Here, we have used an rAAV-GDNF vector to expr ess GDNF long-term (6 months) in either the nigral DA neurons themselves, i n the striatal target cells, or in both of these structures. The results de monstrate that both nigral and striatal transduction provide significant pr otection of nigral DA neurons against the toxin-induced degeneration. Howev er, only the rats receiving rAAV-GDNF in the striatum displayed behavioral recovery, accompanied by significant reinnervation of the lesioned striatum , which developed gradually over the first 4-5 months after the lesion. GDN F transgene expression was maintained at high levels throughout this period . These results provide evidence that rAAV is a highly efficient vector sys tem for long-term expression of therapeutic proteins in the nigrostriatal s ystem.