Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of l -dopa using rAAV-mediated gene transfer

• DOI: 10.1073/pnas.062047599
• Publication Date: 2002-07-26T14:37:36Z
• Authors: Deniz Kirik; Biljana Georgievska; Corinna Burger; Christian Winkler; Nicholas Muzyczka; Ronald J. Mandel; Anders Björklund
• Keywords: Nigrostriatal pathway; MPTP

Intrastriatal delivery of the tyrosine hydroxylase gene by viral vectors is being explored as a tool for local l -dopa in animals with lesions nigrostriatal pathway. The functional effects reported using this approach have been disappointing, probably because striatal levels attained too low. In present study, we defined critical threshold level -dopa, 1.5 pmol/mg tissue, that has to be reached induce any significant effects. Using new generation high-titer recombinant adeno-associated virus vectors, show production exceeding can obtained provided coexpressed cofactor synthetic enzyme, GTP-cyclohydrolase-1. After transduction combination substantial improvement both drug-induced and spontaneous behavior was observed rats either complete or partial 6hydroxydopamine However, reversal motor deficits occurred only which part dopamine innervation left intact. Spared fibers thus may convert store release more physiologically relevant manner denervated striatum mediate better output-dependent function. We conclude intrastriatal viable strategy treatment control adverse side associated oral therapy such on-off fluctuations dyskinesias patients Parkinson's disease.