Long-term restoration of striatal L-aromatic amino acid decarboxylase activity using recombinant adeno-associated viral vector gene transfer in a rodent model of Parkinson's disease

As a potential treatment for Parkinson's disease, viral vector-mediated ove r-expression of striatal a-aromatic amino acid decarboxylase was tested in an attempt to facilitate the production of therapeutic levels of dopamine a fter peripheral L-dihydroxyphenylalanine administration. The results of mic rodialysis and enzyme activity assays indicate that striatal decarboxylatio n of peripherally administered L-dihydroxyphenylalanine was enhanced by rec ombinant adeno-associated virus-mediated gene transfer of a-aromatic amino acid decarboxylase in unilateral 6-hydroxydopamine-lesioned rats. This gene transfer-induced increase in striatal decarboxylase activity was shown to remain undiminished over a six-month period and transgene expression was de monstrated to persist for at least one year. Unlike previous approaches inv olving delivery of either tyrosine hydroxylase, or tyrosine hydroxylase and a-aromatic amino acid decarboxylase transgenes together to accomplish unre gulated dopamine delivery, the current study proposes a pro-drug strategy ( peripheral L-dihydroxyphenylalanine administration after a-aromatic amino a cid decarboxylase transduction). This strategy for dosage control could pot entially allow lowered L-dihydroxyphenylalanine doses and potentially obvia te complicated transcriptional regulation paradigms. These data suggest that the use of the non-pathogenic adeno-associated viru s to transfer the a-aromatic amino acid decarboxylase gene into the striatu m of Parkinson's disease patients may be an attractive gene therapy strateg y. (C) 1999 IBRO. Published by Elsevier Science Ltd.