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 over-expression of striatal L-aromatic amino acid decarboxylase was tested in an attempt to facilitate the production of therapeutic levels of dopamine after peripheral L-dihydroxyphenylalanine administration. The results of microdialysis and enzyme activity assays indicate that striatal decarboxylation of peripherally administered L-dihydroxyphenylalanine was enhanced by recombinant adeno-associated virus-mediated gene transfer of L-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 demonstrated to persist for at least one year. Unlike previous approaches involving delivery of either tyrosine hydroxylase, or tyrosine hydroxylase and L-aromatic amino acid decarboxylase transgenes together to accomplish unregulated dopamine delivery, the current study proposes a pro-drug strategy (peripheral L-dihydroxyphenylalanine administration after L-aromatic amino acid decarboxylase transduction). This strategy for dosage control could potentially allow lowered L-dihydroxyphenylalanine doses and potentially obviate complicated transcriptional regulation paradigms. These data suggest that the use of the non-pathogenic adeno-associated virus to transfer the L-aromatic amino acid decarboxylase gene into the striatum of Parkinson's disease patients may be an attractive gene therapy strategy.
Leff
S E
SE
Department of Neurology, Yerkes Regional Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Spratt
S K
SK
Snyder
R O
RO
Mandel
R J
RJ
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics* / Q000378:metabolism*; D003342:Corpus Striatum / Q000201:enzymology*; D004298:Dopamine / Q000096:biosynthesis; D015870:Gene Expression / Q000502:physiology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D008297:Male; D010300:Parkinson Disease / Q000201:enzymology*; D051381:Rats; D011916:Rats, Inbred F344; D011995:Recombination, Genetic; D013997:Time Factors; D014161:Transduction, Genetic / Q000502:physiology
D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine