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.
Department of Neurology, Yerkes Regional Primate Research Center, Emory University, Atlanta, GA 30329, USA.
S E
SE
Leff
S K
SK
Spratt
R O
RO
Snyder
R J
RJ
Mandel
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