Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer.
Intrastriatal delivery of the tyrosine hydroxylase gene by viral vectors is being explored as a tool for local delivery of L-dopa in animals with lesions of the nigrostriatal pathway. The functional effects reported using this approach have been disappointing, probably because the striatal L-dopa levels attained have been too low. In the present study, we have defined a critical threshold level of L-dopa, 1.5 pmol/mg of tissue, that has to be reached to induce any significant functional effects. Using new generation high-titer recombinant adeno-associated virus vectors, we show that levels of striatal L-dopa production exceeding this threshold can be obtained provided that tyrosine hydroxylase is coexpressed with the cofactor synthetic enzyme, GTP-cyclohydrolase-1. After striatal transduction with this combination of vectors, substantial functional improvement in both drug-induced and spontaneous behavior was observed in rats with either complete or partial 6-hydroxydopamine lesions of the nigrostriatal pathway. However, complete reversal of motor deficits occurred only in animals in which part of the striatal dopamine innervation was left intact. Spared nigrostriatal fibers thus may convert L-dopa to dopamine and store and release dopamine in a more physiologically relevant manner in the denervated striatum to mediate better striatal output-dependent motor function. We conclude that intrastriatal L-dopa delivery may be a viable strategy for treatment and control of adverse side effects associated with oral L-dopa therapy such as on-off fluctuations and drug-induced dyskinesias in patients with Parkinson's disease.
Kirik
Deniz
D
Wallenberg Neuroscience Center, Department of Physiological Sciences, Division of Neurobiology, Lund University, BMC A11, S-221 84, Lund, Sweden.
Georgievska
Biljana
B
Burger
Corinna
C
Winkler
Christian
C
Muzyczka
Nicholas
N
Mandel
Ronald J
RJ
Bjorklund
Anders
A
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics*; D022761:Gene Transfer, Horizontal; D015316:Genetic Therapy; D007980:Levodopa / Q000008:administration & dosage* / Q000378:metabolism; D010300:Parkinson Disease / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*
D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D006136:GTP Cyclohydrolase