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Neurosci."],"published-print":{"date-parts":[[1998,6,1]]},"abstract":"<jats:p>To achieve local, continuous<jats:sc>l<\/jats:sc>-DOPA delivery in the striatum by gene replacement as a model for a gene therapy for Parkinson\u2019s disease, the present studies used high titer purified recombinant adeno-associated virus (rAAV) containing cDNAs encoding human tyrosine hydroxylase (hTH) or human GTP-cyclohydrolase I [GTPCHI, the rate-limiting enzyme for tetrahydrobiopterin (BH<jats:sub>4<\/jats:sub>) synthesis] or both to infect the 6-OHDA denervated rat striatum. Striatal TH and GTPCHI staining was observed 3 weeks after rAAV transduction, with little detectable perturbation of the tissue. Six months after intrastriatal rAAV transduction, TH staining was present but apparently reduced compared with the 3 week survival time. In a separate group of animals, striatal TH staining was demonstrated 1 year after rAAV transduction. Double staining studies using the neuronal marker NeuN indicated that &gt;90% of rAAV-transduced cells expressing hTH were neurons. Microdialysis experiments indicated that only those lesioned animals that received the mixture of MD\u2013TH and MD\u2013GTPCHI vector displayed BH<jats:sub>4<\/jats:sub>independent<jats:italic>in vivo<\/jats:italic><jats:sc>l<\/jats:sc>-DOPA production (mean \u223c4\u20137 ng\/ml). Rats that received the hTH rAAV vector alone produced measurable<jats:sc>l<\/jats:sc>-DOPA (mean \u223c1\u20134 ng\/ml) only after receiving exogenous BH<jats:sub>4<\/jats:sub>.<jats:sc>l<\/jats:sc>-Aromatic amino acid decarboxylase blockade, but not 100 m<jats:sc>m<\/jats:sc>KCl-induced depolarization, enhanced<jats:sc>l<\/jats:sc>-DOPA overflow, and animals in the non-hTH groups (GTPCHI and alkaline phosphatase) yielded minimal<jats:sc>l<\/jats:sc>-DOPA. Although elevated<jats:sc>l<\/jats:sc>-DOPA was observed in animals that received mixed hTH and hGTPCHI rAAV vectors, there was no reduction of apomorphine-induced rotational behavior 3 weeks after intrastriatal vector injection. These data demonstrate that purified rAAV, a safe and nonpathogenic viral vector, mediates long-term striatal hTH transgene expression in neurons and can be used to successfully deliver<jats:sc>l<\/jats:sc>-DOPA to the striatum.<\/jats:p>","DOI":"10.1523\/jneurosci.18-11-04271.1998","type":"journal-article","created":{"date-parts":[[2018,4,3]],"date-time":"2018-04-03T13:35:34Z","timestamp":1522762534000},"page":"4271-4284","source":"Crossref","is-referenced-by-count":181,"title":["Characterization of Intrastriatal Recombinant Adeno-Associated Virus-Mediated Gene Transfer of Human Tyrosine Hydroxylase and Human GTP-Cyclohydrolase I in a Rat Model of Parkinson\u2019s Disease"],"prefix":"10.1523","volume":"18","author":[{"given":"R. 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