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Hum Gene Ther Clin Dev. 2017 Jun;28(2):74-79. doi: 10.1089/humc.2017.010. Epub 2017 Mar 9.

Persistent Expression of Dopamine-Synthesizing Enzymes 15 Years After Gene Transfer in a Primate Model of Parkinson's Disease.

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1 Division of Genetic Therapeutics, Jichi Medical University , Yakushiji, Shimotsuke, Tochigi, Japan .
2 Jichi-idai Station Brain Clinic , Idaimae, Shimotsuke, Tochigi, Japan .
3 Corporation for Production and Research of Laboratory Primates , Sakura, Tsukuba, Ibaraki, Japan .
4 Faculty of Risk and Crisis Management, Chiba Institute of Science , Shiomi-cho, Choshi, Chiba, Japan .
5 Division of Neurology, Jichi Medical University , Yakushiji, Shimotsuke, Tochigi, Japan .
6 Center for Gene and Cell Therapy, The Institute of Medical Science, The University of Tokyo , Shirokanedai, Minatoku, Tokyo, Japan .


Restoring dopamine production in the putamen through gene therapy is a straightforward strategy for ameliorating motor symptoms for Parkinson's disease (PD). In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity-based primate model of PD, we previously showed the safety and efficacy of adeno-associated viral (AAV) vector-mediated gene delivery to the putamen of three dopamine-synthesizing enzymes (tyrosine hydroxylase [TH], aromatic l-amino acid decarboxylase [AADC], and guanosine triphosphate cyclohydrolase I [GCH]) up to 10 months postprocedure. Although three of four monkeys in this study have previously undergone postmortem analysis, one monkey was kept alive for 15 years after gene therapy to evaluate long-term effects. Here, we report that this monkey showed behavioral recovery in the right-side limb that remained unchanged for 15 years, at which time euthanasia was carried out owing to onset of senility. Immunohistochemistry of the postmortem brain from this monkey revealed persistent expression of TH, AADC, and GCH genes in the lesioned putamen. Transduced neurons were broadly distributed, with the estimated transduction region occupying 91% of the left postcommissural putamen. No signs of cytotoxicity or Lewy body pathology were observed in the AAV vector-injected putamen. This study provides evidence of long-term safety and efficacy of the triple-transduction method as a gene therapy for PD.


brain; disease models; neurologic

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