Persistent Expression of Dopamine-Synthesizing Enzymes 15 Years After Gene Transfer in a Primate Model of Parkinson's Disease
Persistent Expression of Dopamine-Synthesizing Enzymes 15 Years After Gene Transfer in a Primate Model of Parkinson's Disease
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DOI：
10.1089/humc.2017.010
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发表时间：
2017-06-01
影响因子：
--
通讯作者：
Muramatsu, Shin-ichi
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文献类型：
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作者：
Sehara, Yoshihide;Fujimoto, Ken-ichi;Muramatsu, Shin-ichi
通过基因治疗恢复壳核中多巴胺的产生是改善帕金森病（PD）运动症状的直接策略。在基于1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）毒性的灵长类PD模型中，我们先前证明了腺相关病毒（AAV）载体介导的三种多巴胺合成酶（酪氨酸羟化酶[TH]，芳香族L-氨基酸脱羧酶[AADC]和鸟苷三磷酸环化水解酶I [GCH]）的壳核基因递送的安全性和有效性，直至术后10个月。尽管这项研究中的四只猴子中有三只之前已经进行了尸检分析，但其中一只猴子在基因治疗后存活了15年，以评估长期影响。在这里，我们报告说，这只猴子表现出右侧肢体的行为恢复，保持不变的15年，在这个时候，安乐死是由于开始衰老。免疫组化显示，从这只猴子死后的大脑TH，AADC和GCH基因的持续表达在受损的壳核。转导神经元广泛分布，估计转导区域占据左后连合壳核的91%。在AAV载体注射的壳核中未观察到细胞毒性或路易体病理学的迹象。这项研究提供了证据的长期安全性和有效性的三重转导方法作为一种基因治疗PD。
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.