Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease
Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease
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DOI：
10.1126/science.290.5492.767
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发表时间：
2000-10-27
期刊：
影响因子：
56.9
通讯作者：
Aebischer, P
中科院分区：
文献类型：
--
作者：
Kordower, JH;Emborg, ME;Aebischer, P
在帕金森病 (PD) 的非人灵长类动物模型中，测试了神经胶质细胞源性神经营养因子 (Lenti-GDNF) 的慢病毒递送对退化黑质纹状体神经元的营养作用。我们将 lenti-GDNF 注射到未病变的老年恒河猴或年轻成年恒河猴的纹状体和黑质中，这些恒河猴提前 1 周接受 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 治疗。在所有动物中均观察到具有顺行和逆行运输的广泛 GDNF 表达。在老年猴子中，Lenti-GDNF 增强了多巴胺能功能。在 MPTP 治疗的猴子中，慢病毒 GDNF 逆转了功能缺陷并完全预防了黑质纹状体变性。此外，对完整恒河猴注射 Lenti-GDNF 后发现了长期基因表达（8 个月）。在 MPTP 治疗的猴子中，慢病毒 GDNF 治疗逆转了伸手任务中的运动缺陷。这些数据表明，使用慢病毒载体系统递送 GDNF 可以预防黑质纹状体变性并诱导 PD 灵长类动物模型再生，并且可能是 PD 患者的可行治疗策略。
Lentiviral delivery of glial cell Line-derived neurotrophic factor (Lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, Lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, Lenti-GDNF injections to intact rhesus monkeys revealed Long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. These data indicate that GDNF delivery using a Lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.