Bioactivity of AAV2-Neurturin Gene Therapy (CERE-120): Differences Between Parkinson's Disease and Nonhuman Primate Brains
Bioactivity of AAV2-Neurturin Gene Therapy (CERE-120): Differences Between Parkinson's Disease and Nonhuman Primate Brains
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DOI：
10.1002/mds.23442
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发表时间：
2011-01-01
影响因子：
8.6
通讯作者：
Kordower, Jeffrey H.
中科院分区：
文献类型：
--
作者：
Bartus, Raymond T.;Herzog, Christopher D.;Kordower, Jeffrey H.
背景：AAV2-neurturin (CERE-120) 旨在将神经营养因子 neurturin 递送至纹状体，以恢复和保护帕金森病 (PD) 中退化的黑质纹状体神经元。一个常见的假设是，神经营养因子如 neurturin (NRTN) 在纹状体中表达后，将从退化末梢转运至黑质致密部 (SNc) 的细胞体。方法：我们使用免疫组织化学测试了这一概念，比较了 PD 患者大脑中 AAV2-neurturin 的生物活性与接受类似治疗的非人灵长类动物大脑中的生物活性。结果：靶标中的 NRTN 免疫染色在所有 PD 病例中均可见纹状体（平均壳核覆盖率：按体积计约为 15%）；在幼猴、老年猴和帕金森病猴中观察到了类似的表达。然而，在 SNc 细胞体中，在 PD 中仅观察到罕见的神经营养因子证据，而在所有猴子中观察到大量强烈的黑质-NRTN 证据。 NRTN 表达与 PD 纹状体中偶尔、稀疏的 TH 诱导相关，但 SNc 中没有明显的表达。在灵长类动物中，NRTN 在整个黑质纹状体神经元中产生了强大的 TH 诱导。讨论：这些数据提供了第一个证据，表明基因治疗可以增加 PD 大脑深处神经营养因子的表达，并且可以诱导退化神经元的明显但适度的增强。他们还提供了有关晚期 PD 黑质纹状体神经元状态缺陷的重要见解，表明严重的轴突运输缺陷通过限制暴露于细胞体的蛋白质来降低 AAV2-NRTN 的生物活性。因此，未来使用神经营养因子治疗神经退行性疾病的努力将需要针对退化神经元的终末场和细胞体，以确保实现最大益处。 (C) 2010 运动障碍学会
Background: AAV2-neurturin (CERE-120) is designed to deliver the neurotrophic-factor, neurturin, to the striatum to restore and protect degenerating nigrostriatal neurons in Parkinson's disease (PD). A common hypothesis is that following expression in the striatum, neurotrophic-factors like neurturin (NRTN) will be transported from degenerating terminals to their cell bodies in the substantia nigra pars compacta (SNc).Methods: We tested this concept using immunohistochemistry, comparing the bioactivity of AAV2-neurturin in brains of PD patients versus those of nonhuman primates similarly treated.Results: NRTN-immunostaining in the targeted striatum was seen in all PD cases (mean putaminal coverage: similar to 15% by volume); comparable expression was observed in young, aged, and parkinsonian monkeys. In the SNc cell bodies, however, only rare evidence of neurturin was seen in PD, while ample evidence of intense nigral-NRTN was observed in all monkeys. NRTN-expression was associated with occasional, sparse TH-induction in the striatum of PD, but nothing apparent in the SNc. In primates, NRTN produced robust TH-induction throughout the nigrostriatal neurons.Discussion: These data provide the first evidence that gene therapy can increase expression of a neurotrophic-factor deep in the PD brain and that clear but modest enhancement of degenerating neurons can be induced. They also provide important insight regarding deficiencies in the status of nigrostriatal neurons in advanced PD, suggesting that serious axon-transport deficits reduced the bioactivity of AAV2-NRTN by limiting the protein exposed to the cell body. Thus, future efforts using neurotrophic-factors to treat neurodegenerative diseases will need to target both the terminal fields and the cell bodies of degenerating neurons to assure maximal benefit is achieved. (C) 2010 Movement Disorder Society