Delivery of neurturin by AAV2 (CERE-120)-mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP-treated monkeys
Delivery of neurturin by AAV2 (CERE-120)-mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP-treated monkeys
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DOI：
10.1002/ana.21032
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发表时间：
2006-12-01
影响因子：
11.2
通讯作者：
Bartus, Raymond T.
中科院分区：
文献类型：
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作者：
Kordower, Jeffrey H.;Herzog, Christopher D.;Bartus, Raymond T.
目的：我们验证了营养因子neurturin的基因传递可以保护偏侧帕金森病猴的运动功能和黑质纹状体回路的假设。（AAV2-NTN;也称为CERE-120）在单侧颈动脉内注射N-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）使他们出现偏侧帕金森病。对照偏侧帕金森病猴接受编码绿色荧光蛋白的AAV 2或制剂buffer.Results：虽然在所有对照猴中观察到稳定的缺陷，但AAV 2-NTN从大约4个月开始显著改善MPTP诱导的运动障碍80 - 90%，并持续到实验结束（10个月）。AAV 2-NTN显著地保存了黑质神经元，显著地保存了纹状体多巴胺能神经支配，并且激活了磷酸细胞外信号调节激酶，这与涉及营养因子启动的分子级联的机制一致。许多脑区，包括小脑的组织学分析，显示正常的细胞结构和没有异常pathology.Interpretation：这些数据表明，AAV 2-NTN（CERE-120）可以保存功能和解剖学在退化的黑质纹状体神经元和帕金森氏病患者正在进行的临床试验的支持。
Objective: We tested the hypothesis that gene delivery of the trophic factor neurturin could preserve motor function and protect nigrostriatal circuitry in hemiparkinsonian monkeys.Methods: An adeno-associated virus-based vector encoding human neurturin (AAV2-NTN; also called CERE-120) was injected into the striatum and substantia nigra of monkeys 4 days after a unilateral intracarotid injection of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) tendered them hemiparkinsonian. Control hemiparkinsonian monkeys received either AAV2 encoding green fluorescent protein or formulation buffer.Results: Although stable deficits were seen in all control monkeys, AAV2-NTN significantly improved MPTP-induced motor impairments by 80 to 90% starting at approximately month 4 and lasting until the end of the experiment (month 10). AAV2-NTN significantly preserved nigral neurons, significantly preserved striatal dopaminergic innervation, and activated phospho-extracellular signal-regulated kinase, consistent with a mechanism involving a trophic factor-initiated molecular cascade. Histological analyses of numerous brain regions, including the cerebellum, showed normal cytoarchitecture and no aberrant pathology.Interpretation: These data demonstrate that AAV2-NTN (CERE-120) can preserve function and anatomy in degenerating nigrostriatal neurons and are supportive of ongoing clinical tests in Parkinson's disease patients.