Department of Molecular Imaging and Neuroscience, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Hum Gene Ther. 2009 May;20(5):511-8. doi: 10.1089/hum.2008.201.
We investigated the safety and neuroregenerative potential of an adeno-associated virus (AAV2) containing human glial cell line-derived neurotrophic factor (GDNF) in an MPTP primate model of Parkinson's disease. Dopaminergic function was evaluated by positron emission tomography with 6-[(18)F]fluoro-l-m-tyrosine (FMT) before and after AAV2-GDNF or phosphate-buffered saline infusion bilaterally into the putamen. FMT uptake was significantly increased bilaterally in the putamen of AAV2-GDNF but not phosphate-buffered saline-treated animals 6 months after infusion, indicating increased dopaminergic activity in the nigrostriatal pathways. AAV2-GDNF-treated animals also showed clinical improvement without adverse effects. These findings are consistent with our previous report in aged nonhuman primates that showed evidence of enhanced use of striatal dopamine and dopaminergic nigrostriatal innervation. Clinical improvement and evidence of functional recovery in the nigrostriatal pathway, and the absence of adverse effects, support the safety of this approach for the delivery of GDNF over a 6-month period.
我们研究了含有胶质细胞源性神经营养因子（GDNF）的腺相关病毒（AAV2）在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的帕金森病猴模型中的安全性和神经再生潜力。通过正电子发射断层扫描用 6-[(18)F]氟-L-多巴（FMT）在 AAV2-GDNF 或磷酸盐缓冲盐水双侧注入纹状体前后评估多巴胺能功能。在输注后 6 个月，AAV2-GDNF 但不是磷酸盐缓冲盐水处理的动物双侧纹状体中的 FMT 摄取显著增加，表明黑质纹状体通路中的多巴胺能活性增加。AAV2-GDNF 处理的动物也没有不良反应，表现出临床改善。这些发现与我们之前在老年非人灵长类动物中的报告一致，表明纹状体多巴胺的利用增强和多巴胺能黑质纹状体传入神经支配的证据。临床改善和黑质纹状体通路的功能恢复的证据，以及没有不良反应，支持这种方法在 6 个月内递送 GDNF 的安全性。
