Gene Therapy And Neuroprotection

基因治疗和神经保护

• 批准号: 6830662
• 负责人: Yun Wang
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6830662
• 关键词: Alphaherpesvirinae; abnormal involuntary movement; artery occlusion; cerebral artery; cerebral ischemia /hypoxia; cysteine endopeptidases; enzyme activity; gene expression; gene therapy; glial fibrillary acidic protein; laboratory rat; neuroprotectants; neurotrophic factors; nonhuman therapy evaluation; psychomotor disorders; stroke; stroke therapy; transfection /expression vector

Direct intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) is neuroprotective against ischemia-induced cerebral injury. Utilizing viral vectors to deliver and express therapeutic genes presents an opportunity to produce GDNF within localized regions of an evolving infarct. We investigated whether a Herpes simplex virus (HSV) amplicon-based vector encoding GDNF (HSVgdnf) would protect neurons against ischemic injury. In primary neuronal cultures HSVgdnf reduced oxidant?induced injury compared to the control vector HSVlac. To test protective effects in vivo, HSVgdnf or HSVlac was injected into the cerebral cortex prior to or subsequent to a 60 minute unilateral occlusion of the middle cerebral artery (MCA). Control stroke animals developed bradykinesia and motor asymmetry; pretreatment with HSVgdnf significantly reduced such motor deficits. Animals receiving HSVlac or HSVgdnf after the ischemic insult did not exhibit any behavioral improvement. Histological analyses performed one month after stroke revealed a reduction in ischemic tissue loss in rats pretreated with HSVgdnf. Similarly, these animals exhibited less immunostaining for glial fibrillary acidic protein (GFAP) and caspase-3. Taken together, our data indicate that HSVgdnf pretreatment provides protection against cerebral ischemia and supports the utilization of the HSV amplicon for therapeutic delivery of trophic factors to the CNS.

直接脑内给予神经胶质细胞源性神经营养因子（GDNF）可对缺血引起的脑损伤具有神经保护作用。利用病毒载体传递和表达治疗基因提供了在不断发展的梗塞局部区域内产生 GDNF 的机会。我们研究了编码 GDNF (HSVgdnf) 的基于单纯疱疹病毒 (HSV) 扩增子的载体是否可以保护神经元免受缺血性损伤。在原代神经元培养物中，与对照载体HSVlac相比，HSVgdnf减少了氧化剂诱导的损伤。为了测试体内保护作用，在单侧大脑中动脉（MCA）闭塞 60 分钟之前或之后将 HSVgdnf 或 HSVlac 注射到大脑皮层中。对照中风动物出现运动迟缓和运动不对称； HSVgdnf 预处理显着减少了这种运动缺陷。在缺血性损伤后接受HSVlac或HSVgdnf的动物没有表现出任何行为改善。中风后一个月进行的组织学分析显示，用 HSVgdnf 预处理的大鼠缺血性组织损失减少。同样，这些动物的神经胶质原纤维酸性蛋白 (GFAP) 和 caspase-3 的免疫染色也较少。总而言之，我们的数据表明 HSVgdnf 预处理可提供针对脑缺血的保护，并支持利用 HSV 扩增子将营养因子治疗性递送至 CNS。