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.

胶质细胞源性神经营养因子（GDNF）直接脑内给药对缺血性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进展性梗死的局部区域内产生GDNF的机会。我们研究了单纯疱疹病毒（HSV）扩增子为基础的载体编码GDNF（HSVgdnf）是否会保护神经元免受缺血性损伤。在原代神经元培养HSVgdnf减少氧化？诱导的损伤。为了测试体内保护作用，在大脑中动脉（MCA）单侧闭塞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;用HSV gdnf预处理显著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HSV gdnf预处理的大鼠缺血性组织损失减少。同样，这些动物表现出较少的神经胶质细胞酸性蛋白（GFAP）和caspase-3的免疫染色。总之，我们的数据表明，HSV gdnf预处理提供了针对脑缺血的保护，并支持利用HSV扩增子将营养因子治疗性递送至CNS。