Gene Therapy, Neural Grafts & Parkinson's Disease

基因治疗、神经移植

• 批准号: 6620635
• 负责人: David M. Yurek
• 金额: $ 24.07万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-15 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620635
• 关键词: Parkinson's disease; age difference; behavioral /social science research tag; cell sorting; cell transplantation; corpus striatum; dopamine; enzyme linked immunosorbent assay; functional ability; gene therapy; glia; immunocytochemistry; juvenile animal; laboratory rat; mature animal; nervous system disorder therapy; nervous system transplantation; neurons; neurotrophic factors; nonhuman therapy evaluation; statistics /biometry; stereotaxic techniques; substantia nigra; transfection /expression vector

Clinical trials have provided encouraging evidence that grafts of fetal dopamine neurons are an effective therapeutic approach toward counteracting the symptoms of Parkinson's disease. Modest therapeutic benefits are observed in grafted patients despite clinical and experimental evidence that survival of grafted cells is low and graft reinnervation is incomplete. The poor survival and limited fiber outgrowth may be a consequence of neural grafts placed ectopically into an environment where the grafted neurons do not receive the proper signals for successful growth and integration into the neural circuitry of the host brain. Gene therapy may be a viable technique to introduce factors [neurotrophic factors] into brain tissue that can potentiate the survival and functional outgrowth of neural grafts, and thus improve the therapeutic value of the graft. In the proposed studies, regulated viral vectors will be injected into the lesioned nigrostriatal pathway of rodents with experimental Parkinson's disease in order to induce transgene expression of several neurotrophic factors that have a history of providing potent neurotrophic support for dopamine neurons. Subsequently, neural grafts will be implanted into lesioned/transduced brain sites and the survival, reinnervation, and function of the grafts will be assessed. Because Parkinson's disease has a higher incidence in the elderly than in the younger population, and recent experimental evidence suggests that the expression of endogenous neurotrophic factors are diminished in the aged striatum following a neurodegenerative lesion, experiments will be performed in young, middle-age, or old rats with experimental Parkinson's disease and the results will be compared within and between each age group. The studies are designed to determine the optimal temporal expression of neurotrophic factors [GDNF, BDNF, FGF-2] that improve graft development and function using regulated viral neurotrophic factors [GDNF, BDNF, FGF-2] that improve graft development and function using regulated viral vectors in young and aged animals with experimental Parkinsonism. These studies will also determine if combinations of viral vectors expressing different neurotrophic factors can be used to improve the therapeutic effects of dopamine grafts.

临床试验提供了令人鼓舞的证据，表明胎儿多巴胺神经元移植是对抗帕金森病症状的有效治疗方法。尽管临床和实验证据表明移植细胞的存活率较低并且移植物神经支配不完全，但在移植患者中观察到了适度的治疗效果。存活率低和纤维生长有限可能是神经移植物异位放置到环境中的结果，在该环境中，移植的神经元无法接收到成功生长和整合到宿主大脑神经回路中的正确信号。基因治疗可能是一种将因子[神经营养因子]引入脑组织的可行技术，可以增强神经移植物的存活和功能生长，从而提高移植物的治疗价值。在拟议的研究中，受调控的病毒载体将被注射到患有实验性帕金森病的啮齿动物受损的黑质纹状体通路中，以诱导几种神经营养因子的转基因表达，这些因子具有为多巴胺神经元提供有效的神经营养支持的历史。随后，神经移植物将被植入受损/转导的大脑部位，并对移植物的存活、神经支配和功能进行评估。由于帕金森病在老年人中的发病率高于年轻人，并且最近的实验证据表明，神经退行性病变后老年纹状体中内源性神经营养因子的表达减少，因此实验将在年轻、中年、或患有实验性帕金森病的老年老鼠，并将结果在每个年龄组内和之间进行比较。这些研究旨在确定神经营养因子 [GDNF、BDNF、FGF-2] 的最佳时间表达，使用调节的病毒神经营养因子 [GDNF、BDNF、FGF-2] 改善移植物发育和功能，使用调节的病毒神经营养因子改善移植物发育和功能患有实验性帕金森症的年轻和老年动物的病毒载体。这些研究还将确定表达不同神经营养因子的病毒载体的组合是否可用于改善多巴胺移植物的治疗效果。