Gene therapy for Parkinson's Disease

帕金森病的基因治疗

• 批准号: 6785860
• 负责人: MEI SUN
• 金额: $ 11.84万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6785860
• 关键词: Parkinson' s disease; aminohydrolases; aromatic L aminoacid decarboxylase; behavior test; biological transport; biotechnology; catecholamines; cell line; corpus striatum; dopamine; gene expression; gene therapy; glycoproteins; guanosine triphosphate; histology; laboratory rat; nervous system disorder therapy; neuroprotectants; neurotransmitter biosynthesis; neurotrophic factors; nonhuman therapy evaluation; postdoctoral investigator; substantia nigra; technology /technique development; transfection /expression vector; tyrosine 3 monooxygenase

DESCRIPTION (provided by applicant): The principal investigator for this proposal, Dr. Mei Sun, is an Instructor at the West Roxbury VA Hospital / Harvard Medical School. The work outlined in this proposal will serve to further the mentored transition of Dr. Sun into gene therapy of aging related neurodegenerative diseases, and from a research associate to an independent academic investigator applying for RO1 level funding. The mentor in this proposal, Dr. Geller is an independent scientist with extensive published experience on neurobiology and gene therapy. A number of scientists and neurologists including Drs. Geller, Goldstein, Maher, Holmes, Cook, and Shiromani will serve as Dr. Sun's advisors. These scientists will provide her both intellectual and technical advice in their fields of expertise, and will oversee Dr. Sun's progress throughout the grant period. In this proposal, we will investigate an improved gene therapy for Parkinson's Disease. Parkinson's Disease (PD) is a neurodegenerative disorder that primarily affects the aging brain, and the symptoms of PD are principally due to degeneration of nigrostriatal neurons. Current treatments center around restoring striatal dopamine levels and are effective initially. But these treatments gradually lose efficacy, and they do not alter the progression of the Disease. Thus, improved treatments for PD should first, restore the function of the nigrostriatal system, and second, alter progression of the Disease by protecting the remaining nigrostriatal neurons. Our laboratory has previously shown that expression of tyrosine hydroxylase (TH) in striatal cells supports long-term biochemical and behavioral correction of a rat model of PD. I have recently shown that co-expression of TH and aromatic amino acid decarboxylase (AADC) supports both biochemical and behavioral correction of the rat model of PD. Many investigators have shown that glial cell line-derived neurotrophic factor (GDNF) can protect nigrostrital neurons in rodent and primate medols of PD. We now propose to systematically develop an improved gene therapy for PD by two complementary treatment strategies. Gene transfer is performed using a helper virus-free Herpes Simplex Virus vector system pioneered in this Laboratory. The first specific aim will improve biochemical and behavioral correction by investigating the preferred combination of genes (TH, GTP cyclohyrolase, AADC, a vesicular monoamine transporter) to support production and release of dopamine. The second specific aim will combine the 'preferred combination of genes to restore striatal dopamine levels with GDNF to protect nigrostriatal neurons. The long-term goal is to develop human gene therapy for PD.

描述（由申请人提供）：本提案的首席研究员孙梅博士是西罗克斯伯里退伍军人医院/哈佛医学院的讲师。该提案中概述的工作将有助于进一步在指导下将孙博士转变为衰老相关神经退行性疾病的基因治疗领域，并从研究员转变为申请 RO1 级资助的独立学术研究员。该提案的导师盖勒博士是一位独立科学家，在神经生物学和基因治疗方面拥有丰富的发表经验。许多科学家和神经学家，包括博士。盖勒、戈尔茨坦、马赫、霍姆斯、库克和希罗马尼将担任孙博士的顾问。这些科学家将在其专业领域为她提供知识和技术建议，并将在整个资助期间监督孙博士的进展。在这项提案中，我们将研究一种改进的帕金森病基因疗法。 帕金森病（PD）是一种神经退行性疾病，主要影响衰老的大脑，PD的症状主要是由于黑质纹状体神经元的变性所致。目前的治疗主要围绕恢复纹状体多巴胺水平，并且最初是有效的。但这些治疗逐渐失效，并且不能改变疾病的进展。因此，改进的帕金森病治疗方法首先应恢复黑质纹状体系统的功能，其次通过保护剩余的黑质纹状体神经元来改变疾病的进展。我们的实验室此前已表明，纹状体细胞中酪氨酸羟化酶 (TH) 的表达支持 PD 大鼠模型的长期生化和行为矫正。我最近发现 TH 和芳香族氨基酸脱羧酶 (AADC) 的共表达支持 PD 大鼠模型的生化和行为矫正。许多研究人员表明，胶质细胞源性神经营养因子（GDNF）可以保护啮齿类和灵长类帕金森病的黑质纹状体神经元。我们现在建议通过两种互补的治疗策略系统地开发一种改进的帕金森病基因疗法。使用本实验室首创的无辅助病毒的单纯疱疹病毒载体系统进行基因转移。第一个具体目标是通过研究支持多巴胺产生和释放的基因（TH、GTP 环化酶、AADC、囊泡单胺转运蛋白）的首选组合来改善生化和行为矫正。第二个具体目标是将恢复纹状体多巴胺水平的基因首选组合与 GDNF 结合起来，以保护黑质纹状体神经元。长期目标是开发针对帕金森病的人类基因疗法。