Gene therapy for Parkinson's Disease

描述(申请人提供)：该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/哈佛医学院的一名讲师。这项提案中概述的工作将有助于进一步推动孙博士在导师的指导下过渡到衰老相关神经退行性疾病的基因治疗，并从一名研究助理转变为申请RO1级资金的独立学术研究员。盖勒博士是这项提案的导师，他是一名独立科学家，在神经生物学和基因疗法方面拥有丰富的出版经验。盖勒、戈尔茨坦、马赫、福尔摩斯、库克和柴罗尼等多位科学家和神经学家将担任孙中山的顾问。这些科学家将在他们的专业领域为她提供智力和技术方面的建议，并将在整个赠款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氏症基因疗法。帕金森病是一种神经退行性疾病，主要影响老化的大脑，帕金森病的症状主要是由于黑质纹状体神经元的退化。目前的治疗方法主要是恢复纹状体的多巴胺水平，最初是有效的。但这些治疗方法逐渐失去疗效，也不能改变疾病的发展。因此，改进的帕金森病治疗方法应该首先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。我们的实验室之前已经证明，纹状体细胞中酪氨酸羟化酶(TH)的表达支持帕金森病大鼠模型的长期生化和行为纠正。我最近发现，TH和芳香族氨基酸脱羧酶(AADC)的共同表达支持帕金森病大鼠模型的生化和行为纠正。许多研究表明，胶质细胞源性神经营养因子(GDNF)对帕金森病啮齿动物和灵长类动物的黑质神经元具有保护作用。我们现在建议通过两种互补的治疗策略来系统地开发一种改进的帕金森病基因治疗方法。基因转移是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的。第一个具体目标将通过研究支持多巴胺产生和释放的首选基因组合(TH、GTP环水解酶、AADC，一种囊泡性单胺转运体)来改善生化和行为纠正。第二个具体目标是将恢复纹状体多巴胺水平的首选基因组合与保护黑质纹状体神经元的GDNF结合起来。长期目标是开发人类治疗帕金森病的基因疗法。

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.