Gene therapy for Parkinson's Disease

描述（由申请人提供）：本提案的主要研究者Mei Sun博士是西罗克斯伯里VA医院/哈佛医学院的讲师。本建议书中概述的工作将有助于孙博士进一步向衰老相关神经退行性疾病的基因治疗过渡，并从研究助理转变为申请RO 1级资助的独立学术研究者。Geller博士是一位独立的科学家，在神经生物学和基因治疗方面拥有丰富的出版经验。一些科学家和神经学家，包括盖勒博士，戈尔茨坦，马赫，霍姆斯，库克和Shiromani将担任孙博士的顾问。这些科学家将在他们的专业领域为她提供知识和技术方面的建议，并将在整个资助期间监督孙博士的进展。在这个提议中，我们将研究一种改进的帕金森病基因治疗方法。 帕金森病（Parkinson's Disease，PD）是一种主要影响大脑老化的神经退行性疾病，其症状主要是由于黑质纹状体神经元的变性。目前的治疗围绕恢复纹状体多巴胺水平，最初是有效的。但这些治疗逐渐失去疗效，它们不会改变疾病的进展。因此，改善PD的治疗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。我们的实验室先前已经表明，纹状体细胞中酪氨酸羟化酶（TH）的表达支持长期的生化和行为矫正的大鼠模型的PD。我最近表明，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。胶质细胞源性神经营养因子（glial cell line-derived neurotrophic factor，GDNF）对PD大鼠黑质纹状体神经元有保护作用。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PD基因治疗。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基因（TH、GTP环化酶、AADC、囊泡单胺转运蛋白）的优选组合来改善生物化学和行为矫正。第二个具体目标将联合收割机的“首选组合基因恢复纹状体多巴胺水平与GDNF保护黑质纹状体神经元。长期目标是开发PD的人类基因治疗。

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.