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RNAi Gene Silencing of alpha-Synuclein for Parkinson's Disease

RNAi 基因沉默 α-突触核蛋白治疗帕金森病

基本信息

批准号：
7369754
负责人：
Martha D Bohn
金额：
$ 16.08万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7369754
关键词：
Affect Alzheimer&apos s Disease Animal Model Basal Nucleus of Meynert Behavioral Brain Brain region Cell Death Cell Line Cells Cessation of life Chronic Clinic Clinical Clinical Trials Complex Cultured Cells Data Dementia Dependovirus Deterioration Development Disease Doctor of Philosophy Dopaminergic Cell Doxycycline Ectopic Expression Experimental Models Exposure to Gene Expression Gene Silencing Goals Histologic Histology Human In Vitro Individual Laboratories Lead Lentivirus Vector Lewy Bodies Lewy Body Disease Link Mitochondria Modeling Mus Nerve Degeneration Neurites Neurodegenerative Disorders Neurons Neurotoxins Parkinson Disease Parkinson&apos s Dementia Pathology Pesticides Pharmaceutical Preparations Point Mutation Process RNA Interference Range Rattus Research Personnel Role Rotenone SNCA gene Safety Structure Substantia nigra structure Syndrome Testing Toxic effect Triplet Multiple Birth Viral Vector adeno-associated viral vector alpha synuclein base behavior test cell growth design dopaminergic neuron dorsal motor nucleus gene therapy in vivo indexing inhibitor/antagonist locus ceruleus structure morphometry motor deficit multicatalytic endopeptidase complex mutant neurochemistry neuron loss neuroprotection nigrostriatal system nonhuman primate novel prevent programs promoter protein aggregate protein degradation small hairpin RNA synuclein therapeutic target vector viral RNA

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a debilitating neurodegenerative disease that affects over i million individuals in the US. Dementia with Lewy Bodies (DLB) is second in occurrence only to Alzheimer's disease. There are presently no treatments for PD or DLB that can halt or reverse the neurodegenerative processes. The RNA interference (RNAi) gene therapy approach in this project has the potential of halting or reversing these diseases. Recent studies suggest a role for a-synuclein (SNCA) in the development of PD and DLB, and other neurodegenerative diseases classified as a-synucleinopathies. Three point mutations in the SNCA gene, as well as triplet SNCA gene repeats, have been linked to familial forms of PD and DLB, revealing both mutant and wild type SNCA as therapeutic targets for these diseases. SNCA is a main components in neuronal inclusions called Lewy bodies, the neuropathological hallmarks of individuals afflicted with PD or DLB. In PD, Lewy bodies are found predominantly in the substantia nigra where the degenerating dopaminergic (DA) neurons reside. In DLB, Lewy bodies are found in many cortical and subcortical structures. Lewy neurites, neuronal processes containing insoluble SNCA protein, are found in both diseases. Insults that lead to death of DA neurons in animal models of PD, including exposure to the pesticide, rotenone, the neurotoxin, MPTP, and drugs that inhibit protein degradation increase SNCA expression and result in SNCA containing Lewy body-like inclusions in DA neurons. Moreover, experimentally increasing expression of human SNCA in a range of laboratory species leads to DA neuronal pathology and functional deterioration. We propose to explore the hypothesis that inhibiting expression of SNCA in DA neurons using a gene therapy approach will prevent DA neurodegeneration. Adeno-associated virus (AAV), the vector of choice for clinical trials will be used in rats in which human SNCA is ectopically expressed in DA neurons leading to DA cell death. The effects of silencing SNCA expression in this model, as well as in an SNCA-dependent cell culture model, will be assessed using morphometry, histology, neurochemistry and behavioral testing. Also, a vector with the silencing construct under control of an inducible promoter will be generated and tested as a possible safety strategy for a clinical gene therapy. The goal of this project is to generate proof-of-principle data supporting the development of clinical trials using a novel RNAi-based gene therapy for individuals afflicted with PD and DLB. ?

描述（由申请人提供）：帕金森病（PD）是一种使人衰弱的神经退行性疾病，在美国影响超过100万人。路易体痴呆症（DLB）是仅次于阿尔茨海默病的第二种发生率。目前没有可以停止或逆转神经退行性过程的PD或DLB治疗。该项目中的RNA干扰（RNAi）基因治疗方法具有阻止或逆转这些疾病的潜力。最近的研究表明α-突触核蛋白（SNCA）在PD和DLB以及其他归类为α-突触核蛋白病的神经退行性疾病的发展中的作用。SNCA基因中的三个点突变以及三联体SNCA基因重复与家族性PD和DLB相关，揭示了突变型和野生型SNCA作为这些疾病的治疗靶点。SNCA是称为路易体的神经元包涵体中的主要成分，路易体是患有PD或DLB的个体的神经病理学标志。在PD中，路易体主要存在于黑质中，其中退化的多巴胺能（DA）神经元驻留。在DLB中，Lewy小体见于许多皮质和皮质下结构。Lewy神经突，含有不溶性SNCA蛋白的神经元突起，在这两种疾病中均发现。导致PD动物模型中DA神经元死亡的损伤，包括暴露于杀虫剂、鱼藤酮、神经毒素、MPTP和抑制蛋白质降解的药物，增加了SNCA表达，并导致DA神经元中含有SNCA的Lewy小体样内含物。此外，在一系列实验室物种中实验性增加人SNCA的表达导致DA神经元病理和功能恶化。我们建议探讨的假设，抑制表达的SNCA在DA神经元使用基因治疗的方法将防止DA神经变性。腺相关病毒（AAV），临床试验的首选载体将用于大鼠，其中人SNCA在DA神经元中异位表达，导致DA细胞死亡。将使用形态测定法、组织学、神经化学和行为测试评估沉默SNCA表达在该模型以及SNCA依赖性细胞培养模型中的作用。此外，将产生具有在诱导型启动子控制下的沉默构建体的载体，并将其作为临床基因治疗的可能安全策略进行测试。该项目的目标是生成支持临床试验开发的原理验证数据，该临床试验使用一种新的基于RNAi的基因疗法治疗患有PD和DLB的个体。?