XIAP Gene Therapy in Huntington's Disease

亨廷顿病的 XIAP 基因治疗

基本信息

批准号：
8580861
负责人：
MICHAEL G KAPLITT
金额：
$ 6.83万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8580861
关键词：
Address Adult Age Reporting Animal Model Animals Apoptosis Apoptotic Behavior Binding Body Weight decreased Brain Brain region Caspase Cell Culture Techniques Cell Death Cell Death Process Cells Cessation of life Clinical Clinical Trials Cognitive Corpus striatum structure Data Dependovirus Development Disease Disease model Dopamine Dopamine Receptor Factor X Family Foundations Functional disorder Gene Delivery Gene Therapy Agent Gene Transduction Agent Gene Transfer Genes Goals Human Huntington Disease Huntington gene Hypothalamic dysfunction Hypothalamic structure Impaired cognition Infusion procedures Inherited Lead Life Link Longevity Mediating Mediator of activation protein Mitochondria Modeling Morbidity - disease rate Motor Movement Disorders Mus Mutation Neostriatum Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Parkinson Disease Pathogenesis Pathology Pathway interactions Patient Selection Patients Pharmaceutical Preparations Pilot Projects Preparation Prevention Principal Investigator Process Proteins Receptor Activation Receptor Signaling Reporting Rodent Signal Transduction Slice Source Symptoms System Therapeutic Time Transgenic Mice Transgenic Organisms Translating Translations adeno-associated viral vector base gene therapy gene therapy clinical trial genetic manipulation human BIRC4 protein human Huntingtin protein improved inhibitor-of-apoptosis protein member mitochondrial dysfunction mortality mouse model mutant nervous system disorder neurogenesis neuron loss neuropathology neuroprotection neuropsychiatry novel ototoxicity overexpression patient expectation polyglutamine protective effect public health relevance putamen response success therapy outcome

项目摘要

DESCRIPTION (provided by principal investigator): Huntington's disease (HD) is a autosomal dominant neurodegenerative disorder which is normally fatal and untreatable and results in a severe movement disorder, cognitive and neuropsychiatric abnormalities. HD is caused by a pathological expansion of polyglutamine repeats in the Huntingtin gene (mhtt), resulting in the eventual loss predominantly of striatal medium spiny neurons although dysfunction and/or degeneration of other brain regions can occur as well. While the mechanism of mhtt-induced neurodegeneration remains unknown, apoptosis (programmed cell death) has emerged as a potential mediator in a variety of prior studies. X-linked inhibitor of apoptosis (XIAP) is the most potent member of a family of apoptosis inhibitor proteins, which is known to bind to and block the function of effectors of apoptosis including caspases and mitochondrial cell death proteins Smac and Omi. We have long used the adeno-associated virus (AAV) vector as a gene transfer agent for neurodegenerative diseases and have recently reported the use of AAV in the first human trial of gene therapy for Parkinson's disease. Based upon this, we received a pilot application R21 NS055003 to examine the potential of AAV-XIAP gene therapy in the striatum as a novel therapy for HD. We have now demonstrated that intrastriatal AAV-XIAP can reverse motor dysfunction in both the N171-82Q and YAC128 transgenic mouse models of HD. The normally shortened lifespan of N171 mice were also significantly extended by 20% while statistically complete prevention of neurodegeneration was demonstrated in the normal lifespan YAC128 mice. While this pilot data along with cell culture studies strongly supports the potential of AAV-XIAP as a potential gene therapy agent, here we propose to address several important remaining questions which have significance for both understanding the pathogenesis of HD as well as specifically translating AAV-XIAP into a clinical gene therapy agent. Aim 1 will further address the breadth and mechanism of AAV-XIAP-mediated neuro protection. Since death was used as an endpoint for the pilot N171 study, histological analysis was not performed so we will determine the effect of AAV-XIAP on neuropathology in this line just prior to death. We will also use XIAP point mutants lacking certain specific functions to explore potential mechanisms of XIAP-mediated neuro protection in order to better define pathways which may be targeted for novel neuro protective therapeutics in HD. In both N171 and YAC128 models, motor function was improved to wild-type levels prior to the reported age at which neuro degeneration normally ensues. This suggests an improvement in neuronal dysfunction by XIAP distinct from neuro protective effects. Aim 2 will use both striatal slices and a novel transgenic HD mouse to determine the effect of XIAP on dopamine receptor signaling in HD striatal neurons. Finally, aim 3 will address certain remaining questions which would inform a potential human clinical trial of AAV-XIAP for HD. This study should help develop AAV-XIAP into a human therapeutic and provide novel information to develop drugs to reverse neuronal dysfunction and/or loss in HD.

描述（由主要研究者提供）：亨廷顿病 (HD) 是一种常染色体显性神经退行性疾病，通常是致命且无法治疗的，会导致严重的运动障碍、认知和神经精神异常。 HD 是由亨廷顿基因 (mhtt) 中聚谷氨酰胺重复序列的病理性扩张引起的，最终导致纹状体中型多棘神经元主要丧失，尽管其他脑区域的功能障碍和/或退化也可能发生。虽然 mhtt 诱导的神经退行性变的机制仍不清楚，但细胞凋亡（程序性细胞死亡）已成为各种先前研究中的潜在介质。 X 连锁凋亡抑制剂 (XIAP) 是凋亡抑制剂蛋白家族中最有效的成员，已知它可以结合并阻断凋亡效应子的功能，包括半胱天冬酶和线粒体细胞死亡蛋白 Smac 和 Omi。我们长期以来一直使用腺相关病毒（AAV）载体作为神经退行性疾病的基因转移剂，最近报道了 AAV 在帕金森病基因治疗的首次人体试验中的使用。基于此，我们收到了一项试点申请 R21 NS055003，以检查纹状体中 AAV-XIAP 基因疗法作为 HD 新型疗法的潜力。我们现在已经证明，纹状体内 AAV-XIAP 可以逆转 N171-82Q 和 YAC128 转基因 HD 小鼠模型的运动功能障碍。 N171 小鼠通常缩短的寿命也显着延长了 20%，而正常寿命的 YAC128 小鼠在统计学上完全预防了神经退行性变。虽然这些试点数据以及细胞培养研究有力地支持了 AAV-XIAP 作为潜在基因治疗剂的潜力，但在这里我们建议解决几个重要的剩余问题，这些问题对于理解 HD 的发病机制以及专门翻译 AAV- XIAP成为临床基因治疗剂。目标 1 将进一步解决 AAV-XIAP 介导的神经保护的广度和机制。由于死亡被用作 N171 试点研究的终点，因此没有进行组织学分析，因此我们将在死亡之前确定 AAV-XIAP 对这条线的神经病理学的影响。我们还将使用缺乏某些特定功能的 XIAP 点突变体来探索 XIAP 介导的神经保护的潜在机制，以便更好地定义可能针对 HD 的新型神经保护治疗的途径。在 N171 和 YAC128 模型中，运动功能在报告的神经退行性通常发生的年龄之前就已改善至野生型水平。这表明 XIAP 对神经元功能障碍的改善与神经保护作用不同。目标 2 将使用纹状体切片和新型转基因 HD 小鼠来确定 XIAP 对 HD 纹状体神经元中多巴胺受体信号传导的影响。最后，目标 3 将解决某些剩余问题，这些问题将为 AAV-XIAP 治疗 HD 的潜在人体临床试验提供信息。这项研究应有助于将 AAV-XIAP 开发为人类治疗药物，并为开发逆转神经元功能障碍和/或 HD 丧失的药物提供新信息。