XIAP Gene Therapy in Huntington's Disease

亨廷顿病的 XIAP 基因治疗

• 批准号: 8022829
• 负责人: MICHAEL G KAPLITT
• 金额: $ 36.23万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8022829
• 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

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. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is a lethal and untreatable inherited neurological disorder caused by a mutation in the Huntington (htt) gene. Here we propose to use gene therapy to introduce a powerful cell protective gene called XIAP into brain of mouse HD models. The results of this application should lead to a better understanding of the currently unknown mechanism of cell death and dysfunction in the brains of HD could lead to novel therapies to reverse this process. Given our promising preliminary data and recent use of gene therapy in human Parkinson's disease, this application may also facilitate development of XIAP gene therapy for human HD.

描述(由首席研究人员提供)：亨廷顿病(HD)是一种常染色体显性遗传性神经退行性疾病，通常是致命的，无法治疗，会导致严重的运动障碍、认知和神经精神异常。HD是由Huntingtin基因(MHTT)中多谷氨酰胺重复序列(MHTT)的病理性扩张引起的，最终导致主要是纹状体中棘神经元的丧失，但也可以发生其他大脑区域的功能障碍和/或退化。虽然mHTT诱导神经退行性变的机制尚不清楚，但在先前的各种研究中，细胞凋亡(程序性细胞死亡)已成为一种潜在的媒介。X连锁凋亡抑制蛋白(XIAP)是凋亡抑制蛋白家族中最有效的成员，它可以结合和阻断caspase和线粒体细胞死亡蛋白Smac和Omi等凋亡效应蛋白的功能。长期以来，我们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第一次人体试验中的使用。基于此，我们获得了R21 NS055003的试验性应用，以检验纹状体AAV-XIAP基因治疗作为HD的一种新疗法的潜力。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小鼠正常缩短的寿命也显著延长了20%，而正常寿命的YAC128小鼠在统计上完全防止了神经退行性变。虽然这些先导数据和细胞培养研究有力地支持了AAV-XIAP作为一种潜在的基因治疗药物的潜力，但在这里，我们建议解决几个重要的遗留问题，这些问题对于理解HD的发病机制以及将AAV-XIAP具体转化为临床基因治疗药物具有重要意义。目标1将进一步阐述AAV-XIAP介导的神经保护的广度和机制。由于死亡被作为先导性N171研究的终点，没有进行组织学分析，所以我们将在死亡前确定AAV-XIAP对这一系列神经病理学的影响。我们还将利用缺乏某些特定功能的XIAP点突变来探索XIAP介导的神经保护的潜在机制，以便更好地确定可能成为HD新的神经保护治疗靶点的途径。在N171和YAC128模型中，运动功能在报告的神经退行性变正常接踵而至的年龄之前被改善到野生型水平。这表明XIAP改善了神经元功能障碍，而不是神经保护作用。目的2将利用纹状体切片和一种新型的转基因HD小鼠来确定XIAP对HD纹状体神经元多巴胺受体信号的影响。最后，目标3将解决某些剩余的问题，这些问题将为AAV-XIAP治疗HD的潜在人体临床试验提供信息。这项研究将有助于将AAV-XIAP发展成为一种人类治疗方法，并为开发逆转HD神经元功能障碍和/或丢失的药物提供新的信息。 公共卫生意义：亨廷顿病(HD)是一种致命的、无法治愈的遗传性神经疾病，由亨廷顿(HTT)基因突变引起。在这里，我们建议使用基因疗法将一种名为XIAP的强大细胞保护性基因导入到小鼠HD模型的脑中。这一应用的结果应该会使人们更好地理解目前尚不清楚的HD大脑细胞死亡和功能障碍的机制，可能会导致逆转这一过程的新疗法。考虑到我们有希望的初步数据和最近在人类帕金森病基因治疗中的应用，这一应用也可能促进XIAP基因治疗人类HD的发展。