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（由首席研究者提供）：亨廷顿氏病（HD）是一种常染色体显性神经退行性疾病，通常是致命的且不可治疗的，导致严重的运动障碍，认知和神经精神异常。 HD是由亨廷顿蛋白基因（MHTT）中聚谷氨酰胺重复序列的病理扩张引起的，尽管其他大脑区域的功能障碍和/或退化也可能发生，但最终导致纹状体培养基神经元的最终损失。尽管MHTT诱导的神经变性的机制尚不清楚，但在各种先前的研究中，细胞凋亡（程序性细胞死亡）已成为潜在的介体。 X连锁的凋亡抑制剂（XIAP）是凋亡抑制剂蛋白家族中最有效的成员，该家族已知与包括caspase和线粒体细胞死亡蛋白SMAC和OMI结合并阻止凋亡效应子的功能。我们长期以来一直将与腺相关病毒（AAV）载体用作神经退行性疾病的基因转移剂，最近报告说在帕金森氏病基因治疗的首次人类试验中使用了AAV。基于此，我们收到了一个试点应用R21 NS055003，以检查AAV-XIAP基因疗法在纹状体中的潜力，作为HD的新疗法。现在，我们已经证明，在N171-82Q和YAC128 HD的N171-82Q和YAC128转基因小鼠模型中，纹状体内AAV-XIAP可以逆转运动功能障碍。 N171小鼠正常缩短的寿命也显着延伸了20％，而在正常的寿命YAC128小鼠中证明了神经变性的统计完整预防。尽管该试验数据以及细胞培养研究强烈支持AAV-XIAP作为潜在基因治疗剂的潜力，但我们在这里建议解决几个重要的剩余问题，这些问题对于了解HD的发病机理以及专门将AAV-XIAP的发病机理具有重要意义。 AIM 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研究的终点，因此未进行组织学分析，因此我们将在死亡前确定AAV-XIAP对这一线中神经病理学的影响。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，以更好地定义可能针对HD中新型神经保护性疗法的途径。在N171和YAC128模型中，运动功能在报告的年龄正常发生之前，将运动功能提高到野生型水平。这表明XIAP与神经保护作用不同。 AIM 2将使用纹状体切片和新型的转基因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，AIM 3将解决某些剩余的问题，这些问题将为AAV-XIAP对HD的潜在人类临床试验提供信息。这项研究应有助于将AAV-XIAP开发为人类的治疗性，并提供新的信息来开发药物以逆转HD的神经元功能障碍和/或损失。