Neuroprotection via XIAP gene therapy in Huntington's disease

通过 XIAP 基因治疗对亨廷顿病进行神经保护

• 批准号: 7076473
• 负责人: MICHAEL G KAPLITT
• 金额: $ 22.68万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076473
• 关键词: apoptosis; birth; cysteine endopeptidases; gene therapy; genes; model; mutant; neural degeneration; neuroprotectants

DESCRIPTION (provided by applicant): Huntington's disease (HD) is devastating hereditary neurodegenerative disorder characterized by a severe movement disorder, mood and emotional disturbances, and cognitive decline before premature death. It is caused by a CAG repeat expansion in the gene encoding huntingtin (htt), but the mechanism whereby mutant htt (mhtt) ultimately induces selective neurodegeneration is still unknown. There is substantial evidence from multiple HD models that mhtt induces apoptotic cell death processes and mitochondrial dysfunction. XIAP is a potent inhibitor of apoptosis and thus represents an attractive target for neuroprotection in Huntington's disease. The goal of this proposal is to determine the potential therapeutic utility of a novel gene delivery approach, using an AAV-vector approach to deliver the gene encoding XIAP to the major site of neurodegeneration in Huntington's disease, the neostriatum. The proposed experiments in genetic mouse models of Huntington's disease arise from the observations that (i) we have found that XIAP has neuroprotective actions against mhtt- induced toxicity in vitro, (ii) that this effect is potentially mediated by inhibitory actions against Smac/DIABLO or Omi, rather than caspase inhibition, (iii) that our adeno-associated viral (AAV) vector delivery system results in widespread gene expression within the striatum, and (iv) pilot experiments suggest that XIAP gene delivery improves phenotype in a mouse model of Huntington's disease. Specifically, we will examine whether an AAV gene therapy approach to deliver the anti-apoptotic agent XIAP to striatal neurons improves outcome and reduces neurodegeneration in animal models of Huntington's disease, by examining AAV-dXIAP's effects in the N171-82Q "fragment" mouse model of Huntington's disease, and in a second "full length" HD model, YAC-128 HD mice. We will also elucidate whether XIAP'S neuroprotective anti-apoptotic actions are due to inhibition of Smac/DIABLO or Omi/HtrA2, rather than direct effects on caspases in HD mice. We will generate AAV vectors carrying dXlAP with point mutations either disabling its ability to bind to Smac/DIABLO-Omi, or caspases, and examine their effects on HD pathobiology in an HD mouse model. The outcomes of these studies will provide a substantial foundation for larger studies to determine cell damage pathways underlying HD pathogenesis, and to develop an effective gene-delivery approach for the treatment of Huntington's disease.

描述（由申请人提供）：亨廷顿病（HD）是一种毁灭性的遗传性神经退行性疾病，其特征是严重的运动障碍、情绪和情绪障碍以及过早死亡之前的认知能力下降。它是由编码亨廷顿蛋白 (htt) 的基因中的 CAG 重复扩增引起的，但突变 htt (mhtt) 最终诱导选择性神经变性的机制仍不清楚。多个 HD 模型的大量证据表明 mhtt 会诱导细胞凋亡过程和线粒体功能障碍。 XIAP 是一种有效的细胞凋亡抑制剂，因此是亨廷顿病神经保护的一个有吸引力的靶点。该提案的目标是确定一种新型基因递送方法的潜在治疗效用，即使用 AAV 载体方法将编码 XIAP 的基因递送至亨廷顿病神经变性的主要部位（新纹状体）。亨廷顿病遗传小鼠模型中的拟议实验源于以下观察：（i）我们发现 XIAP 对体外 mhtt 诱导的毒性具有神经保护作用，（ii）这种作用可能是通过对 Smac/DIABLO 或 Omi 的抑制作用介导的，而不是半胱天冬酶抑制，（iii）我们的腺相关病毒（AAV）载体传递系统导致 (iv) 初步实验表明，XIAP 基因传递可改善亨廷顿病小鼠模型的表型。具体来说，我们将通过检查 AAV-dXIAP 在亨廷顿病 N171-82Q“片段”小鼠模型和第二种“全长”HD 模型 YAC-128 HD 小鼠中的作用，来检查将抗凋亡剂 XIAP 递送至纹状体神经元的 AAV 基因治疗方法是否可以改善亨廷顿病动物模型的结果并减少神经变性。我们还将阐明 XIAP 的神经保护性抗凋亡作用是否是由于抑制 Smac/DIABLO 或 Omi/HtrA2，而不是直接作用于 HD 小鼠的半胱天冬酶。我们将生成携带 dXlAP 的 AAV 载体，该载体具有点突变，使其无法结合 Smac/DIABLO-Omi 或半胱天冬酶，并在 HD 小鼠模型中检查它们对 HD 病理学的影响。这些研究的结果将为更大规模的研究奠定坚实的基础，以确定 HD 发病机制的细胞损伤途径，并开发治疗亨廷顿病的有效基因传递方法。