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）：亨廷顿氏病（HD）是毁灭性的遗传神经退行性疾病，其特征在于严重的运动障碍，情绪和情绪障碍以及在过早死亡之前的认知能力下降。它是由编码亨廷汀（HTT）基因中的CAG重复扩展引起的，但是突变体HTT（MHTT）最终诱导选择性神经变性的机制仍然未知。来自多种HD模型有大量证据，这些模型会诱导凋亡细胞死亡过程和线粒体功能障碍。 XIAP是凋亡的有效抑制剂，因此代表了亨廷顿氏病神经保护的有吸引力的靶标。该提案的目的是使用AAV矢量方法来确定一种新型基因递送方法的潜在治疗效用，以将XIAP编码为亨廷顿氏病神经变性的主要部位传递给亨廷顿氏病NeoStriatum的主要部位。在亨廷顿氏病遗传小鼠模型中提出的实验是由（i）发现XIAP在体外对MHTT诱导的毒性具有神经保护作用的观察结果，（ii）这种作用潜在地介导了抑制作用是通过对SMAC/DIABLO或OMI的抑制作用而不是Caspase抑制（III）（III）（III）的（III）（III）（III）介导的（III）。纹状体内的广泛基因表达，（iv）试验实验表明，XIAP基因递送改善了亨廷顿氏病小鼠模型中的表型。具体而言，我们将研究AAV基因疗法将抗凋亡剂XIAP传递给纹状体神经元是否可以通过检查N171-82Q中的AAV-DXIAP在N171-82Q“ huntington eathy of Huntington nypery of Secons and y secons”模型中，改善亨廷顿氏病动物模型中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，而不是对HD小鼠中胱天蛋白酶的直接影响。我们将生成带有DXLAP的AAV矢量，并具有点突变，以使其与SMAC/DIABLO-OMI或caspase结合的能力或caspase，并检查其对HD小鼠模型中HD病理生物学的影响。这些研究的结果将为更大的研究提供基础，以确定HD发病机理的细胞损伤途径，并开发出一种有效的基因分娩方法来治疗亨廷顿氏病。