Substrate Based Proteolytic Inhibitors for the Treatment of Huntington's Disease

描述（申请人提供）：亨廷顿病（HD）是一种遗传性常染色体显性遗传性中枢神经系统疾病。这种疾病从父母传给后代，有50%的机会遗传。HD是一种多聚谷氨酰胺疾病。正常个体在亨廷顿（Htt）基因中具有7至34个CAG重复，其编码Htt蛋白中的谷氨酰胺氨基酸。CAG重复序列在HD患者中扩增且不稳定，重复序列长度与疾病发作年龄呈负相关。重复长度大于40个谷氨酰胺总是导致HD，而重复长度大于100个谷氨酰胺通常导致幼年发病。HD是一种神经退行性疾病，其特征在于运动障碍、痴呆和精神障碍，通常在生命的第四或第五个十年中发展，疾病持续时间为10至30年。3万美国人患有HD，每年给美国社会造成25亿美元的损失，另有25万人面临遗传这种疾病的风险。没有治疗或预防HD的方法。HD发病机制的理论包括兴奋性毒性、不适当的凋亡、线粒体功能障碍和转录失调。目前HD的治疗是用目前市售的治疗剂管理症状。人们对开发HD的有效治疗方法非常感兴趣。许多已发表的研究表明，在大量化合物的临床前研究中有效，但很少有结果转化为对人类的疗效。基于HD的潜在致病机制的人类HD疗法在预防或阻止疾病进展方面具有很大的前景。在模型系统以及人类中有迹象表明，Htt的酶促加工或裂解是HD的先决条件。一个关键的机械干预点似乎是胱天蛋白酶6在氨基酸586处切割Htt。研究表明，通过改变胱天蛋白酶6识别位点的氨基酸来防止胱天蛋白酶6在Htt 586处裂解，可以防止HD小鼠模型系统中HD样神经发病机制的发展。因此，开发半胱天冬酶6酶活性抑制剂似乎是有利的治疗目标。然而，胱天蛋白酶6处理许多其他重要的生物底物，因此这种抑制剂将预测显着的副作用。通过一种创新的方法，我们建议识别和开发在Htt586或附近结合的分子，以防止caspase 6在Htt586位点特异性结合和切割。我们称这种化合物为底物结合抑制剂分子（SBIM）。因为胱天蛋白酶6的Htt586切割位点周围的氨基酸序列与其它胱天蛋白酶6底物位点不同，所以这样的SBIM将对Htt586具有特异性并且对HD具有特异性。Htt586 SBIM的鉴定将验证SBIM策略，为II期研究中的HD治疗剂的开发奠定基础，并为开发有效的HD治疗剂提供潜在的有希望的途径。公共卫生相关性：目前有3万美国人患有亨廷顿氏病（HD），每年给美国社会造成超过25亿美元的损失。亨廷顿病（Huntington's disease，HD）是一种遗传性常染色体显性遗传性神经退行性疾病，由亨廷顿基因CAG重复序列增加引起。HD症状以运动障碍、痴呆和精神障碍为特征，通常开始发展于生命的第三和第四个十年，疾病持续时间为10至30年。目前没有治愈或治疗HD的方法。我们正在确定一种底物结合抑制剂分子，这是开发HD治疗药物的一种创新方法。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is an inherited autosomal dominant disorder of the central nervous system. The disease is passed from parent to progeny with a 50 percent chance of inheritance. HD is a polyglutamine disorder. Normal individuals have 7 to 34 CAG repeats in the Huntingtin (Htt) gene which encode glutamine amino acids in the Htt protein. The CAG repeats are expanded and unstable in HD patients, with repeat lengths inversely correlating with age of disease onset. Repeat lengths greater than 40 glutamines invariably cause HD, and repeats of greater than 100 glutamines typically cause juvenile onset. HD is a neurodegenerative disease characterized by movement disorder, dementia, and psychiatric disturbance which typically develops in the fourth or fifth decade of life with a disease duration of 10 to 30 years. Thirty thousand Americans have HD at an annual cost to American society of $2.5 billion with another 250,000 individuals at risk to inherit the disease. There is no cure or preventative for HD. Theories of HD pathogenesis include excitotoxicity, inappropriate apoptosis, mitochondrial dysfunction, and transcriptional dysregulation. Present treatment of HD is management of symptoms with currently marketed therapeutics. There is great interest in the development of an effective therapeutic for HD. Numerous published investigations have shown effectiveness in preclinical studies of a significant number of compounds but few if any results have translated to efficacy in humans. Human HD therapeutics based on the underlying pathogenic mechanisms of HD have great promise in preventing or stopping progression of the disease. There are indications in model systems as well as in humans that enzymatic processing or cleavage of Htt is a prerequisite for HD. One key mechanistic intervention point appears to be the cleavage of Htt by caspase 6 at amino acid 586. Studies have shown that preventing caspase 6 cleavage at Htt586 by changing the amino acids of the caspase 6 recognition site prevents development of the HD like neuropathogenesis in a HD mouse model system. Therefore, development of a caspase 6 enzymatic activity inhibitor would seem to be a advantageous therapeutic goal. However, caspase 6 processes many other important biological substrates and therefore such an inhibitor would predict significant side effects. With an innovative approach, we propose to identify and develop molecules that bind at or near Htt586 to prevent caspase 6 from binding and cleaving specifically at the Htt586 site. We call such a compound a substrate binding inhibitor molecule (SBIM). Because the amino acid sequence around the caspase 6 Htt586 cleavage site is different from other caspase 6 substrate sites, such a SBIM would be specific to the Htt586 and specific to HD. The identification of a Htt586 SBIM will validate the SBIM strategy, set the stage for development of an HD therapeutic in Phase II research and provide a potentially promising route to the development of an effective HD therapeutic. PUBLIC HEALTH RELEVANCE: Thirty thousand Americans currently have Huntington's disease (HD) at a cost to American society of over $2.5 billion per year. Huntington's disease (HD) is an inherited autosomal dominant neurodegenerate disorder that is caused by increased repeats of CAG in the Huntingtin gene. HD symptoms, characterized by movement disorder, dementia, and psychiatric disturbance, typically begin developing in the third and fourth decade of life, with a disease duration of 10 to 30 years. Currently there is no cure or treatment for HD. We are identifying a substrate binding inhibitor molecule, an innovative approach to the development of a HD therapeutic.