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

描述（由申请人提供）：亨廷顿舞蹈病（HD）是一种遗传性常染色体显性中枢神经系统疾病。这种疾病由父母遗传给后代，遗传几率为50%。HD是一种多谷氨酰胺疾病。正常人的亨廷顿蛋白（Htt）基因中有7到34个CAG重复序列，该基因编码Htt蛋白中的谷氨酰胺氨基酸。在HD患者中，CAG重复序列扩增且不稳定，重复序列长度与疾病发病年龄呈负相关。超过40个谷氨酰胺的重复长度总是会导致HD，超过100个谷氨酰胺的重复长度通常会导致青少年发病。HD是一种以运动障碍、痴呆和精神障碍为特征的神经退行性疾病，通常发生在生命的第四或第五十年，病程为10至30年。3万名美国人患有HD，每年给美国社会造成25亿美元的损失，另外还有25万人面临遗传这种疾病的风险。目前还没有治愈或预防HD的方法。HD发病机制的理论包括兴奋毒性、不适当凋亡、线粒体功能障碍和转录失调。目前HD的治疗方法是使用目前上市的治疗方法对症状进行管理。人们对开发一种有效的HD治疗方法非常感兴趣。许多已发表的研究表明，大量化合物在临床前研究中有效，但很少有结果转化为对人体的功效。基于HD潜在致病机制的人类HD疗法在预防或阻止疾病进展方面有很大的希望。有迹象表明，在模型系统和人类中，酶处理或切割Htt是HD的先决条件。一个关键的机制干预点似乎是半胱天冬酶6在586氨基酸处切割Htt。研究表明，在HD小鼠模型系统中，通过改变caspase 6识别位点的氨基酸来阻止Htt586上caspase 6的切割可以阻止HD样神经发病机制的发展。因此，开发一种caspase 6酶活性抑制剂似乎是一个有利的治疗目标。然而，caspase 6处理许多其他重要的生物底物，因此这种抑制剂会预测显著的副作用。通过一种创新的方法，我们提出鉴定和开发在Htt586位点或附近结合的分子，以防止caspase 6特异性地在Htt586位点结合和切割。我们称这种化合物为底物结合抑制剂分子（SBIM）。由于caspase 6 Htt586切割位点周围的氨基酸序列与其他caspase 6底物位点不同，因此这种SBIM对Htt586具有特异性，对HD具有特异性。Htt586 SBIM的鉴定将验证SBIM策略，为II期研究的HD治疗方法的开发奠定基础，并为开发有效的HD治疗方法提供一条潜在的有前途的途径。公共卫生相关性：目前有3万美国人患有亨廷顿舞蹈病（HD），每年给美国社会造成的损失超过25亿美元。亨廷顿氏病（HD）是一种遗传性常染色体显性神经退行性疾病，由亨廷顿基因CAG重复增加引起。HD的症状以运动障碍、痴呆和精神障碍为特征，通常在生命的第三和第四个十年开始发展，病程为10至30年。目前还没有治愈或治疗HD的方法。我们正在鉴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.