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。这种疾病是从父母传给后代的，遗传几率为50%。HD是一种多谷氨酰胺疾病。正常人的亨廷顿(Htt)基因有7到34个CAG重复序列，编码Htt蛋白中的谷氨酰胺氨基酸。HD患者CAG重复序列扩增且不稳定，重复序列长度与发病年龄呈负相关。重复长度大于40的谷氨酸总是会导致HD，重复长度大于100的谷氨酸通常会导致青少年发病。HD是一种神经退行性疾病，以运动障碍、痴呆症和精神障碍为特征，通常发生在生命的第四或第五个十年，病程为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25万人面临遗传疾病的风险。HD没有治愈或预防的方法。HD的发病机制包括兴奋性毒性、不适当的细胞凋亡、线粒体功能障碍和转录失调。目前HD的治疗方法是通过目前市场上销售的治疗方法来管理症状。开发一种有效的HD治疗方法引起了人们的极大兴趣。许多已发表的研究表明，在相当数量的化合物的临床前研究中是有效的，但很少有结果转化为对人类的疗效。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具有很大的前景。在模型系统中以及在人类中都有迹象表明，Htt的酶处理或切割是HD的先决条件。一个关键的机械干预点似乎是Htt被位于586位氨基酸的caspase6切割。研究表明，通过改变caspase 6识别位点的氨基酸来阻止caspase 6在Htt586处的切割，可以防止HD小鼠模型系统中HD样神经发病的发生。因此，开发一种caspase6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，因此这样的抑制剂将预测显著的副作用。通过一种创新的方法，我们建议识别和开发结合在Htt586或附近的分子，以防止caspase 6特异性地结合和切割Htt586位点。我们将这种化合物称为底物结合抑制分子(SBIM)。由于caspase 6Htt586裂解位点周围的氨基酸序列不同于其他caspase 6底物位点，这种SBIM可能是Htt586所特有的，也是HD所特有的。Htt586 SBIM的识别将验证SBIM战略，为第二阶段研究中HD治疗的开发奠定基础，并为开发有效的HD治疗提供一条潜在的有希望的途径。与公共卫生相关：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的损失超过25亿美元。亨廷顿病(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重复增加引起。HD症状以运动障碍、痴呆症和精神障碍为特征，通常在生命的第三和第四个十年开始发展，疾病持续时间为10至30年。目前还没有治愈或治疗HD的方法。我们正在确定一种底物结合抑制分子，这是开发HD治疗的一种创新方法。

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.