CEHCs as Therapeutics for 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三联体重复疾病，完全外显，表现为进行性运动和认知能力下降。HD影响男性和女性的人数相对相等，通常在生命的第三到第四个十年出现症状。这种疾病在世界各地的不同地理和种族人群中都会发生。HD的频率似乎在不同的人群中有所不同，估计每10万人中有4到10人患有HD。HD是一种进行性神经疾病，通常在神经或心理损害发生15-20年后导致死亡。 通过Encore制药公司和俄克拉荷马医学研究基金会(OMRF)科学家的合作，最近的发现表明，伽马-羧乙基羟色曼(伽马-CEHC)具有新的抗氧化、抗炎和神经保护活性，伽马-生育酚是一种天然代谢物。在肌萎缩侧索硬化症(ALS，或Lou Gehrig病)的小鼠模型中，Gamma-CEHC可以减缓疾病的进展，即使在疾病后期使用Gamma-CEHC也是如此。由于ALS和亨廷顿病(HD)具有共同的神经病理特征，我们已经开始研究伽玛-CEHC是否在HD的临床前模型中显示出保护作用。我们发现，全身给药的伽马-CEHC完全保护小鼠免受3NP诱导的慢性HD样神经损伤，这表明它对亨廷顿氏病有治疗潜力。 EncorePharma和OMRF在生育酚类似物领域建立了互补的专利保护，特别是在伽马-生育酚及其代谢物和衍生物领域的七项美国专利(及其外国对应专利)，包括伽马-CEHC的物质组成专利。最近，我们两个实体发展了战略关系，将科学和商业的敏锐结合在一起。通过这一合作关系，我们计划利用这种新型生育酚代谢物提供的商业潜力。显然，通过这一合作关系，我们希望利用我们最近的发现，通过进一步阐明伽马-CEHC的体内治疗作用，启动产品商业化努力。 在这项第一阶段申请中定义的研究的目标目标是在一个被接受的小鼠遗传模型中对伽马-CEHC减缓HD进展进行全面评估，该模型是表达突变的人类亨廷顿蛋白(Htt)的第一个外显子的R6/2小鼠，该突变人亨廷顿蛋白(Htt)包含致病的多谷氨酰胺扩展。我们具有独特的优势，可以在HD的临床前模型中进行伽马-CEHC的机制研究，并进行转化性研究，从而快速进行人类临床试验。在HD的小鼠遗传模型中成功证明伽马-CEHC的疗效，最终将导致在执行必要的临床前安全性研究后，提交用于治疗HD的伽马-CEHC的研究新药(IND)申请，随后启动具有孤儿药物名称的临床开发活动。尽管该药的临床前开发过程尚处于早期阶段，但几乎没有出现或预期会出现任何安全问题。对于一种几乎没有治疗选择的疾病，推进这一潜在治疗方法的必要性不可低估。

DESCRIPTION (provided by applicant): Huntington's Disease (HD) is a hereditary autosomal dominant triplet-repeat disease with complete penetrance, manifest by progressive motor and cognitive deterioration. HD affects males and females in relatively equal numbers, typically presenting with symptoms in the 3rd-4th decade of life. The disorder occurs in various geographic and ethnic populations worldwide. The frequency of HD appears to vary among different populations, ranging from an estimated 4 to 10 individuals per 100,000. HD is a progressive neurological disorder usually leading to death 15-20 years after onset of neurological or psychological impairment. Recent discoveries made through the collaborative work of scientists at Encore Pharmaceuticals, Inc. and the Oklahoma Medical Research Foundation (OMRF) have demonstrated novel antioxidant, anti-inflammatory and neuroprotective activities for gamma-carboxyethyl hydroxychroman (gamma-CEHC), a natural metabolite of gamma-tocopherol. gamma-CEHC slows disease progression in a mouse model of amyotrophic lateral sclerosis (ALS, or Lou Gehrig's Disease) even when gamma-CEHC is administered late in the disease. Because ALS and Huntington's Disease (HD) share common neuropathic features, we have begun to investigate whether gamma-CEHC might show protection in preclinical models of HD. We find that systemically administered gamma-CEHC completely protects mice against chronic 3NP-induced HD-like neurological damage, suggesting its therapeutic potential in Huntington's Disease. EncorePharma and the OMRF established complementary patent protection in the field of tocopherol analogs, specifically seven United States patents (and their foreign counterparts) in the area of gamma-tocopherol, its metabolites and derivatives, including composition of matter patents for gamma-CEHC. Recently our two entities have developed a strategic relationship in order to combine scientific and business acumen. Through this relationship we plan to capitalize on the commercial potential offered by the novel tocopherol metabolites. Expressly, through this partnership we wish to leverage our recent discoveries and initiate product commercialization efforts by further elucidating the in vivo therapeutic of gamma-CEHC. The targeted objectives of the research defined in this Phase I application are to conduct a complete evaluation of gamma-CEHC for the slowing of HD progression in an accepted mouse genetic model, the R6/2 mouse that expresses the first exon of mutant human huntingtin (Htt) containing a pathogenic polyglutamine expansion. We are uniquely positioned to perform mechanistic studies of gamma-CEHC in preclinical models of HD and to pursue translational research leading quickly to human clinical trials. Successful demonstration of gamma-CEHC efficacy in a mouse genetic model of HD will ultimately result in the filing of an investigational new drug (IND) application for gamma-CEHC for the treatment of HD, after performing the necessary preclinical safety studies, followed by initiation of clinical development activities with Orphan Drug Designation. Although early in the preclinical development process for this agent, few if any safety issues have been seen or are anticipated. The need to move this potential therapeutic forward for a disease that has very few treatment alternatives cannot be understated.