HDAC1 Activating Compounds as Therapeutics for Neurodegenerative Disorders

描述（由申请人提供）：本申请涉及广泛挑战领域（15）翻译科学和特定挑战主题：15- ns -103神经系统疾病新治疗方法的“概念验证”演示。阿尔茨海默病（AD）是一种不可逆转的神经系统疾病，它会逐渐削弱患者的认知能力，最终导致死亡。阿尔茨海默病是所有神经退行性疾病中最常见的，全世界估计有2500万患者。随着预期寿命的持续增长，阿尔茨海默病正变得越来越普遍，据估计，到2050年，患有阿尔茨海默病的人数将增加到1.14亿，如果不采取措施遏制这种疾病，每年的成本将超过7000亿美元。尽管有大量的研究，这种疾病的发病机制仍有待阐明，有效的治疗方法仍有待发现。最近的研究结果表明，治疗淀粉样蛋白积累可能不足以治疗阿尔茨海默病，并提出了科学和企业研究工作过于狭隘地集中在阿尔茨海默病的淀粉样蛋白方面的可能性。替代治疗策略可能最终被证明是关键。特别是，靶向在阿尔茨海默病中被破坏的细胞存活和维持的基本机制也可能导致其他神经退行性疾病的治愈，因为这些下游事件经常在多种年龄依赖性神经退行性疾病中被报道。重要的是，我们最近表明，HDAC1的失调可能在中枢神经系统病理中起关键作用，而中枢神经系统病理可能与中风/缺血和阿尔茨海默病有关。通过诱导p25/Cdk5神经变性小鼠模型，我们观察到组蛋白去乙酰化酶（HDAC1）的催化活性被p25/Cdk5抑制，HDAC1是表观遗传修饰的关键调节因子。神经元中HDAC1通过多种途径丧失功能，导致DNA损伤积累、细胞周期活性增加和神经元死亡。相反，HDAC1的过表达可以挽救p25诱导的DNA损伤和神经元死亡。这些结果表明HDAC1在维持DNA完整性和抑制成年神经元细胞周期中的作用。此外，在啮齿动物中风模型中，HDAC1的过表达对DNA损伤和神经变性有显著的拯救作用，证明了HDAC1功能获得的治疗潜力。由于p25积累、细胞周期再进入和DNA损伤似乎是多种神经退行性疾病的共同特征，预计HDAC1功能获得可能是治疗阿尔茨海默病、中风和其他疾病的有效策略。我们在此建议通过高通量筛选确定可以增加HDAC1去乙酰化酶活性的小分子，从而开发该策略的“概念验证”。初步结果表明这些努力的可行性和这种小分子探针预防神经毒性的能力。鉴于拟议的策略与之前正在开发或已被放弃的任何治疗策略都有很大不同，这些研究有很大的机会对人类健康产生重大影响。

DESCRIPTION (provided by applicant): This application addresses Broad Challenge Area (15) Translation Science and Specific Challenge Topic: 15-NS-103 Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease. Alzheimer's disease (AD) is an irreversible neurological disorder that progressively attenuates the cognitive abilities of those afflicted, ultimately leading to death. AD is the most common of all neurodegenerative disorders, with an estimated 25 million victims worldwide. As life expectancies continue to rise, AD is becoming increasingly common, and it is estimated that the number of those afflicted with AD will increase to 114 million by the year 2050, and cost over $700 billion a year if nothing is done to curb the disease. Despite intensive studies, the pathogenesis of this illness remains to be elucidated and effective therapies still await discovery. Recent findings suggest that treatment of amyloid accumulation may be insufficient for treating Alzheimer's disease, and raise the possibility that scientific and corporate research efforts have been too narrowly focused on the amyloid aspect of Alzheimer's disease. Alternative therapeutic strategies may ultimately prove to be key. In particular, targeting fundamental mechanisms of cell survival and maintenance that are disrupted in Alzheimer's disease may lead to cures of other neurodegenerative disease as well, as these downstream events are often reported in multiple age-dependent neurodegenerative disorders. Importantly, we have recently shown that deregulation of HDAC1 may be critically involved in CNS pathology that may be relevant to stroke/ischemia and Alzheimer's disease. Using an inducible p25/Cdk5 neurodegeneration mouse model, we have observed that the catalytic activity of the histone deacetylase (HDAC1), a key regulator of epigenetic modifications, was inhibited by p25/Cdk5. Loss-of-function of HDAC1 in neurons through multiple means resulted in the accumulation of DNA damage, cell cycle activity, and neuronal death. Conversely, overexpression of HDAC1 resulted in a rescue against p25-induced DNA damage and neuronal death. These results suggest a role for HDAC1 in the maintenance of DNA integrity and cell cycle suppression in adult neurons. Furthermore, overexpression of HDAC1 resulted in significant rescue against DNA damage and neurodegeneration in a rodent stroke model, demonstrating therapeutic potential for HDAC1 gain-of-function. As p25 accumulation, cell cycle reentry, and DNA damage appear to be features shared in multiple neurodegenerative conditions, it is anticipated that HDAC1 gain-of-function may be a valid therapeutic strategy against Alzheimer's disease, stroke, and other disorders. We propose here to develop a "proof-of-concept" of this strategy by identifying small molecules through a high-throughput screen that can increase the deacetylase activity of HDAC1. Preliminary results suggest the feasibility of these efforts and the ability of such small-molecule probes to prevent neurotoxicity. Given that the proposed strategy is significantly different from any of the previous therapeutic strategies that are undergoing development or have been abandoned, there is tremendous opportunity for these studies to have a high impact on human health. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to discover and characterize selective chemical activators of the HDAC1 that can be tested for the ability to prevent neurotoxicity. Findings from this application may offer novel therapeutic strategy against Alzheimer's disease, stroke, and other neurological disorders.