Preclinical Development of a Selective Suppressor of Neuroinflammation for MCI/AD

 描述(申请人提供)：阿尔茨海默病(AD)是我们今天面临的最大的全球公共卫生危机之一，预计在未来几十年内随着世界人口老龄化而急剧增加。目前还没有有效的治疗方法来预防、治愈或减缓疾病的发展，迫切需要新的治疗策略。我们的策略是针对AD进展早期出现的异常胶质细胞激活和神经炎症，这些正在成为治疗的靶点。失调的神经炎症反应，如由异常激活的胶质细胞过度产生促炎细胞因子，在AD早期被发现，并被认为是下游突触功能障碍和认知障碍的关键因素。这增加了选择性靶向失调的细胞因子反应可能是一种有用的治疗方法的可能性。这项申请寻求三年的支持，以使一种新的实验性治疗方法(称为MW151)处于IND状态，其药理作用机制是减轻疾病和损伤诱导的促炎细胞因子的过度生产，从而减少中枢神经系统疾病的多种动物模型的下游突触和认知功能障碍。MW151是一种水溶性、口服生物利用型、CNS渗透剂、具有优异的化学和代谢稳定性的小分子药物。通过几个非GLP药理和毒理学筛选，MW151已被广泛降低风险，并已开发出与GMP兼容的生产方案。然而，MW151还没有进入最终的GLP临床前开发阶段。我们的假设是，MW151将成为开发一种口服制剂的成功候选者，用于未来治疗因AD而导致的轻度认知障碍的个人。利用U01资金，我们将追求三个具有里程碑意义的目标，并制定明确的通过/不通过决策标准。目的1：进行MW151的临床前药代动力学和安全性评价。目的2：制备GMP原料药(原料药)及口服制剂。目的3：获得用于未来人类首例临床研究的IND。该项目将推动一种有希望的候选药物的开发，该候选药物有可能防止向AD的过渡或减缓其进展。此外，MW151的成功开发不仅对AD，而且对其他一些中枢神经系统疾病具有广泛的临床应用价值，在这些疾病中，促炎症细胞因子失调是病理生理进展机制的一部分。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is one of the largest global public health crises facing us today, and is predicted to increase dramatically over the next decades as the world population ages. There are no effective therapies available to prevent, cure, or slow the progression of disease, and new therapeutic strategies are urgently needed. Our strategy is to target the abnormal glial activation and neuroinflammation that arises early in AD progression and that is becoming of increased interest as a therapeutic target. Dysregulated neuroinflammation responses such as proinflammatory cytokine overproduction from abnormally activated glia are seen early in AD, and are thought to be a key contributor to downstream synaptic dysfunction and cognitive deficits. This raises the possibility that selective targeting of the dysregulated cytokine response may be a useful therapeutic approach. This application seeks three years of support to bring to IND status a novel experimental therapeutic (termed MW151) whose pharmacological mechanism of action is to attenuate disease- and injury-induced proinflammatory cytokine overproduction, thereby reducing downstream synaptic and cognitive dysfunction in multiple animal models of CNS disorders. MW151 is a water-soluble, orally bioavailable, CNS-penetrant, small molecule with outstanding chemical and metabolic stability. MW151 has been extensively de-risked through several non-GLP pharmacological and toxicology screens, and a GMP compatible production scheme has been developed. However, MW151 has not progressed into final GLP preclinical development. Our hypothesis is that MW151 will be a successful candidate for development as an oral formulation for the future treatment of individuals with mild cognitive impairment due to AD. With U01 funding, we will pursue three aims that are milestone-driven with clear Go/No Go decision criteria. Aim 1: Perform preclinical pharmacokinetics and safety assessment of MW151. Aim 2: Produce GMP drug substance (API) and oral drug product. Aim 3: Obtain an IND for future first-in-human clinical investigations. This project will advance development of a promising drug candidate with the potential to prevent the transition to or slow the progression of AD. In addition, successful development of MW151 could have broad clinical applications not only to AD but to a number of other CNS disorders where proinflammatory cytokine dysregulation is part of the pathophysiology progression mechanism.