Allopregnanolone a Regenerative Therapy for Alzheimer's: FDA-Required Toxicolog

描述（由申请人提供）：预防、延迟和治疗阿尔茨海默病（AD）的治疗方法仍有待实现。目前，超过500万美国人被诊断患有阿尔茨海默病，如果治疗方法不取得进展，预计这一数字将在20年内增加到1100万至1600万。本文提出了一种再生医学、系统生物学方法，该方法针对大脑的再生系统，同时激活系统以减少AD病理。异孕酮（Allo）是一种多用途再生治疗药物，在临床前AD模型和野生型老年小鼠中都能促进神经发生和恢复认知功能，并减少临床前AD模型的病理。此外，Allo促进人类神经干细胞再生。Allo是一种低分子量的脑内源性神经类固醇，具有血脑屏障渗透性，在动物和人类中已有丰富的安全性数据。其神经干细胞增殖和认知功能恢复的机制已被很好地描述，并与已描述的脑神经发生机制一致。Allo通过完善的上游胆固醇清除途径减少AD病理，以防止β的产生，同时也减少炎症和增加髓磷脂的产生。本文建议进行一项转化性ind毒理学和安全性分析，以推进神经类固醇异孕酮（Allo）治疗阿尔茨海默病（AD）或早期AD所致MCI患者的2期临床试验。FDA IND #113,772批准进行1期临床试验，需要进行额外的慢性暴露安全性分析，以推进2期临床试验。该U01申请中提出的目标专门针对FDA指导以及专注于监管文件和ii期试验设计的目标。每个具体目标都是里程碑式的，带有明确的Go / no-Go决策标准。目标一和目标二将在两个物种中进行。Specific Aim I旨在进行一项为期9个月的慢性毒理学研究，以确定肌肉注射异孕酮的毒性动力学和安全性。Specific Aim II旨在进行为期6个月的慢性毒理学研究，以确定肌肉注射异孕酮的毒性动力学和安全性。特异性Aim III旨在测定老年AD小鼠模型暴露于每周一次异孕酮后脑微出血的风险。Specific Aim IV旨在进行监管评估，生成提交给FDA的文件，并生成2期临床试验设计和计划。一个具有Allo系统生物学、转化研究和阿尔茨海默病治疗临床试验专业知识的多学科研究小组致力于该项目。这些分析的结果将支持和推进Allo在阿尔茨海默病和早期阿尔茨海默病导致的轻度认知损伤患者的2期临床试验的治疗发展。

DESCRIPTION (provided by applicant): Therapeutics to prevent, delay and treat Alzheimer's disease (AD) remains to be achieved. Currently, over 5 million Americans are diagnosed with AD and the number is projected to increase to 11-16 million within two decades unless therapeutic advances are made. Proposed herein is a regenerative medicine, systems biology approach that targets the regenerative system of the brain while simultaneously activating systems to reduce AD pathology. Allopregnanolone (Allo) is a pleiotropic regenerative therapeutic that promotes neurogenesis and restores cognitive function in both a preclinical AD model and wild type aged mice and reduces pathology in a preclinical AD model. Further Allo promotes regeneration of human neural stem cells. Allo is a neurosteroid endogenous to the brain of low molecular weight and blood brain barrier penetrant with abundant existing safety data in animals and humans. Its mechanisms of neural stem cell proliferation and restoration of cognitive function are well characterized and consistent with well-described neurogenic mechanisms in brain. Allo reduces AD pathology via well-established cholesterol clearance pathways upstream to prevent the generation of Abeta while also decreasing inflammation and increasing myelin generation. Proposed herein is a program of translational IND-enabling toxicological and safety analyses required to advance to a Phase 2 clinical trial of the neurosteroid, allopregnanolone (Allo), for the treatment of persons with MCI due to Alzheimer's disease (AD) or early AD. FDA IND #113,772 is approved for a Phase 1 clinical trial with additional chronic exposure safety analyses required to advance to a Phase 2 clinical trial. Aims proposed within this U01 application specifically address FDA guidance as well as an Aim focused on regulatory documentation and design of the Phase 2 trial. Each specific aim is milestone driven with clearly articulated Go / no-Go decision criteria. Aims I and II will be conducted in two species. Specific Aim I is designed to conduct a nine-month chronic toxicology study to determine the toxicokinetic and safety profiles for intramuscularly administered allopregnanolone. Specific Aim II is designed to conduct a six-month chronic toxicology to determine the toxicokinetic and safety profiles for intramuscularly administered allopregnanolone. Specific Aim III is designed to determine the risk of cerebral micro-hemorrhages after exposure to once per week allopregnanolone in aged mouse model of AD. Specific Aim IV is designed to conduct regulatory assessments and generate documentation for submission to FDA and to generate Phase 2 clinical trial design and plan. A multidisciplinary team of investigators with expertise in Allo systems biology, translational research and clinical trials for AD therapeutics are committed to the project. Outcomes of these analyses will support and advance therapeutic development of Allo to a Phase 2 clinical trial in persons with MCI due to AD and early AD.