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

Allopregnanolone 是阿尔茨海默病的再生疗法：FDA 要求的毒理学

• 批准号: 8674966
• 负责人: ROBERTA EILEEN BRINTON
• 金额: $ 72.13万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8674966
• 关键词: Acute; Address; Allopregnanolone; Alzheimer' s Disease; Alzheimer' s disease model; Amendment; American; Amyloid beta-Protein; Animals; Annual Reports; Blood - brain barrier anatomy; Brain; Brain hemorrhage; Budgets; Canis familiaris; Cell Proliferation; Cerebrum; Cholesterol; Chronic; Clinical; Clinical Trials; Clinical Trials Design; Commit; Conduct Clinical Trials; Cyclic GMP; Data; Data Reporting; Diagnosis; Documentation; Dose; Drug Formulations; Ensure; Exposure to; FDA approved; Generations; Hemorrhage; Human; Human Resources; Incidence; Inflammation; Learning; Letters; Memory; Molecular Weight; Mus; Myelin; Natural regeneration; Nerve Regeneration; Neurons; Outcome; Pathology; Pathway interactions; Persons; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Property; Rattus; Regenerative Medicine; Research; Research Personnel; Risk; Rodent; Safety; Secure; System; Systems Biology; Therapeutic; Time; Toxicokinetics; Toxicology; Translational Research; Traumatic Brain Injury; Treatment Protocols; Validation; aged; analytical method; base; brain tract; burden of illness; cognitive function; design; meetings; method development; mouse model; multidisciplinary; nerve stem cell; neurogenesis; neurosteroids; pre-clinical; prevent; programs; public health relevance; regenerative; regenerative therapy; restoration; safety study; therapeutic development

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.

描述（由申请人提供）：预防，延迟和治疗阿尔茨海默氏病（AD）的治疗学尚待实现。目前，超过500万美国人被诊断出患有AD，除非取得治疗性进步，否则预计该人数将在二十年内增加到1,1600万。本文提出的是一种再生医学，即系统生物学方法，它针对大脑的再生系统，同时激活系统以减少AD病理。 Allopregnanolone（Allo）是一种多效性再生治疗，可促进神经发生并恢复临床前AD模型和野生型老年小鼠的认知功能，并在临床前AD模型中降低病理学。进一步的Allo促进了人类神经干细胞的再生。 Allo是低分子量和血脑屏障渗透物的神经固醇，具有动物和人类的现有安全数据。它的神经干细胞增殖的机制和认知功能的恢复是很好的特征，并且与大脑中描述的神经源性机制一致。 Allo通过公认的胆固醇清除途径在上游降低AD病理，以防止ABETA产生，同时还减少炎症并增加髓磷脂产生。本文提出的是一项计划，旨在促进神经类固醇（Allopregnanolone（Allo））进行2期临床试验所需的毒理学和安全性分析，以治疗由于阿尔茨海默氏病（AD）或早期AD的MCI治疗。 FDA IND＃113,772被批准用于1期临床试验，并进行了额外的慢性暴露安全性分析，才能推进2期临床试验。在本U01应用程序中提出的目的专门针对FDA指南，以及针对2阶段试验的监管文档和设计的目的。每个特定目标都是以明确的GO / NO-GO决策标准驱动的里程碑。目标I和II将在两个物种中进行。特定目的I旨在进行九个月的慢性毒理学研究，以确定肌肉内给药的毒素和安全性概况。特定的目标II旨在进行六个月的慢性毒理学，以确定肌肉内给药的毒素和安全性概况。特定的AIM III旨在确定AD老年小鼠模型中每周一次暴露于每周一次Allopregnanolone后脑微毛病的风险。特定目标IV旨在进行监管评估并生成文件以提交FDA并生成2阶段临床试验设计和计划。具有Allo Systems生物学，翻译研究和广告疗法临床试验方面具有专业知识的研究人员的多学科团队，致力于该项目。这些分析的结果将支持并推进Allo的治疗性开发，以在AD和早期AD的MCI患者中进行第二阶段的临床试验。