Development of Allopregnanolone as a Neurogenic Regenerative Therapeutic

开发四氢孕酮作为神经源性再生治疗药物

基本信息

批准号：
7907511
负责人：
ROBERTA EILEEN BRINTON
金额：
$ 31.02万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7907511
关键词：
Abbreviations Address Affect Age Age-associated memory impairment Allopregnanolone Alzheimer&apos s Disease Amyloid Animals Appearance Basic Science Behavioral Behavioral Assay Brain Chemistry Clinical Clinical Investigator Clinical Trials Clinical Trials Design Clinical assessments Cognitive Conduct Clinical Trials Contracts Cyclic GMP Data Development Diagnostic Documentation Dose Drug Formulations Drug Industry Drug Kinetics Ensure Excretory function Female Foundations Gender Generations Goals Human In Vitro International Investigation Investigational Drugs Investigational New Drug Application Kinetics Learning Memory Memory impairment Metabolism Methodology Mus Neurobiology Neurodegenerative Disorders Neurologic Nootropic Agents Pamphlets Pathology Patients Persons Pharmaceutical Preparations Pharmacodynamics Phase I Clinical Trials Placebos Preparation Process Proliferating Property Regulation Regulatory Affairs Research Research Institute Research Personnel Rodent Route Safety Scientist Sex Characteristics System Therapeutic Time Toxicology Transgenic Mice Treatment Efficacy absorption age related base dentate gyrus design drug development follow-up good laboratory practice in vivo meetings mild neurocognitive impairment mouse model nerve stem cell neurogenesis neurosteroids pre-clinical prevent programs regenerative regenerative agent subventricular zone therapeutic development web-enabled

项目摘要

DESCRIPTION (provided by applicant): The long-range goal of our therapeutic development endeavors is to develop efficacious and safe agents to prevent and/or delay progression of age-related neurodegenerative disease such as Alzheimer's. Toward that end, we propose a preclinical project to develop the neurosteroid, allopregnanolone as a neurogenic regenerative therapeutic. The current proposal is a translational therapeutic development project to conduct preclinical analyses required for an Investigational New Drug (IND) application to the FDA to determine the efficacy of allopregnanolone as a neurogenic regenerative agent. Preclinical IND studies proposed herein build upon our foundation of basic science discovery and mechanistic understanding of allopregnanolone action in neural progenitor cells. To conduct the proposed project, we have assembled an interdisciplinary team of scientists with expertise in 1) neurobiology of allopregnanolone (Brinton USC research team), 2) behavioral analyses to determine therapeutic efficacy on learning and memory functions affected in mild cognitive impairment and Alzheimer's disease (PsychoGenics), and 3) pharmacokinetics, pharmacodynamics, toxicology, therapeutic formulation, regulatory affairs and IND document preparation (Stanford Research Institute International; SRI) 4). In addition, we have assembled a team of Consultants with expertise in development of therapeutics for AD within the following domains: 1) AD therapeutic development within the pharmaceutical industry, 2) regulatory affairs, 3) pharmacokinetics and dynamics, 4) therapeutic formulation, 5) design of clinical trials and 6) cognitive and neurological deficits diagnostic of mild cognitive impairment and AD. Consistent with preclinical analyses required for an FDA IND application, we propose four IND related Specific Aims and one project management Specific Aim. Together these aims are designed to [I] Determine therapeutic efficacy of allopregnanolone and impact of age and gender on efficacy in the triple transgenic mouse model of Alzheimer's; [II] Determine pharmacodynamics, pharmacokinetics (ADME) and toxicology of allopregnanolone; [III] Acquire cGMP quality allopreganaolone for Phase I Clinical Trial; [IV] Generation of FDA Investigational New Drug Application and Clinical Investigator Brochure documents; and [V] Project Management to achieve IND filing goal. Each Specific Aim is designed to address preclinical IND requirements and each is milestone driven with clearly articulated Go / no-Go decision criteria.

描述（由申请人提供）：我们的治疗开发努力的长期目标是开发有效且安全的药物来预防和/或延迟与年龄相关的神经退行性疾病（例如阿尔茨海默病）的进展。为此，我们提出了一个临床前项目，开发神经类固醇四氢孕酮作为神经再生治疗剂。目前的提案是一个转化治疗开发项目，旨在进行向 FDA 申请研究性新药 (IND) 所需的临床前分析，以确定四氢孕酮作为神经再生剂的功效。本文提出的临床前 IND 研究建立在我们对神经祖细胞中四氢孕酮作用的基础科学发现和机制理解的基础上。为了开展拟议的项目，我们组建了一个跨学科科学家团队，他们拥有 1) 四氢孕酮神经生物学（布林顿南加州大学研究团队）的专业知识，2) 行为分析，以确定对轻度认知障碍和阿尔茨海默病影响的学习和记忆功能的治疗效果（PsychoGenics），3) 药代动力学、药效学、毒理学、治疗配方、法规事务和 IND 文件准备（斯坦福国际研究所；SRI）4)。此外，我们还组建了一支顾问团队，他们在 AD 治疗药物开发方面具有以下领域的专业知识：1) 制药行业内的 AD 治疗药物开发，2) 监管事务，3) 药代动力学和动力学，4) 治疗配方，5 ) 临床试验设计和 6) 轻度认知障碍和 AD 的认知和神经缺陷诊断。与 FDA IND 申请所需的临床前分析一致，我们提出了四项 IND 相关的具体目标和一项项目管理具体目标。这些目标共同旨在 [I] 确定四氢孕酮的治疗效果以及年龄和性别对阿尔茨海默病三重转基因小鼠模型疗效的影响； [II] 确定四氢孕酮的药效学、药代动力学（ADME）和毒理学； [III]获得cGMP品质别加诺酮进行I期临床试验； [IV] 生成 FDA 新药研究申请和临床研究者手册文件； [V] 实现 IND 申报目标的项目管理。每个具体目标都是为了满足临床前 IND 要求而设计的，每个目标都是由明确阐明的通过/不通过决策标准驱动的里程碑。