IND Enabling Studies for RASRx 1902, a novel Mas receptor agonist, for treatment of cognitive impairment in patients at risk for Alzheimer's disease.

RASRx 1902 的 IND 启用研究是一种新型 Mas 受体激动剂，用于治疗有阿尔茨海默病风险的患者的认知障碍。

• 批准号: 10644987
• 负责人: KATHLEEN E. RODGERS
• 金额: $ 152.86万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644987
• 关键词: ACE2; Advanced Development; Affect; Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Angiotensin II; Angiotensins; Animal Model; Behavioral Symptoms; Biological Availability; Brain; Canis familiaris; Cardiovascular Diseases; Cerebrovascular Circulation; Chemistry; Chronic; Clinical; Clinical Data; Clinical Protocols; Clinical Research; Cognitive; Data; Dementia; Development; Disease; Documentation; Dose; Elderly; Enzymes; Evaluation; Formulation; Frequencies; Generations; Genetic; Goals; Good Manufacturing Process; Half-Life; Hypertension; Impaired cognition; Incidence; Inflammation; Inflammatory; Intervention; Investigation; Investigational Drugs; Investigational New Drug Application; Link; Memory Loss; Mesenchymal Stem Cells; Methodology; Modality; Modeling; Mus; Neurobehavioral Manifestations; Neuronal Dysfunction; Operative Surgical Procedures; Oral; Organ; Oxidative Stress; Pamphlets; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Play; Preparation; Rattus; Receptor, Angiotensin, Type 1; Regenerative pathway; Renin-Angiotensin System; Reporting; Request for Applications; Research; Research Design; Risk; Rodent Model; Role; Route; Serum; Signal Pathway; Systemic disease; Testing; Therapeutic; Tissues; Toxicology; Treatment Efficacy; Validation; analog; aorta constriction; apolipoprotein E-4; arm; cerebrovascular; clinical development; cognitive function; comparison control; efficacy evaluation; endothelial stem cell; global health; high risk; improved; in vivo; manufacture; meetings; mouse model; neuroinflammation; novel; novel strategies; novel therapeutics; pharmacokinetics and pharmacodynamics; preclinical study; prevent; receptor; regenerative; scale up; sex; small molecule; stability testing; stem cell population; study characteristics

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a progressive multifactorial disease affecting more than 50 million people worldwide, and is the most common dementia of late-life. To date, no interventions have demonstrated substantial therapeutic efficacy to prevent, delay or treat AD. In recent years, both cardiovascular disorders (CVD) and genetic factors (ApoE4) have been attributed to an increased risk of developing AD. The pathological arm of the Renin Angiotensin System (RAS) has been implicated in both CVD and AD, whereas the protective arm, including Angiotensin (1-7)[A(1-7)], Mas receptor and ACE2 are known to counter-regulate these effects. A(1- 7), through the Mas receptor, is known to reduce inflammation and oxidative (OS) in several disease states and it also has regenerative effects by upregulating endogenous stem cell populations. Data from clinical studies have shown that both A(1-7) and ACE2 are reduced in AD patients and several in-vivo studies support the efficacy of A(1-7) in treating AD. While the effects of A(1-7) in AD models have been extremely promising, its short half-life and lack of oral bioavailability make it challenging to develop as a therapeutic modality. In order to overcome this shortcoming, our lab has developed an equipotent small molecule analogues of A(1-7), RASRx1902 and RASRx1911. RASRx1902 and RASRx1911 have been shown to reduce inflammation and OS in target organs as well as having a regenerative effect on damaged tissues. A recent study from our lab showed that RASRx1902 and RASRx1911 were able to improve cognitive function as well as reduce OS in the brain in a mouse model of hypertension induced cognitive dysfunction (transverse aortic constriction [TAC]). Since Mas agonism is known to have a beneficial effect in AD, we hypothesize that these molecules can be developed as a potential new therapeutic for the treatment of AD and related dementias. The primary objective of this proposal are to advance development of one small molecule Mas agonist to submission of an Investigation New Drug Application (IND) for the treatment of AD and related dementias through: 1. Evaluation of the oral efficacy of RASRx1902 and RASRx1911 in TAC and AD mouse models (5xFAD & ApoE4); 2. Assessment of the efficacy of RASRx1902 in TAC-ApoE4 mice, 3. Scale up of one Mas agonist manufactured under Good Manufacturing Practices (GMP); 4. Development of a formulation of one Mas agonist for Phase I clinical trial; 5. Completion of ADME, (PK) and IND-enabling Toxicology studies; 6. Preparation Pre IND and IND Documentation; 7. Conduct of a Pre IND meeting; and 8. Filing of an IND. Research proposed herein is responsive to PAS 18-820 to develop and evaluate therapies “that prevent Alzheimer's disease (AD), slow its progression or treat its cognitive and behavioral symptoms”.

项目概要/摘要 阿尔茨海默病 (AD) 是一种进行性多因素疾病，影响全球超过 5000 万人， 是晚年最常见的痴呆症。迄今为止，还没有任何干预措施显示出实质性的 预防、延迟或治疗 AD 的治疗功效。近年来，心血管疾病（CVD）和 遗传因素（ApoE4）被认为会增加患 AD 的风险。的病理臂 肾素血管紧张素系统 (RAS) 与 CVD 和 AD 都有关联，而保护臂， 已知血管紧张素 (1-7)[A(1-7)]、Mas 受体和 ACE2 等可以抵消这些作用。 A(1- 7) 通过 Mas 受体，已知可减少多种疾病状态下的炎症和氧化 (OS)， 它还通过上调内源干细胞群而具有再生作用。临床研究数据 已经表明 AD 患者中 A(1-7) 和 ACE2 均减少，并且多项体内研究支持这一观点 A(1-7)治疗AD的功效。虽然 A(1-7) 在 AD 模型中的效果非常有希望，但它 半衰期短和缺乏口服生物利用度使得开发作为一种治疗方式具有挑战性。为了 为了克服这个缺点，我们实验室开发了A(1-7)的等价小分子类似物， RASRx1902 和 RASRx1911。 RASRx1902 和 RASRx1911 已被证明可以减少炎症和 OS 对靶器官以及受损组织具有再生作用。我们实验室最近的一项研究表明 RASRx1902 和 RASRx1911 能够改善认知功能并减少大脑中的 OS 高血压引起的认知功能障碍（横主动脉缩窄[TAC]）的小鼠模型。自从马斯 已知激动作用对 AD 有有益作用，我们假设这些分子可以开发为 一种治疗 AD 和相关痴呆症的潜在新疗法。本提案的主要目标 将推进一种小分子 Mas 激动剂的开发，以提交研究新药 通过以下方式治疗 AD 和相关痴呆症的申请（IND）： 1. 评估口服药物的疗效 TAC 和 AD 小鼠模型（5xFAD 和 ApoE4）中的 RASRx1902 和 RASRx1911； 2.疗效评价 TAC-ApoE4 小鼠中的 RASRx1902，3. 良好制造条件下生产的一种 Mas 激动剂的放大 实践（GMP）； 4. 一种Mas激动剂制剂的开发，用于I期临床试验； 5. 完成 ADME、（PK）和 IND 毒理学研究； 6. 准备 IND 前和 IND 文件； 7. 行为 IND 前会议； 8. 提交 IND。本文提出的研究响应 PAS 18-820 进行开发 并评估“预防阿尔茨海默病（AD）、减缓其进展或治疗其认知和认知障碍的疗法” 行为症状”。