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: 10396541
• 负责人: KATHLEEN E. RODGERS
• 金额: $ 151.56万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396541
• 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; 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; Half-Life; Hypertension; Impaired cognition; Incidence; Inflammation; Inflammatory; Intervention; Investigational Drugs; Investigational New Drug Application; Link; Memory Loss; Mesenchymal; 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; apolipoprotein E-4; arm; cerebrovascular; clinical development; cognitive function; constriction; efficacy evaluation; endothelial stem cell; global health; high risk; improved; in vivo; 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”.

项目摘要/摘要 阿尔茨海默氏病（AD）是一种进步的多因素疾病，影响了全球超过5000万人 是后期最常见的痴呆症。迄今为止，尚无干预措施证明 预防，延迟或治疗AD的治疗效率。近年来，心血管疾病（CVD）和 遗传因素（APOE4）归因于发展AD的风险增加。病理部门 肾素血管紧张素系统（RAS）已在CVD和AD中暗示，而受保护的臂， 已知包括血管紧张素（1-7）[A（1-7）]，MAS受体和ACE2可以抵抗这些作用。 a（1- 7）通过MAS受体，已知在几种疾病状态下降低感染和氧化（OS） 它还通过上调内源性干细胞种群具有再生作用。来自临床研究的数据 已经表明，AD患者的A（1-7）和ACE2都降低了，并且几项体内研究支持了 A（1-7）在治疗AD中的影响。尽管A（1-7）在AD模型中的影响非常有前途，但 半衰期和缺乏口服生物利用度使发展成为一种治疗方式的挑战。为了 克服了这一缺点，我们的实验室开发了一个等效的小分子类似物（1-7）， RASRX1902和RASRX1911。 RASRX1902和RASRX1911已显示可减少注射和OS 在目标器官以及对损坏组织的再生作用。我们实验室的最新研究表明 RASRX1902和RASRX1911能够改善认知功能，并减少大脑中的OS 高血压诱导认知功能障碍的小鼠模型（横向主动脉收缩[TAC]）。自MAS以来 众所周知，激动剂在AD中具有有益作用，我们假设这些分子可以发展为 一种潜在的新理论，用于治疗AD和相关痴呆症。该提议的主要目标 要推进一种小分子mas激动剂来提交调查新药 应用（IND）通过以下方式治疗AD和相关痴呆症 TAC和AD鼠标模型中的RASRX1902和RASRX1911（5XFAD＆APOE4）; 2。评估效率 rasrx1902在tac-apoe4小鼠中，3。在良好的制造下制造的一只mas激动剂缩放 实践（GMP）； 4。开发一个MAS激动剂的公式进行I期临床试验； 5。完成 Adme，（PK）和辅助毒理学研究； 6.准备和IND文档的准备； 7。行为 举行前的会议；和8。本文提出的研究对PAS响应18-820以发展 并评估“预防阿尔茨海默氏病（AD）的疗法，减慢其进展或治疗其认知和 行为症状”。