IND Enabling Studies for a Novel Mas Receptor Agonist for Treatment of Cognitive Impairment in Patients at Risk for Alzheimer's Disease Related Dementia

新型 Mas 受体激动剂的 IND 使研究能够治疗有阿尔茨海默病相关痴呆风险的患者的认知障碍

• 批准号: 10378076
• 负责人: Meredith Hay
• 金额: $ 114.56万
• 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: 2020-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378076
• 关键词: Acute; Agonist; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Angiotensins; Anti-Inflammatory Agents; Arizona; Brain; Canis familiaris; Cardiovascular Diseases; Cerebrovascular Circulation; Chronic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Consultations; Data; Dementia; Development; Diagnosis; Disease; Documentation; Dose; Drug Formulations; Drug Industry; Encephalitis; Endothelium; Exhibits; FDA approved; Formulation; Frequencies; GTP-Binding Proteins; Generations; Genetic; Glycopeptides; Heart Diseases; Heart failure; Hippocampus (Brain); Hypoxia; Impaired cognition; In Vitro; Individual; Inflammation; Inflammatory; Lead; Medical; Memory impairment; Microglia; Nature; Neurodegenerative Disorders; Neurons; Oxygen; Patients; Penetration; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phase; Preparation; Production; Protocols documentation; Rattus; Reporting; Research; Risk; Safety; Specialist; Testing; Therapeutic; Toxic effect; Toxicokinetics; Toxicology; Universities; Validation; Vascular Dementia; Vascular Diseases; Vascular Endothelial Cell; Vision; analytical method; cardiovascular risk factor; chronic inflammatory disease; clinical development; cognitive function; experience; improved; in vivo; lead candidate; link protein; meetings; method development; mild cognitive impairment; mouse model; novel; novel strategies; pharmacokinetics and pharmacodynamics; polypeptide; prevent; programs; receptor; safety study; scale up; subcutaneous; systemic inflammatory response; vascular cognitive impairment and dementia

PROJECT SUMMARY In the proposed early stage NIA U01 ADDP program, we will: 1) finalize dose-optimization of our lead compound, 2) complete PK/PD testing and, 3) begin manufacturing, formulation and the toxicological and safety analyses required to advance our lead compound to IND submission and clinical studies for patients at risk for Vascular Contributions to Cognitive Impairment and Dementia (VCID) and conversion to Alzheimer’s Disease and Related Dementias (ADRD). Our vision is to be a first-in-class therapy to reduce inflammatory-disease related cognitive impairment and inhibit dementia development in patients at risk for VCID and ADRD. We will leverage our experience with our currently approved FDA IND # 125320 and ongoing trials for the use of native Ang-(1-7) treatment of cognitive impairment in patients with heart failure (HF) or cardiac disease to advance our 2nd-generation glycosylated Ang-(1-7), to complete full regulatory toxicology needed for IND submission and Phase I safety studies. Our comprehensive University of Arizona and ProNeurogen team of peptide medicinal chemists, neuroscientists, pharmacologists and drug industry specialists have developed a novel approach to take advantage of the anti-inflammatory and neuroprotective nature of the G-protein linked Mas receptor and our extensive experience with Ang-(1-7) agonists. Within the brain, the Mas receptor is expressed on neurons, microglia and vascular endothelial cells and activation of Mas decreases ROS and brain inflammation, increases cerebral circulation via increases in endothelial NO release and inhibits hypoxia-inducing factor-1alpha (1), (2), (3). Our research team has developed, optimized and completed high-throughput in vitro and in vivo screens of novel synthetic glycopeptide derivatives of Ang-(1-7) that have outstanding brain penetration and enhanced stability (4), (5, 6), (7), (8). We have completed full physiochemical profiling of our lead candidate. With the completion of the Aims below, we will obtain the protocols and necessary documentation to file a new IND with the FDA to begin clinical trials for cognitive impairment in patients as risk for developing VCID or ADRD. Specific Aim I: Dose and Dose Frequency Optimization, ADME, Multi-dose PK/PD, Target Engagement Specific Aim II. Scale up synthesis. GMP manufacturing and formulation of our final lead glycosylated Ang (17) compound will be synthesized by our CRO, PolyPeptide Group. (Completed by CRO) Specific Aim III Regulatory Toxicology Studies (Completed by CRO). Specific Aim IV: IND Preparation and Submission (UA and FDA regulatory consultant).

项目概要 在拟议的早期 NIA U01 ADDP 计划中，我们将：1) 最终确定我们的先导化合物的剂量优化， 2) 完成 PK/PD 测试，3) 开始生产、配制以及毒理学和安全性分析。 需要将我们的先导化合物推进 IND 提交并针对有血管风险的患者进行临床研究 导致认知障碍和痴呆症 (VCID) 以及转变为阿尔茨海默病及相关疾病 我们的愿景是成为减少炎症性疾病相关疾病的一流疗法。 认知障碍并抑制有 VCID 和 ADRD 风险的患者的痴呆发展。 利用我们目前批准的 FDA IND # 125320 的经验以及正在进行的使用天然药物的试验 Ang-(1-7) 治疗心力衰竭 (HF) 或心脏病患者的认知障碍，以推进我们的研究 第二代糖基化 Ang-(1-7)，以完成 IND 提交和所需的完整监管毒理学 我们的亚利桑那大学和 ProNeurogen 肽药物综合团队进行了第一阶段安全性研究。 化学家、神经科学家、药理学家和制药行业专家开发了一种新方法 利用 G 蛋白连接的 Mas 受体的抗炎和神经保护性质， 我们在 Ang-(1-7) 激动剂方面拥有丰富的经验，在大脑中，Mas 受体在神经元上表达。 小胶质细胞和血管内皮细胞以及 Mass 的激活会减少 ROS 和脑部炎症，增加 通过增加内皮 NO 释放并抑制缺氧诱导因子 1α 来促进脑循环 (1), (2), (3).我们的研究团队开发、优化并完成了高通量体外和体内筛选。 Ang-(1-7) 的新型合成糖肽衍生物具有出色的脑渗透性和增强性 稳定性 (4)、(5、6)、(7)、(8) 我们已经完成了我们的主要候选药物的完整理化分析。 完成以下目标后，我们将获得提交新 IND 的协议和必要文件 FDA 开始针对患有 VCID 或 ADRD 风险的患者进行认知障碍临床试验。 具体目标 I：剂量和剂量频率优化、ADME、多剂量 PK/PD、目标参与 具体目标 II. 扩大最终糖基化 Ang 的合成规模和配方。 (17)化合物将由我们的CRO多肽组合成（由CRO完成）。 具体目标 III 监管毒理学研究（由 CRO 完成）。 具体目标 IV：IND 准备和提交（UA 和 FDA 监管顾问）。