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).

项目摘要 在拟议的早期NIA U01 ADDP程序中，我们将：1）最终确定铅化合物的剂量优化， 2）完整的PK/PD测试和3）开始制造，制定和毒理学和安全分析 需要将我们的铅化合物推进IND提交和临床研究 对认知障碍和痴呆症（VCID）的贡献，并转换为阿尔茨海默氏病及相关 痴呆症（ADRD）。我们的愿景是成为减少炎症性疾病相关的第一类疗法 认知障碍和抑制VCID和ADRD风险的患者的痴呆症发育。我们将 利用我们当前已批准的FDA IND＃125320的经验以及正在进行的使用本地的试验 Ang-（1-7）心力衰竭（HF）或心脏病患者的认知障碍治疗以促进我们 第二代糖基化的Ang-（1-7），以完成IND提交和 第一阶段的安全研究。我们的亚利桑那州综合大学和辣椒医学的下尿团队 化学家，神经科学家，制药学家和药品行业专家已经开发了一种新颖的方法 利用G蛋白连接的MAS受体的抗炎和神经保护性 我们在Ang-（1-7）激动剂方面的丰富经验。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MAS的激活减少ROS和脑感染，增加 内皮无释放的增加脑循环，并抑制缺氧诱导的因子-1alpha（1），（2），，（2），（2）， （3）。我们的研究团队已经开发，优化和完成了体外和体内的高通量 具有出色脑穿透和增强的Ang-（1-7）的新型合成糖肽衍生物 稳定性（4），（5，6），（7），（8）。我们已经完成了主要候选人的完整理化学分析。与 完成以下目的的完成，我们将获得协议和必要的文档，以提交新的IND FDA开始对患者的认知障碍进行临床试验，因为患者患有VCID或ADRD的风险。 特定目的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。扩展合成。 GMP制造和制定我们的最终铅糖基化ANG （17）我们的CRO多肽组将合成化合物。 （由CRO完成） 特定的目标III监管毒理学研究（由CRO完成）。 特定目标IV：IND准备和提交（UA和FDA监管顾问）。