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).

项目总结