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: 10271099
• 负责人: Meredith Hay
• 金额: $ 1.6万
• 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/10271099
• 关键词: Address; Agonist; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Angiotensins; Anti-Inflammatory Agents; Arizona; Biological Assay; Biological Availability; Biological Markers; Brain; Cardiovascular Diseases; Cerebrovascular Circulation; Clinical Research; Clinical Trials; Cognitive; Dementia; Development; Disease; Documentation; Dose; Drug Industry; Encephalitis; Endothelium; FDA approved; Female; Formulation; Frequencies; GTP-Binding Proteins; Generations; Glycopeptides; Heart Diseases; Heart failure; Hypoxia; Impaired cognition; In Vitro; Inflammatory; Lead; Menopause; Microglia; Nature; Neurons; Parents; Patients; Penetration; Peptides; Phase; Protocols documentation; Research; Risk; Risk Factors; Safety; Sex Differences; Specialist; Testing; Toxicology; Underserved Population; Universities; Vascular Dementia; Vascular Endothelial Cell; Vision; blood-brain barrier disruption; experience; improved; in vivo; lead candidate; link protein; male; novel; novel strategies; pharmacokinetics and pharmacodynamics; programs; receptor; safety study; sex; sexual dimorphism; 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 1,3,17. 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 2,4,6,10,12. 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. The diversity supplement will focus on Specific Aim of the parent application with a focus on the inclusion of menopausal females. The pertinent specific hypothesis that will be directly addressed by the supplement candidate is as follows: Hypothesis. The glycosylated Ang 1-7 peptide (PNA5) will significantly improve bio-availability of Ang 1-7 and increase PNA5 concentration in the brain, in menopausal females, with little to no BBB disruption, who demonstrate VCID cognitive impairment via activation of the G-protein linked Mas receptor. Accordingly, to address the specific hypothesis, the following Specific Aims will be executed: Aim Ia. Identify Minimal Effective Dose (MED), Optimal Effective Dose (OED) and Optimal Dose Frequency for native Ang-(1-7) and PNA5 for cognitive protection in menopausal females. Aim Ib. Assess and compare ADME and PK for native Ang-(1-7) and PNA5 in menopausal females. Aim Ic. Target Engagement and Biomarker Inflammatory Assay in menopausal females.

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）完成PK/PD测试，3）开始制造，配方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肽药物的胸腺尿液团队 化学家，神经科学家，药理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和脑部炎症，增加 内皮无释放的增加，脑循环循环，并抑制诱导缺氧因子-1alpha 1,3,17。我们的 研究团队已经开发，优化和完成了新颖的体外和体内屏幕 Ang-（1-7）的合成糖肽衍生物具有出色的大脑渗透和增强的稳定性 2,4,6,10,12。我们已经完成了主要候选人的完整理化学分析。随着目标的完成 下面，我们将获取协议和必要的文档，以向FDA提交新的IND以开始临床 患者认知障碍的试验是患有VCID或ADRD的风险。多样性补充将 专注于父母应用的特定目的，重点是将绝经女性纳入其中。这 补充候选人将直接解决的相关特定假设如下： 假设。糖基化ANG 1-7肽（PNA5）将显着改善ANG 1-7和 增加大脑中的PNA5浓度，绝经女性，几乎没有BBB破坏 通过激活G蛋白连接的MAS受体来证明VCID认知障碍。 因此，为了解决特定假设，将执行以下特定目标： 瞄准。确定最小有效剂量（MED），最佳有效剂量（OED）和最佳剂量 天然ang-（1-7）和PNA5的频率用于绝经女性的认知保护。 目标IB。评估并比较了绝经女性中天然Ang-（1-7）和PNA5的ADME和PK。 瞄准IC。绝经女性的目标参与和生物标志物炎症测定法。