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

项目总结 在拟议的早期NIA U01 ADDP计划中，我们将：1)最终确定我们先导化合物的剂量优化， 2)完成PK/PD测试，3)开始制造、配方和毒理学和安全性分析 需要将我们的先导化合物提交给IND，并对有血管风险的患者进行临床研究 认知损害和痴呆(VCID)和阿尔茨海默病的转化及相关因素 痴呆(ADRD)。我们的愿景是成为减少炎症性疾病相关疾病的一流疗法。 VCID和ADRD高危患者的认知障碍和抑制痴呆的发展。我们会 利用我们目前批准的FDA IND#125320和正在进行的本机使用试验的经验 Ang-(1-7)治疗心力衰竭或心脏病患者的认知障碍以促进我们的 第二代糖基化Ang-(1-7)，以完成IND提交所需的全面调节毒理学和 第一阶段安全研究。我们的亚利桑那大学和多肽药物的前神经原团队 化学家、神经学家、药理学家和制药业专家已经开发出一种新的方法来 利用G蛋白连接的Mas受体的抗炎和神经保护特性 我们使用Ang-(1-7)激动剂的丰富经验。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的激活减少了ROS和脑部炎症，增加了 脑循环通过促进内皮细胞释放NO和抑制缺氧诱导因子-1α(1)、(2)、 (3)。我们的研究团队已经开发、优化并完成了体外和体内的高通量筛选 Ang-(1-7)的新型合成糖肽衍生物具有显著的脑穿透和增强作用 稳定性(4)、(5、6)、(7)、(8)。我们已经完成了我们的主要候选人的全面物理化学分析。与 完成以下目标，我们将获得协议和必要的文件，以提交新的IND FDA将开始对有患VCID或ADRD风险的患者进行认知障碍的临床试验。 具体目标一：剂量和剂量频率优化、ADME、多剂量PK/PD、靶点接触 特定目标II.放大合成。GMP制备及最终糖化铅Ang的配方 (17)化合物将由我们的CRO，多肽基团合成。(CRO填写) 特定目标III监管毒理学研究(由CRO完成)。 具体目标四：IND的编制和提交(UA和FDA监管顾问)。

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).