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

项目摘要 在拟定的早期NIA U 01 ADDP项目中，我们将：1）完成我们的先导化合物的剂量优化， 2)完成PK/PD检测，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到IND提交和针对有血管风险的患者的临床研究中 对认知障碍和痴呆（VCID）的贡献以及向阿尔茨海默病和相关疾病的转化 痴呆症（ADRD）。我们的愿景是成为一流的治疗，以减少炎症性疾病相关的 认知障碍和抑制痴呆症的发展，在患者的风险为VCID和ADRD。我们将 利用我们目前批准的FDA IND # 125320和正在进行的使用天然药物的试验的经验， 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提交所需的全部监管毒理学， I期安全性研究。我们的综合亚利桑那大学和ProNeurogen团队的肽药用 化学家、神经科学家、药理学家和制药工业专家已经开发出一种新的方法， 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和Mas的激活降低ROS和脑炎症，增加 脑循环通过增加内皮NO释放和抑制缺氧诱导因子-1 α（1），（2）， （三）、我们的研究团队已经开发、优化并完成了高通量的体外和体内筛选 新型合成的Ang-（1-7）糖肽衍生物，其具有突出的脑渗透性和增强的 稳定性（4），（5，6），（7），（8）。我们已经完成了对主要候选人的全面理化分析。与 完成以下目标后，我们将获得方案和必要的文件，以提交新的IND， FDA将开始临床试验，在有发生VCID或ADRD风险的患者中进行认知障碍。 具体目标I：剂量和给药频率优化、ADME、多次给药PK/PD、靶点结合 具体目标二。放大合成。我们的最终先导糖基化Ang的GMP生产和配方 (17)化合物将由我们的CRO PolyPeptide Group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IV：IND准备和提交（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).