IND Enabling Studies for RASRx 1902, a novel Mas receptor agonist, for treatment of cognitive impairment in patients at risk for Alzheimer's disease.

脑部炎症通路的激活导致淀粉样蛋白堆积、神经元功能障碍、认知功能障碍 损伤和记忆丧失是阿尔茨海默病(AD)的主要病理特征。确实有 治疗阿尔茨海默病的方法很少，而且现有的治疗方法的效用有限。因此，人们迫切需要治疗方法。 涉及治疗阿尔茨海默病的新靶点。开发阿尔茨海默病疗法的部分困难是 种群和病原学的异质性以及终点的不敏感性，特别是在早期- 阶段性临床试验。对于这些早期试验，结果衡量集中在目标参与或生物方面 通路分析可能会改善试验结果，更好地支持药物开发过程。 基于这些令人信服的数据，我们选择RASRx1902作为AD的临床候选药物。基于 与主要广告意见领袖的对话，我们拥有目标参与度的生物标记物和 在临床试验中使用的有效性。该提案要求支持确定RASRx1902靶的血液生物标志物 RASRx1902在AD的临床研究中促进剂量优化和患者登记的参与度 病人。根据已知的MAS激动剂减少神经退行性变的机制，我们假设 MAS激动剂将减少神经元死亡、星形胶质细胞增生症、炎症和氧化应激的标志物。 修正目标1.传统上，用于监测神经损伤程度的生物标记物包括 反映直接神经元损伤(磷酸化Tau，p-Tau)和星形胶质细胞增生症以及基于血液的 神经丝光、S100钙结合蛋白B和泛素羧基末端等生物标志物 水解酶同工酶L1。因此，在目标1中，我们评估了RASRx1902治疗对这些经典疾病的影响 神经退行性生物标志物。 修正目标2.为了对生物标志物的发现采取公正的方法，我们将使用SomaScan(一种适体- 基于测量血浆中7,000种蛋白质的系统)和新陈代谢公司的全球代谢组学™(LC-MS 全球代谢组学平台)，以确定AD和RASRx1902改变的途径。我们将分析和 将SomaScan获得的数据与认知和神经变化联系起来。全面 代谢学和脂体学分析将在新陈代谢公司使用其全球代谢组学(&gt；1000)进行 涉及氨基酸、碳水化合物、能量、脂肪和核苷酸代谢的代谢物)。 修改目标3.在目标3中，我们将寻求将外周标记物--神经退行性变 生物标志物(目标1)和无偏生物标志物(目标2)--与认知功能和脑病理、小胶质细胞 活化、星形胶质细胞增多症和淀粉样蛋白负荷。探索性分析将包括途径浓缩分析， 多变量可视化。统计假设将基于分析物之间的差异而生成 RASRx1902和车辆在多个时间点治疗5xFAD和WT。从这些分析来看，生物标记物 我们将进行探索。

Activation of brain inflammatory pathways contributes to amyloid accumulation, neuronal dysfunction, cognitive impairment, and memory loss which are the main pathological features of Alzheimer's disease (AD). There are few treatments for AD and those available have limited utility. As a result, there is a desperate need for therapies involving novel targets for the treatment of AD. Part of the difficulty in the development of therapeutics for AD is the heterogeneity of the population and etiology as well as the insensitivity of the endpoints, particularly in early- stage clinical trials. For these early trials, outcome measures focused on target engagement or biological pathway analysis might improve trial outcomes and better support the drug development process. Based upon these compelling data, we have chosen RASRx1902 as our clinical candidate for AD. Based on conversations with key AD opinion leaders, it is crucial that we have biomarkers of target engagement and efficacy for use in clinical trials. This proposal requests support to identify blood biomarkers of RASRx1902 target engagement to facilitate dose optimization and patient enrollment during the clinical study of RASRx1902 in AD patients. Using the known mechanisms by which Mas agonists reduced neurodegeneration, we hypothesize that Mas agonism will reduce markers of neuronal death, astrogliosis, inflammation and oxidative stress. Amendment Aim 1. Classically, the biomarkers used to monitor the degree of neurological injury include those that reflect direct neuronal damage (phosphorylated Tau, p-Tau) and astrogliosis as well as blood-based biomarkers such as neurofilament light, S100 calcium binding protein B, and ubiquitin carboxyl-terminal hydrolase isoenzyme L1. Therefore, in Aim 1, we assess the effects of RASRx1902 treatment on these classic neurodegenerative biomarkers. Amendment Aim 2. To take an unbiased approach to biomarker discovery, we will use SomaScan (an aptamer- based system that measures 7,000 proteins in the plasma) and Metabolon’s Global Metabolomics™ (an LC-MS global metabolomics platform) to identify pathways both altered in AD and by RASRx1902. We will analyze and correlate the data acquired by SomaScan with cognition and neurological changes. Comprehensive metabolomic and lipidomic analyses will be conducted at Metabolon using their Global Metabolomics (>1000 metabolites involved in amino acid, carbohydrate, energy, lipid and nucleotide metabolism). Amendment Aim 3. In Aim 3, we will seek to correlate the peripheral markers — the neurodegenerative biomarkers (Aim 1) and the unbiased biomarkers (Aim 2) — with cognitive function and brain pathology, microglial activation, astrogliosis and amyloid burden. Exploratory analyses will include pathway enrichment analyses, multivariable visualization. Statistical hypothesis will be generated based on analyte differences between the RASRx1902 and vehicle treated 5xFAD and WT at multiple time points. From these analyses, biomarker discovery will be conducted.