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

大脑炎症通路的激活导致淀粉样蛋白积累、神经元功能障碍、认知障碍 功能障碍和记忆丧失是阿尔茨海默病（AD）的主要病理特征。有 AD 的治疗方法很少，而且现有的治疗方法效用有限。因此，迫切需要治疗 涉及治疗 AD 的新靶点。开发 AD 疗法的部分困难是 人群和病因的异质性以及终点的不敏感性，特别是在早期 阶段临床试验。对于这些早期试验，结果测量侧重于目标参与或生物 路径分析可能会改善试验结果并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 AD 意见领袖的对话中，至关重要的是我们拥有目标参与度和目标参与度的生物标志物 用于临床试验的功效。该提案请求支持鉴定 RASRx1902 目标的血液生物标志物 在 RASRx1902 治疗 AD 的临床研究期间参与促进剂量优化和患者入组 患者。利用 Mas 激动剂减少神经变性的已知机制，我们假设 Mas激动剂将减少神经元死亡、星形胶质细胞增生、炎症和氧化应激的标志物。 修订目标 1. 传统上，用于监测神经损伤程度的生物标志物包括 反映直接神经元损伤（磷酸化 Tau、p-Tau）和星形胶质细胞增生以及基于血液的 生物标志物，例如神经丝光、S100 钙结合蛋白 B 和泛素羧基末端 水解酶同工酶L1。因此，在目标 1 中，我们评估了 RASRx1902 治疗对这些经典药物的影响。 神经退行性生物标志物。 修正案目标 2. 为了采取公正的方法来发现生物标志物，我们将使用 SomaScan（一种适配体） 基于系统，可测量血浆中 7,000 种蛋白质）和 Metabolon 的 Global Metabolomics™（LC-MS 全球代谢组学平台）来识别 AD 和 RASRx1902 改变的途径。我们将分析并 将 SomaScan 获取的数据与认知和神经变化相关联。综合 Metabolon 将使用其全球代谢组学（>1000 涉及氨基酸、碳水化合物、能量、脂质和核苷酸代谢的代谢物）。 修正案目标 3。在目标 3 中，我们将寻求关联外周标记物——神经退行性 生物标志物（目标 1）和无偏生物标志物（目标 2）——具有认知功能和脑病理学、小胶质细胞 激活、星形胶质细胞增生和淀粉样蛋白负担。探索性分析将包括途径富集分析， 多变量可视化。将根据分析物之间的差异生成统计假设 RASRx1902 和载体在多个时间点处理 5xFAD 和 WT。根据这些分析，生物标志物 将进行发现。

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.