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

RASRx 1902 的 IND 启用研究是一种新型 Mas 受体激动剂，用于治疗有阿尔茨海默病风险的患者的认知障碍。

• 批准号: 10530821
• 负责人: KATHLEEN E. RODGERS
• 金额: $ 38.38万
• 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: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530821
• 关键词: ACE2; Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Amendment; Amino Acids; Amyloid; Angiotensins; Animal Model; Biological; Biological Markers; Blood; Brain; Brain Pathology; Cardiovascular Diseases; Clinical Research; Clinical Trials; Cognition; Data; Disease; Dose; Energy Metabolism; Etiology; Genetic; Goals; Hydrolase; Impaired cognition; Incidence; Inflammation; Inflammatory; Intervention; Investigational Drugs; Investigational New Drug Application; Isoenzymes; Light; Link; Measures; Memory Loss; Monitor; Nerve Degeneration; Nervous System Trauma; Neurologic; Neuronal Dysfunction; Neurons; Outcome; Outcome Measure; Oxidative Stress; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Patients; Peripheral; Persons; Phase I Clinical Trials; Plasma; Population Heterogeneity; Process; Proteins; Renin-Angiotensin System; Request for Proposals; S100 Calcium Binding Protein; System; Testing; Time; Treatment Efficacy; Ubiquitin; Visualization; analog; apolipoprotein E-4; aptamer; arm; astrogliosis; base; biomarker discovery; blood-based biomarker; carbohydrate metabolism; clinical candidate; cognitive function; drug development; improved; lipid metabolism; lipidomics; metabolomics; neurofilament; neuron loss; novel; nucleotide metabolism; participant enrollment; prevent; protein B; receptor; small molecule; targeted biomarker; tau-1; therapeutic development; β-amyloid burden

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.

脑炎症通路的激活有助于淀粉样蛋白积累、神经元功能障碍、认知功能障碍、神经元损伤和神经元损伤。 损害和记忆丧失，这是阿尔茨海默病（AD）的主要病理特征。有 AD的治疗很少，并且那些可用的治疗具有有限的效用。因此，迫切需要治疗 涉及治疗AD的新靶点。开发AD治疗方法的部分困难在于 人群和病因的异质性以及终点的不敏感性，特别是在早期- 临床试验阶段。对于这些早期试验，结果指标侧重于靶向参与或生物学 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RASRx 1902作为我们的AD临床候选药物。基于 与关键的AD意见领袖的对话，至关重要的是，我们有目标参与的生物标志物， 用于临床试验的有效性。该提案要求支持确定RASRx 1902靶标的血液生物标志物 参与促进在AD中进行RASRx 1902临床研究期间的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激动作用将减少神经元死亡、星形胶质细胞增生、炎症和氧化应激的标志物。 修正案目标1.传统上，用于监测神经损伤程度的生物标志物包括那些 反映了直接神经元损伤（磷酸化Tau，p-Tau）和星形胶质细胞增生以及基于血液的 生物标志物如神经丝轻链、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RASRx 1902治疗对这些经典的 神经退行性生物标志物。 修正案目标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， Metabolon的Global Metabolomics ™（LC-MS）和Metabolon的Global Metabolomics ™（LC-MS 全球代谢组学平台），以鉴定AD中和RASRx 1902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相关联。全面 代谢组学和脂质组学分析将在Metabolon使用其Global Metabolomics（> 1000 参与氨基酸、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，我们将寻求将外周标记物-神经退行性病变 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学，小胶质细胞 活化、星形胶质细胞增生和淀粉样蛋白负荷。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， 在多个时间点用RASRx 1902和媒介物处理5xFAD和WT。根据这些分析，生物标志物 将进行调查。