TREM2 Genotype-Informed Drug Repurposing and Combination Therapy Design for Alzheimers Disease

基于 TREM2 基因型的阿尔茨海默病药物再利用和联合治疗设计

基本信息

批准号：
10418459
负责人：
Feixiong Cheng
金额：
$ 83.15万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10418459
关键词：
3-Dimensional AKT inhibition Affect African American Age Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy American Amyloid Amyloid beta-Protein Anti-Inflammatory Agents Area Asthma Attention Biology Brain Cell Line Cell Nucleus Cells Cerebrum Clinic Clinical Clinical Trials Combination Drug Therapy Combined Modality Therapy Communication Computers Data Databases Development Disease Disease Outcome Disease Progression Disease associated microglia Dose Drug Combinations Drug Screening Drug Targeting Drug usage Electronic Health Record Gene Targeting Generations Genes Genetic Genetic Transcription Genome Genomics Genotype Health system Human Human Genetics Immune Incidence Inflammation Inflammatory Intelligence Intervention Investigation Knock-in Mouse Knowledge Portal Late Onset Alzheimer Disease Lead Link Machine Learning Medicine Methodology Methods Microglia Molecular Molecular Target Mus Mutation Nature Nerve Degeneration Network-based Neurodegenerative Disorders Neuroglia New York City Observational Study Organoids Pathogenesis Patients Penetration Persons Pharmaceutical Preparations Pharmacoepidemiology Pharmacology Pharmacotherapy Play Population Process Property Research Risk Role Signal Transduction Source System Systems Biology TREM2 gene Tauopathies Testing Toxic effect United States Validation Variant analytical tool base bench to bedside brain endothelial cell cell type clinical efficacy cohort deep learning drug candidate drug discovery drug repurposing drug testing experimental study fluticasone genome-wide genomic data human disease in vitro Assay induced pluripotent stem cell knowledge graph metropolitan molecular targeted therapies mouse model multimodality multiple omics mutant neuroinflammation novel population based preclinical efficacy prevent risk variant side effect success targeted treatment tau Proteins therapy design transcriptome sequencing treatment effect trial design

项目摘要

PROJECT SUMMARY The cumulative evidence indicates neuro-inflammation play crucial roles in Alzheimer’s disease (AD) and anti- inflammatory agents (i.e., microglia-targeted therapies) show potential treatments for AD. The treatment window for microglia-targeted therapies may at least be open later in AD due to the nature of microglial biology. If amyloid-β is the trigger for AD, and tau is the executioner, then microglia are accelerators of disease progression. Microglia-targeted approaches have a better chance of success in mild to moderate disease compared to anti-amyloid therapies that have to prevent the trigger early in AD. Among the microglial genes, triggering receptor expressed on myeloid cells 2 (TREM2) has received much attention because a hemizygous R47H variant of TREM2 (TREM2R47H) increases the AD risk by 2-7 folds in various populations, including African American. Our preliminary single-nucleus RNA-sequencing (snRNAseq) study identified disease-associated microglia (DAM) with enhanced AD pro-inflammatory signatures (i.e., activation of Akt-signaling) associated with the TREM2R47H variant and pharmacological Akt inhibition reversed the TREM2R47H induced inflammation, showing proof-of-concept of TREM2R47H targeted drug discovery in AD. Using multimodal snRNAseq analysis, we identified two approved anti-inflammatory asthma drugs (fluticasone and mometasone) that were predicted to modulate DAM molecular networks are associated with a reduced incidence of AD in electronic health record (EHR) data of 7 million patients. We therefore posit that understanding how the AD-linked mutations (i.e., TREM2R47H) enhance microglial toxicity could lead to understanding how microglia become maladaptive/toxic and development of microglia-targeted therapeutic strategy for late-onset sporadic AD in general. This application calls for novel microglia-targeted drug repurposing and combination therapies for AD using our well-established multi-omics and deep learning-based EHR approaches, and functional observations in AD patient-induced pluripotent stem cells (iPSCs), cerebral organoids, and mouse models, with three specific Aims. Aim 1 will test the TREM2R47H informed microglia-targeted therapeutic hypothesis for identifying cell type-specific molecular drivers/networks, repurposable drugs, and combination therapies for AD using multi-omics evidence aggregation. These analyses will leverage our existing snRNAseq data (n = 24 TREM2R47H and n = 23 common variant (CV)-TREM2 with matched age, AD pathology and APOE genotypes) and public genomic data from the AD knowledge portal. Aim 2 will identify repurposable drugs and combination therapies using high-throughput EHR-based hypothesis generation and sequential deep learning-based propensity score matching approaches. We will leverage de-identified EHRs from the INSIGHT networks (~11 million patients across New York City’s 5 health systems and the greater metropolitan area). Aim 3 will screen, test and validate drugs using AD patient- derived iPSC lines carrying TREM2R47H in conjunction with cerebral organoid and mouse models. The successful completion of this project will offer a viable strategy to move AD drug repurposing from bench to bedside rapidly. 1

项目概要累积的证据表明神经炎症在阿尔茨海默病（AD）和抗衰老中发挥着至关重要的作用。炎症药物（即小胶质细胞靶向疗法）显示出治疗 AD 的潜在疗法。由于小胶质细胞生物学的性质，小胶质细胞靶向治疗的窗口至少可能会在 AD 后期打开。如果β淀粉样蛋白是AD的触发因素，tau蛋白是刽子手，那么小胶质细胞就是疾病的加速器针对小胶质细胞的进展方法在轻度至中度疾病中成功的机会更大与必须在 AD 早期预防触发小胶质细胞基因的抗淀粉样蛋白疗法相比，骨髓细胞表达的触发受体 2 (TREM2) 受到了广泛关注，因为半合子 TREM2 的 R47H 变体 (TREM2R47H) 使不同人群的 AD 风险增加 2-7 倍，包括非洲人美国。我们的初步单核 RNA 测序 (snRNAseq) 研究发现了与疾病相关的疾病。小胶质细胞 (DAM) 具有增强的 AD 促炎症特征（即 Akt 信号传导的激活） TREM2R47H 变体和药理学 Akt 抑制逆转了 TREM2R47H 诱导的炎症，使用多模式 snRNAseq 分析显示 TREM2R47H 靶向药物发现的概念验证，我们确定了两种已批准的抗炎哮喘药物（氟替卡松和莫米松），它们是预测的调节 DAM 分子网络与电子健康记录中 AD 发病率降低相关因此，我们假设了解 AD 相关突变（即， TREM2R47H）增强小胶质细胞毒性可能有助于了解小胶质细胞如何变得适应不良/有毒以及针对晚发散发性 AD 的小胶质细胞靶向治疗策略的开发。申请要求使用我们的研究成果对 AD 进行新型小胶质细胞靶向药物再利用和联合疗法完善的多组学和基于深度学习的 EHR 方法以及 AD 中的功能观察患者诱导的多能干细胞 (iPSC)、脑类器官和小鼠模型，具有三个特定目标。目标 1 将测试 TREM2R47H 知情的小胶质细胞靶向治疗假设，以识别细胞类型特异性使用多组学证据进行 AD 的分子驱动/网络、可重复利用药物和联合疗法这些分析将利用我们现有的 snRNAseq 数据（n = 24 TREM2R47H 和 n = 23 common）变体（CV）-TREM2，具有匹配的年龄、AD 病理学和 APOE 基因型）和来自 AD 知识门户。目标 2 将使用高通量识别可重复利用的药物和联合疗法。基于 EHR 的假设生成和基于顺序深度学习的倾向评分匹配方法。我们将利用来自 INSIGHT 网络的去识别化 EHR（纽约市 5 个地区的约 1100 万患者）目标 3 将使用 AD 患者筛选、测试和验证药物携带 TREM2R47H 的 iPSC 系与脑类器官和小鼠模型相结合取得了成功。该项目的完成将为将 AD 药物重新利用从实验室快速转移到临床提供可行的策略。 1