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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：
10665664
负责人：
Feixiong Cheng
金额：
$ 81.74万
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/10665664
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 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 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 bench to bedside brain based brain endothelial cell candidate identification 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 pharmacologic population based preclinical efficacy prevent risk variant side effect single nucleus RNA-sequencing success targeted treatment tau Proteins therapy design 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

项目摘要越来越多的证据表明，神经炎症在阿尔茨海默病（AD）中起着至关重要的作用，炎性物质（即，小胶质细胞靶向疗法）显示出对AD的潜在治疗。治疗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可能至少在AD后期开放。如果β淀粉样蛋白是AD的触发器，而tau蛋白是刽子手，那么小胶质细胞就是疾病的加速器进展靶向小胶质细胞的方法在轻度至中度疾病中有更好的成功机会与必须预防AD早期触发的抗淀粉样蛋白疗法相比。在小胶质细胞基因中，髓样细胞表达的触发受体2（TREM 2）受到了广泛关注，因为半合子的 TREM 2的R47 H变体（TREM 2 R47 H）使各种人群（包括非洲人）的AD风险增加2-7倍美国人我们初步的单核RNA测序（snRNAseq）研究确定了疾病相关的具有增强的AD促炎特征的小胶质细胞（DAM）（即，Akt信号传导的激活）与 TREM 2 R47 H变体和药理学Akt抑制逆转了TREM 2 R47 H诱导的炎症，显示了AD中TREM 2 R47 H靶向药物发现的概念验证。使用多模式snRNAseq分析，我们确定了两种经批准的抗炎性哮喘药物（氟替卡松和莫米松），调节DAM分子网络与电子健康记录中AD发病率的降低相关 (EHR)700万患者的数据。因此，我们认为，了解AD连锁突变（即， TREM 2 R47 H）增强小胶质细胞毒性可能导致理解小胶质细胞如何变得适应不良/有毒以及一般迟发性散发性AD的小胶质细胞靶向治疗策略的开发。这申请要求使用我们的新的小胶质细胞靶向药物再利用和AD的联合治疗。成熟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，具有三个特定的目的。目的1将测试TREM 2 R47 H告知的小胶质细胞靶向治疗假设，用于鉴定细胞类型特异性的肿瘤细胞。分子驱动/网络、可再利用药物和使用多组学证据的AD联合治疗聚合来这些分析将利用我们现有的snRNAseq数据（n = 24个TREM 2 R47 H和n = 23个常见具有匹配的年龄、AD病理学和APOE基因型的变异体（CV）-TREM 2）和来自 AD知识门户。目标2将利用高通量技术鉴定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分数匹配方法。我们将利用来自INSIGHT网络的去识别化EHR（纽约市5个城市的约1100万患者卫生系统和大都市区）。Aim 3将使用AD患者筛选、测试和验证药物- 携带TREM 2 R47 H的衍生iPSC系与脑类器官和小鼠模型联合。成功该项目的完成将提供一个可行的策略，将AD药物再利用从实验室迅速转移到床边。 1