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

项目摘要累积证据表明，神经炎症在阿尔茨海默氏病（AD）和抗 - 炎症剂（即小胶质细胞靶性疗法）显示出对AD的潜在治疗方法。治疗小胶质细胞靶向疗法的窗口至少由于小胶质细胞生物学的性质，至少可以在AD中打开。如果淀粉样蛋白β是AD的触发因素，而Tau是执行者，则小胶质细胞是疾病的加速器进展。针对小胶质细胞的方法在轻度至中度疾病中有更大的成功机会与必须防止AD早期触发的抗淀粉样疗法相比。在小胶质基因中，触发在髓样细胞2（trem2）上表达的接收器引起了很多关注，因为半合子 R47H的TREM2（TREM2R47H）的R47H变体在包括非洲在内的各种人群中将AD风险增加2-7倍美国人。我们的初步单核RNA序列（SNRNASEQ）研究确定了与疾病相关的小胶质细胞（DAM）具有增强的AD促炎性特征（即Akt-Signaling的激活） TREM2R47H变体和药物Akt抑制作用逆转了TREM2R47H诱导的注射，显示AD中有针对性药物发现的TREM2R47H的概念证明。使用多模式SNRNASEQ分析，我们确定了两种批准的抗炎性哮喘药物（氟替卡松和莫莫酮）被预测调节大坝分子网络与电子健康记录中的AD入射减少有关（EHR）700万患者的数据。因此，我们肯定了解如何与广告相关的突变（即 TREM2R47H）增强小胶质细胞毒性可能导致了解小胶质细胞如何变形/有毒以及针对晚期发作零星广告的小胶质细胞靶向治疗策略的制定。这应用新颖的小胶质细胞靶向药物重新利用和联合疗法的应用程序使用我们成熟的多摩斯和基于深度学习的EHR方法以及AD的功能观察患者诱导的多能干细胞（IPSC），大脑器官和小鼠模型，具有三个特定目的。 AIM 1将测试trem2R47H知情的小胶质细胞靶向治疗假设，以识别特定细胞类型分子驱动因素/网络，可再效果的药物和使用多词的AD的组合疗法聚合。这些分析将利用我们现有的SNRNASEQ数据（n = 24 trem2r47h，n = 23 common 具有匹配年龄，AD病理学和APOE基因型的变体（CV）-Treem2）和公共基因组数据广告知识门户。 AIM 2将使用高通量来鉴定可重新验证的药物和组合疗法基于EHR的假设产生和基于深度学习的改进得分匹配方法。我们将利用洞察力网络（纽约市5的约1100万患者）利用识别的EHR。卫生系统和更大的大都市地区）。 AIM 3将使用AD患者筛选，测试和验证药物 - 衍生的IPSC系列与大脑器官和小鼠模型一起携带TREM2R47H。成功该项目的完成将提供可行的策略，以将AD药物重新利用从长凳上转移到床边。 1