Synovial Macrophage Transcriptional Signatures for Predicting Therapeutic Efficacy

用于预测治疗效果的滑膜巨噬细胞转录特征

• 批准号: 9766023
• 负责人: Harris R Perlman
• 金额: $ 63.65万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766023
• 关键词: Aftercare; Anti-Tumor Necrosis Factor Therapy; Antirheumatic Agents; Biological Markers; Biological Response Modifier Therapy; Biology; Biopsy; Cell Separation; Characteristics; Clinical; Clinical Data; Clinical Trials; Computational Biology; Computer Analysis; Consumption; Data; Decision Making; Disease; Disease Pathway; Epidemiology; Exhibits; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Individual; Joints; Medical center; Methotrexate; Monitor; Mutation; Oncologist; Organ; Patient Recruitments; Patients; Pharmaceutical Preparations; Pharmacotherapy; Prediction of Response to Therapy; Predictive Value; Predisposition; Process; Publishing; Randomized; Research Personnel; Resistance; Rheumatoid Arthritis; Sample Size; Subgroup; Synovial Membrane; TNF gene; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Ultrasonography; United States; Work; arthritis registry; arthritis therapy; base; clinical practice; cohort; cost; differential expression; effective therapy; functional genomics; indexing; individual patient; ineffective therapies; inhibitor/antagonist; macrophage; novel; novel marker; patient response; patient stratification; peripheral blood; precision medicine; predicting response; predictive marker; predictive signature; recruit; response; rheumatologist; standard of care; tool; transcriptome sequencing; transcriptomics; tumor

Despite the many therapies for patients with rheumatoid arthritis (RA), there is little information to guide selection of the most effective treatment for an individual patient. Forty-sixty percent of patients with RA respond (defined by ACR50 response criteria) to conventional disease modifying anti-rheumatic drugs (cDMARDs) or cDMARDs plus anti-tumor necrosis factor (TNF) therapy. Moreover, 20-40% of RA subjects in clinical trials never demonstrate even a minimal response (ACR20 response criteria). Hence, there is a clear need to develop precision-based therapy for patients with RA, whereby novel biomarkers will enhance our ability to predict therapeutic response and limit ineffective therapy. For the most part, peripheral blood has been utilized for identifying predictive biomarkers, but these studies lacked sufficient precision to allow their incorporation into clinical practice. Thus, similar to an oncologist, who identify mutations through sequencing of tumor biopsies to direct therapy, our approach is to biopsy the synovium, the target organ in RA to identify changes that reflect sensitivity or resistance to a particular therapy. We brought together six leading medical centers to create REASON, a consortium with an established framework for patient recruitment, curation of clinical data, ultrasound-guided synovial biopsies, cell sorting, RNA sequencing (RNA-seq), and computational analyses. Our data show that macrophages isolated from ultrasound-guided synovial tissue biopsies obtained from patients with RA are sufficient for RNA-seq, exhibit transcriptional differences across patients with RA, and, importantly, set the framework for the stratification of patients with RA according to the most prominent disease pathway. We are the first to identify 6 transcriptional modules of co-regulated genes from isolated synovial macrophages via ultrasound-guided synovial biopsy, that are individually associated with clinical disease status and cDMARD or biologic therapy (bDMARD). This study established REASON as a leader in the United States for ultrasound-guided synovial biopsies and demonstrates the feasibility and therapeutic potential of isolating low numbers of synovial macrophages for RNA-seq to establish a precision-medicine approach for RA therapy and to understand pathobiology. While our published study identified transcriptional signatures associated with bDMARD or methotrexate usage in RA patients with active disease, there is a central need to identify genes that are predictive of response to therapy. Our overarching hypothesis is that functional genomic analysis of synovial macrophages will identify novel transcriptional signatures that inform on response to particular therapies in individual patients, thereby enabling researchers and, ultimately, clinicians to identify the drug most likely to work for each patient.

尽管针对类风湿关节炎（RA）患者有多种疗法，但几乎没有信息 指南选择为个别患者的最有效治疗方法。百分之四十六 RA反应的患者（由ACR50反应标准定义）对常规疾病的修改 抗毛刺药（CDMARDS）或CDMARDS加上抗肿瘤坏死因子（TNF）治疗。 此外，在临床试验中，有20-40％的RA受试者也不会证明最少的反应 （ACR20响应标准）。因此，显然需要开发基于精确的治疗 RA患者，新型生物标志物将增强我们预测治疗的能力 反应和限制无效的治疗。在大多数情况下，外周血已被用于 识别预测性生物标志物，但是这些研究缺乏足够的精度 纳入临床实践。因此，类似于肿瘤科医生，他们通过 肿瘤活检的测序进行直接治疗，我们的方法是活检滑膜，目标 RA中的器官以识别反映对特定疗法敏感性或抵抗力的变化。 我们汇集了六个领先的医疗中心来创建理性，这是一个与 一个既定的患者招聘框架，临床数据的策划，超声引导 滑膜活检，细胞分选，RNA测序（RNA-SEQ）和计算分析。我们的 数据表明，从超声引导的滑膜组织活检中分离出的巨噬细胞 来自RA患者的RNA-seq足以表现出患者的转录差异 使用RA，重要的是，根据RA患者的分层设定框架 最突出的疾病途径。我们是第一个确定6个转录模块的人 通过超声引导的滑膜滑膜巨噬细胞从分离的滑膜巨噬细胞中共同调节的基因 活检，与临床疾病状况和CDMARD或CDMARD或 生物疗法（BDMARD）。这项研究确立了作为美国领导者的理由 对于超声引导的滑膜活检，并证明了可行性和治疗潜力 隔离RNA-seq的滑膜巨噬细胞数量少，以建立精确的中氨酸 RA治疗和了解病理生物学的方法。而我们已发表的研究确定 RA患者中与BDMARD或甲氨蝶呤使用相关的转录特征 活性疾病，有一个核心需要鉴定可预测对治疗反应的基因。 我们的总体假设是，滑膜巨噬细胞的功能基因组分析将 确定新颖的转录特征，以告知对特定疗法的反应 个别患者，从而使研究人员并最终使临床医生识别该药物 最有可能为每个患者工作。