Circulating MicroRNAs as Disease Biomarkers in Multiple Sclerosis

描述（由申请人提供）： 该申请是为了响应 NIH FOA 邀请项目申请，以识别和鉴定源自人体体液的基于细胞外 RNA (exRNA) 的生物标志物，以诊断和监测疾病进展和对治疗的反应。我们建议在明确的多发性硬化症 (MS) 患者群体中识别和验证候选循环 miroRNA。 NIH FOA 强烈鼓励使用现有的人类生物样本进行研究，对于 UH2 阶段，我们将利用名为 CLIMB（布莱根妇女医院多发性硬化症综合纵向调查）的独特资源。 CLIMB 是一个由 2000 多名多发性硬化症患者组成的队列，于 12 年前开始招募，包括每年的血液样本、临床检查和定量 MRI 成像。我们提供的初步数据表明，我们确实可以测量 MS 队列中的循环 miRNA，并发现其与疾病阶段、治疗反应和残疾之间的联系。对于 UH3 阶段，我们已经从学术和制药合作者那里确定了有价值的血液样本来源，这些样本将用于验证我们的 UH2 研究结果，并为临床中使用循环 miRNA 提供基础。 UH2 阶段的具体目标： 1) 通过将多发性硬化症患者与健康对照、患有其他神经系统疾病的患者和患有其他自身免疫性疾病的患者进行比较，鉴定可作为诊断生物标志物的 miRNA。 2) 通过比较 RRMS 患者、SPMS 患者和 PPMS 患者来识别疾病阶段 miRNA 生物标志物。 3) 通过确定两年内每个 miRNA 的变化并评估哪些 miRNA 对疾病状态的长期变化敏感，来识别预后 miRNA 生物标志物。 4) 通过比较治疗反应者和非反应者的基线 miRNA 表达来识别治疗反应 miRNA 生物标志物。 5) 通过将 miRNA 与疾病状态的 EDSS 和 MRI 测量值关联起来，识别残疾 miRNA 生物标志物。 UH3 阶段的具体目标：将广泛研究 UH2 阶段鉴定的循环 miRNA，我们将实现以下两个目标： 1. 在明确定义的独立患者队列中验证 UH2 阶段鉴定的 miRNA 生物标志物。 2.确定在UH2阶段鉴定出的哪些miRNA可以用作临床前疾病生物标志物。我们将利用来自多个来源的经过充分表征的血清样本，包括：SUMMIT 国际 MS 联盟、NIH 赞助的 CombiRx 临床试验、Biogen Idec 赞助的 IMPACT 试验、瑞典 EIMS MS 流行病学调查、加拿大儿科脱髓鞘疾病研究和 GEMS（基因与环境 MS 研究）。

DESCRIPTION (provided by applicant): This application is in response to an NIH FOA inviting applications for projects to identify and qualify extracellular RNA (exRNA)-based biomarkers derived from human body fluids to diagnose and monitor disease progression and response to therapy. We propose to identify and validate candidate circulating miroRNAs in well-defined multiple sclerosis (MS) patient populations. Studies using existing human biospecimen collections were strongly encouraged by the NIH FOA and for the UH2 phase we will take advantage of a unique resource termed CLIMB (Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital). CLIMB is a cohort of over 2000 MS patients that began enrollment 12 years ago and includes yearly blood samples, clinical exams and quantitative MRI imaging. We present preliminary data that we can indeed measure circulating miRNAs in our MS cohort and have found links to disease stage, response to therapy and disability. For the UH3 phase we have identified valuable sources of blood samples from both academic and pharmaceutical collaborators that will be used to validate our UH2 findings and provide the basis for the use of circulating miRNAs in the clinic. SPECIFIC AIMS FOR UH2 PHASE: 1) Identify miRNAs that will act as diagnostic biomarkers by comparing MS patients to healthy controls, patients with other neurological diseases and patients with other autoimmune diseases. 2) Identify disease stage miRNA biomarkers by comparing RRMS patients, SPMS patients and PPMS patients. 3) Identify prognostic miRNA biomarkers by determining the change in each miRNA over two years and assessing which miRNAs are sensitive to long-term change in disease status. 4) Identify treatment response miRNA biomarkers by comparing the baseline miRNA expression in responders and non- responders to treatment. 5) Identify disability miRNA biomarkers by correlating miRNAs with EDSS and MRI measures of disease status. SPECIFIC AIMS FOR UH3 PHASE: Circulating miRNAs identified in the UH2 phase will be extensively studied and we will address the following two aims: 1. Validation of miRNA biomarkers identified in the UH2 phase in well defined independent patient cohorts. 2. Determine which miRNAs identified in the UH2 phase can be used as preclinical disease biomarkers. We will take advantage of well characterized serum samples from a number of sources including: The SUMMIT International MS Consortium, the NIH sponsored CombiRx clinical trial, the Biogen Idec sponsored IMPACT trial, the Swedish EIMS epidemiologic investigation of MS, the Canadian Pediatric Demyelinating Disease Study and the GEMS (Genes and Environment MS study).