Biomarker Signatures for Duchenne Muscular Dystrophy

杜氏肌营养不良症的生物标志物特征

• 批准号: 10592353
• 负责人: Utkarsh J Dang
• 金额: $ 56.65万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592353
• 关键词: Affinity; Age; Antibodies; Benchmarking; Biological Assay; Biological Markers; Biology; Blood; Calibration; Categories; Classification; Clinical; Clinical Data; Clinical Trials; Complement; Cox Models; Data; Decision Making; Diagnostic; Discrimination; Disease; Disease Progression; Duchenne muscular dystrophy; Ensure; Evaluation; Future; Genes; Goals; Intervention; Knowledge; Literature; Mass Spectrum Analysis; Measurement; Measures; Methods; Modeling; Monitor; Muscle; Myopathy; Netherlands; Outcome Measure; Pathogenesis; Patients; Performance; Phase; Physicians; Program Development; Proteins; Proteomics; Publishing; Reproducibility; Sampling; Sensitivity and Specificity; Serum; Serum Proteins; Severity of illness; Signal Transduction; Specificity; Statistical Methods; Testing; Time; Training; Translating; Validation; Vital capacity; aptamer; bench to bedside; biomarker discovery; biomarker signature; blood-based biomarker; burden of illness; candidate marker; clinical biomarkers; clinical predictors; cohort; drug development; effective therapy; follow-up; performance tests; prognostic; prospective; protein biomarkers; response; screening; tandem mass spectrometry; tool

Duchenne muscular dystrophy (DMD) is a debilitating muscle disease that remains without an effective treatment despite the accumulated knowledge about the causative gene and muscle pathogenesis. Several clinical trials have failed partly because of a lack of reliable and sensitive outcome measures to assess disease progression and changes in disease course in response to an intervention. Current outcome measures such as timed physical tests and forced vital capacity (FVC) are laborious and often less objective than ideal, and moreover not sufficiently sensitive to detect meaningful short-term changes. We hypothesize that blood accessible biomarkers provide useful tools as surrogate outcome measures to monitor disease course and early changes in disease direction in DMD. Highly specific, precise, and reproducible analytical assays are needed to identify such biomarkers. We have extensively published on biomarker discoveries in DMD using SomaScan aptamer-based assay and mass spectrometry. The next step is to further develop and test biomarkers for their clinical utility. The goal of this R61/R33 proposal is to use a rigorous workflow to evaluate monitoring biomarker signatures that could be translated from bench to clinic and bench to clinical trials to help with drug development programs. We have generated strong preliminary data that support our hypothesis and feasibility. For the R61 phase, we propose two aims. Specific Aim 1 is to develop reliable, specific, and accurate methods for discovery and measurement of serum protein biomarkers in DMD. Specific Aim 2 is to define optimal monitoring biomarker signatures with robust statistical methods using longitudinal serum samples with clinical data collected from well-defined and well annotated cohorts. Specific Aim 3 is to carry out an evaluation of the developed monitoring biomarker signatures in external independent samples (retrospective or prospective) using longitudinal sera samples and clinical data collected through independent cohorts. If successful, this proposal will provide proof of concept of monitoring biomarker signatures for DMD to help with go/no-go decision making in future short term clinical trials or in day to day clinical usage by a physician to judge disease burden and severity, i.e., sensitive to short-term changes in function and predictive of longer-term disease milestones.

Duchenne肌肉营养不良（DMD）是一种使人衰弱的肌肉疾病，无效 尽管有关于病因基因和肌肉发病机理的积累知识。一些 由于缺乏可靠和敏感的结果评估疾病，临床试验部分失败了 响应干预措施的进展和疾病病程的变化。当前的结果指标，例如 定时的物理测试和强迫生命能力（FVC）是费力的，通常比理想的客观较少，并且 此外，不足以检测有意义的短期变化。我们假设血液 可访问的生物标志物提供有用的工具作为替代结果指标，以监测疾病课程和 DMD中疾病方向的早期变化。高度具体，精确和可重复的分析测定是 需要识别此类生物标志物。我们已经在DMD中广泛发表了有关生物标志物发现 基于索马斯加的适体测定法和质谱法。下一步是进一步开发和测试 生物标志物的临床实用性。该R61/R33建议的目的是使用严格的工作流程来评估 监视可以从长凳和诊所转换为临床试验的生物标志物签名 与药物开发计划。我们产生了强大的初步数据，以支持我们的假设和 可行性。对于R61阶段，我们提出了两个目标。特定目标1是开发可靠，具体和 DMD中血清蛋白生物标志物发现和测量的准确方法。具体目标2是 使用纵向血清定义具有强大统计方法的最佳监测生物标志物特征 从定义明确且注释良好的同类群体收集的临床数据的样品。特定目标3是执行 对外部独立样本中开发的监测生物标志物签名的评估 （回顾性或前瞻性）使用纵向血清样品和通过独立收集的临床数据 同伙。如果成功，该建议将提供监视DMD生物标志物签名的概念证明 在将来的短期临床试验或日常临床用法中，帮助/不执行决策 判断疾病负担和严重程度的医师，即对功能和预测性的短期变化敏感 长期疾病里程碑。