Prospective Development of a Multimodal Biomaker Platform for Predictive Risk Stratification of Cardiac Disease in Duchenne Muscular Dystrophy

多模式 Biomaker 平台的前瞻性开发，用于杜氏肌营养不良症心脏病的预测风险分层

• 批准号: 10016246
• 负责人: Jonathan Harvey Soslow
• 金额: $ 57.79万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10016246
• 关键词: Prospective; Development; Multimodal; Biomaker; Platform

PROJECT SUMMARY/ABSTRACT Duchenne muscular dystrophy (DMD) is a rare and devastating disease with no cure affecting 1 in 4700 male births. DMD results in loss of ambulation, respiratory failure, cardiomyopathy (CM), and premature death. CM is the leading cause of death in DMD, but CM progression is variable. Currently, there are no genetic, blood, or imaging biomarkers that can predict high- or low-risk cardiovascular phenotype. More importantly, there are no established cardiac outcome measures. Novel, targeted therapeutics are necessary to treat DMD CM, but this knowledge gap makes clinical trials challenging. A better understanding of CM disease progression is critical to improve clinical trial efficiency. To address these obstacles, we propose a rigorous, prospective, serial evaluation in the largest cohort of DMD patients with complete cardiovascular phenotyping. This study will assess serum and imaging markers of fibrosis as surrogate biomarkers of disease progression and ultimately mortality. It will leverage the DMD Cardiac Consortium (created as part of the PIs R56), which has standardized cardiac MRI and skeletal muscle protocols for the assessment of DMD progression. We will combine this prospective evaluation with a comprehensive assessment of genetic polymorphisms performed using DNA collected from the largest DMD registry. The central hypothesis of this proposal is that imaging and blood biomarkers detect subclinical myocardial fibrosis with potential for use as surrogate biomarkers of CM in DMD. We further hypothesize genotyping in a large sample size of DMD patients can determine the impact of genetic polymorphisms on DMD CM progression. Aim 1 will collect DNA using the largest DMD registry to discover genetic variants that determine DMD CM severity. Aim 2 will identify serum biomarkers that characterize DMD CM disease severity. Aim 3 will define the longitudinal progression of DMD CM in the current era and determine serum and imaging measures of myocardial fibrosis that herald a subsequent change in cardiac function. The proposed studies will include four of the larger cardiac muscular dystrophy centers in the country and will create the largest cohort of DMD patients with rigorous cardiovascular phenotyping. The consortium has been constructed to allow additional sites to join in order to foster the larger collaborative efforts necessary to achieve meaningful results in this rare disease. This project directly addresses the goals of the funding mechanism to characterize the natural history of rare diseases, identify genotype and phenotype subpopulations, and develop clinical outcome measures. These results will have clinical relevance for other similar diseases, including Becker muscular dystrophy and female mutation carriers. The innovation of this grant is the integration of genetic polymorphisms with imaging and blood biomarkers to identify surrogate biomarkers of cardiovascular disease. The ability to readily test novel and targeted therapies is crucial for lengthening and improving the quality of life in boys and men with DMD.

项目概要/摘要 杜氏肌营养不良症 (DMD) 是一种罕见且毁灭性的疾病，无法治愈，每 4700 名男性中就有 1 人受到影响 出生。 DMD 会导致行走能力下降、呼吸衰竭、心肌病 (CM) 和过早死亡。厘米 是 DMD 死亡的主要原因，但 CM 进展情况各不相同。目前，没有遗传、血液或 可以预测高风险或低风险心血管表型的成像生物标志物。更重要的是，没有 制定的心脏结局指标。治疗 DMD CM 需要新颖的靶向疗法，但这 知识差距使临床试验充满挑战。更好地了解 CM 疾病进展对于 提高临床试验效率。为了解决这些障碍，我们提出了一个严格的、前瞻性的、系列的 对具有完整心血管表型的最大 DMD 患者队列进行评估。这项研究将 评估纤维化的血清和成像标记物作为疾病进展的替代生物标记物，并最终 死亡。它将利用 DMD 心脏联盟（作为 PI R56 的一部分创建），该联盟已 用于评估 DMD 进展的标准化心脏 MRI 和骨骼肌方案。我们将 将这种前瞻性评估与对遗传多态性的综合评估相结合 使用从最大的 DMD 登记处收集的 DNA。该提案的中心假设是成像和 血液生物标志物检测亚临床心肌纤维化，有可能用作 CM 的替代生物标志物 DMD。我们进一步假设对 DMD 患者的大样本进行基因分型可以确定 遗传多态性对 DMD CM 进展的影响。目标 1 将使用最大的 DMD 登记处收集 DNA 发现决定 DMD CM 严重程度的基因变异。目标 2 将鉴定血清生物标志物 表征 DMD CM 疾病的严重程度。目标 3 将定义 DMD CM 的纵向进展 当前时代并确定心肌纤维化的血清和影像学指标，这预示着随后的心肌纤维化 心脏功能的变化。拟议的研究将包括四项较大的心肌营养不良症 全国的中心，并将创建最大的 DMD 患者队列，患有严格的心血管疾病 表型分析。该联盟的建立是为了允许更多站点加入，以培育更大的 为了在这种罕见疾病上取得有意义的成果，需要共同努力。这个项目直接 解决资助机制的目标，以描述罕见疾病的自然史，确定 基因型和表型亚群，并制定临床结果指标。这些结果将会有 与其他类似疾病的临床相关性，包括贝克尔肌营养不良症和女性突变携带者。 该资助的创新之处在于将遗传多态性与成像和血液生物标志物相结合，以 识别心血管疾病的替代生物标志物。能够轻松测试新颖的靶向疗法 对于延长患有 DMD 的男孩和男性的生活质量并提高其生活质量至关重要。