Magnetic Resonance Imaging and Biomarkers for Muscular Dystropy

肌营养不良症的磁共振成像和生物标志物

• 批准号: 8958272
• 负责人: KRISTA H VANDENBORNE
• 金额: $ 147.27万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-05 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958272
• 关键词: 7 year old; Academia; Address; Adrenal Cortex Hormones; Advocacy; Age; Age Distribution; Biological; Biological Markers; Blood; Clinical Trials; Clinical Trials Design; Communities; Data; Data Collection; Deposition; Development; Disease; Disease Progression; Duchenne muscular dystrophy; Educational workshop; Enrollment; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Forearm; Funding; Future; Genetic; Goals; Grant; Incidence; Industry; Inflammation; Knowledge; Left; Leg; Life; Link; Lower Extremity; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Monitor; Multicenter Studies; Muscle; Muscle Weakness; Muscular Dystrophies; Natural History; Neuromuscular Diseases; Outcome Measure; Pathology; Patients; Performance; Population; Predictive Value; Recruitment Activity; Research Infrastructure; Resources; Sampling; Shoulder; Site; Spectrum Analysis; Staging; Statistical Models; Stress; Testing; Time; Tissues; Upper Extremity; Upper arm; Urine; Validation; Walking; arm; biceps brachii muscle; boys; cohort; deltoid muscle; design; emerging adult; experience; imaging biomarker; improved; inclusion criteria; interest; loss of function; meetings; multidisciplinary; muscular structure; public health relevance; spectroscopic imaging; therapeutic development; therapeutic target; therapy development

 DESCRIPTION (provided by applicant): Over the last decade tremendous progress has been made in identifying therapeutic targets for Duchenne muscular dystrophy (DMD), a devastating progressive neuromuscular disease. However the design of clinical trials has been challenging, with sparse natural history data, a limited patient pool to recruit from, and few sensitive noninvasive outcome measures. Recent setbacks in several clinical trials have underscored the crucial need for transitional outcome measures that are sensitive across various stages of disease progression, including in non-ambulatory boys, and can reliably be implemented at multiple sites. In the initial funding cycle of this grant, we successfully implemented the first multicenter MR study in DMD and demonstrated that lower extremity quantitative MR measures (e.g. MRS fat fraction and MRI/MRS T2) are sensitive to disease progression in ambulatory boys, responsive to corticosteroid treatment, and reliable across multiple sites. In Aim 1 of this renewal application, we propose to extend the natural history MR biomarker study (iDMD) in the lower extremity muscles. Given the age distribution of the iDMD subject cohort (n=136; ages 7-18 years) we have an unprecedented opportunity to examine the sensitivity of quantitative MR measures (including 8-point Dixon and UTE) at different stages of disease progression, assess their value in predicting loss of ambulation, and obtain extremely valuable long term natural history data. In Aim 2, we will develop and validate upper extremity MR biomarkers and outcome measures in the same subject cohort. Specifically, we will perform a detailed MRI/MRS characterization of the forearm, upper arm and shoulder girdle. No prior MR imaging studies in DMD have been performed on upper extremity muscles that are essential for function, such as the biceps and deltoid, leaving a considerable gap in knowledge. MR measures in boys with DMD will be repeated at yearly intervals. In addition, we will correlate changes in MRI/MRS measures with loss in upper extremity function and strength. Finally, in Aim 3 we will build on our current infrastructure to establish a National Tissue and Data Resource, linking biological samples (fibroblasts, blood/urine) with genetic, detailed MRI/MRS, strength, functional, and demographic data collected in iDMD and making them available to the larger DMD community. This project addresses several critical barriers in therapeutic development and has the potential to significantly improve future clinical trials in DMD, as well as other neuromuscular diseases.

 描述（由申请人提供）：在过去十年中，在确定杜氏肌营养不良症（DMD）（一种破坏性进行性神经肌肉疾病）的治疗靶点方面取得了巨大进展。然而，临床试验的设计一直具有挑战性，自然历史数据稀疏，可供招募的患者库有限，而且敏感的非侵入性结果指标也很少。最近几项临床试验的挫折凸显了对过渡结果测量的迫切需要，这些测量对疾病进展的各个阶段（包括不能行走的男孩）都敏感，并且可以在多个地点可靠地实施。在这笔资助的初始资助周期中，我们成功实施了第一个 DMD 多中心 MR 研究，并证明下肢定量 MR 测量（例如 MRS 脂肪分数和 MRI/MRS T2）对流动男孩的疾病进展敏感，对皮质类固醇治疗有反应，并且在多个部位可靠。在本次更新申请的目标 1 中，我们建议扩展下肢肌肉的自然史 MR 生物标志物研究 (iDMD)。鉴于 iDMD 受试者队列的年龄分布（n=136；年龄 7-18 岁），我们有前所未有的机会来检查定量 MR 测量（包括 8 点 Dixon 和 UTE）在疾病进展不同阶段的敏感性，评估其在预测行走丧失方面的价值，并获得极其有价值的长期自然史数据。在目标 2 中，我们将在同一受试者队列中开发并验证上肢 MR 生物标志物和结果测量。具体来说，我们将对前臂、上臂和肩带进行详细的 MRI/MRS 表征。先前尚未对 DMD 的 MR 成像研究对功能至关重要的上肢肌肉（如二头肌和三角肌）进行过，因此在知识上存在相当大的空白。患有 DMD 的男孩的 MR 测量将每年重复一次。此外，我们还将 MRI/MRS 测量的变化与上肢功能和力量的丧失联系起来。最后，在目标 3 中，我们将在现有基础设施的基础上建立国家组织和数据资源，将生物样本（成纤维细胞、血液/尿液）与 iDMD 中收集的遗传、详细 MRI/MRS、强度、功能和人口统计数据联系起来，并将其提供给更大的 DMD 社区。该项目解决了治疗开发中的几个关键障碍，并有可能显着改善 DMD 以及其他神经肌肉疾病的未来临床试验。