Magnetic Resonance Imaging and Biomarkers for Muscular Dystropy

 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，自然史数据稀少，招募的患者有限，敏感的非侵入性结局指标很少。最近几项临床试验的挫折强调了对过渡性结局指标的迫切需要，这些指标在疾病进展的各个阶段都是敏感的，包括在卧床男孩中，并且可以在多个地点可靠地实施。在该资助的初始资助周期中，我们成功实施了DMD的第一项多中心MR研究，并证明下肢定量MR测量（例如MRS脂肪分数和MRI/MRS T2）对非卧床男孩的疾病进展敏感，对皮质类固醇治疗有反应，并且在多个站点可靠。在本更新申请的目标1中，我们建议扩展下肢肌肉中的自然史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检查定量MR测量（包括8点狄克逊和UTE）在疾病进展不同阶段的灵敏度，评估其在预测Ambloid丢失方面的价值，并获得极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和验证上肢MR生物标志物和结局指标。具体来说，我们将对前臂、上臂和肩带进行详细的MRI/MRS表征。以前没有对DMD进行过上肢肌肉的MR成像研究，这些肌肉对功能至关重要，例如二头肌和三角肌，这留下了相当大的知识空白。DMD男孩的MR测量将每年重复一次。此外，我们将MRI/MRS测量的变化与上肢功能和力量的丧失相关联。最后，在目标3中，我们将在现有基础设施的基础上建立一个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，详细的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。

 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.