Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

描述（由申请人提供）：本申请的总体目标是验证无创磁共振成像（MRI）和波谱（MRS）监测疾病进展的潜力，并作为杜氏肌营养不良症（DMD）临床试验的替代结果测量。DMD是最具破坏性的遗传相关神经肌肉疾病之一，其特征是缺乏肌营养不良蛋白，导致进行性肌肉无力，丧失行走能力和过早死亡。尽管肌肉萎缩症患者预后不良，但缺乏治疗干预措施，临床试验的结果测量仅限于肌肉功能和生活质量的测量，肌肉分解的血清生物标志物和侵入性肌肉活检。为了促进从临床前研究到临床试验的有希望的新干预措施的快速转化，需要额外的非侵入性和对肌肉结构和成分变化敏感的定量结果测量。因此，本提案的目标是开发和验证磁共振作为肌萎缩症疾病进展的非侵入性生物标志物。采用多位点研究设计，本研究将使用MRI和MRS技术结合检查100名患有DMD的流动男孩和50名健康年龄匹配的男孩的肌肉内脂质含量、肌肉损伤/炎症和下肢肌肉收缩面积。为了评估每种MR测量对疾病进展的敏感性，所有患有DMD的男孩将每隔一年或6个月重新评估一次。此外，我们将把MR测量的变化与疾病进展的标准测量相关联，如肌肉力量和功能能力的丧失。使用MRI/MRS，我们还将检查启动皮质类固醇治疗对骨骼肌特征和组成的影响。最后，我们将在已建立的组织库中保存来自参与本研究的经过仔细鉴定的DMD男孩的永生化成纤维细胞。我们预计，在本提案中开发和验证的MR技术将适用于广泛的肌肉萎缩症和其他神经肌肉疾病的临床试验。此外，MR表征可以作为一个强大的工具，进一步推进我们对肌萎缩症发病机制的理解，并帮助指导未来试验的设计。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to validate the potential of noninvasive magnetic resonance imaging (MRI) and spectroscopy (MRS) to monitor disease progression and to serve as a surrogate outcome measure for clinical trials in Duchenne muscular dystrophy (DMD). DMD is one of the most devastating genetically linked neuromuscular diseases and is characterized by the absence of dystrophin, resulting in progressive muscle weakness, loss of walking ability and premature death. Despite the poor prognosis for patients with muscular dystrophy, therapeutic interventions have been lacking, and outcome measures for clinical trials have been limited to measures of muscle function and quality of life, serum biomarkers of muscle breakdown and invasive muscle biopsies. Additional quantitative outcome measures that are noninvasive and sensitive to changes in muscle structure and composition are needed to facilitate the rapid translation of promising new interventions from preclinical studies to clinical trials. As such, this proposal targets the development and validation of magnetic resonance as a noninvasive biomarker of disease progression in muscular dystrophy. Using a multi-site research design this study will examine the intramuscular lipid content, muscle damage/inflammation and contractile area in the lower extremity muscles of 100 ambulatory boys with DMD and 50 healthy age matched boys using a combination of MRI and MRS technologies. In order to assess the sensitivity of each MR measure to disease progression, all boys with DMD will be re-evaluated in yearly or 6 month intervals. In addition, we will correlate changes in MR measures with standard measures of disease progression, such as loss in muscle strength and functional ability. Using MRI/MRS we will also examine the effect of initiating corticosteroid treatment on skeletal muscle characteristics and composition. Finally, we will deposit immortalized fibroblasts from carefully characterized DMD boys participating in this study in established tissue repositories. We anticipate that the MR techniques developed and validated in this proposal will be suitable for clinical trials in a wide range of muscular dystrophies and other neuromuscular diseases. In addition, MR characterization may serve as a powerful tool to further advance our understanding of the pathogenesis of muscular dystrophy and help guide the design of future trials. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a way to observe whether or not new therapies are effective in correcting the disease process in muscles of boys with Duchenne muscular dystrophy (DMD) without the need to take muscle biopsies. We have evidence in mouse models of both DMD and limb girdle muscular dystrophy that magnetic resonance imaging can be used to track disease progression and monitor the effectiveness of therapeutic interventions. We will extend our past mouse studies to boys with DMD.