Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

描述（由申请人提供）：本提案的总体目标是验证无创磁共振成像（MRI）和光谱学（MRS）监测疾病进展的潜力，并作为杜氏肌营养不良症临床试验的替代结果指标（DMD）。DMD是最具破坏性的遗传相关神经肌肉疾病之一，其特征在于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。尽管肌营养不良症患者的预后不良，但缺乏治疗干预措施，临床试验的结局指标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。需要对肌肉结构和组成变化敏感的非侵入性定量结果测量，以促进有前景的新干预措施从临床前研究到临床试验的快速转化。因此，该提案旨在开发和验证磁共振作为肌营养不良症疾病进展的非侵入性生物标志物。采用多中心研究设计，本研究将使用MRI和MRS技术相结合，检查100名患有DMD的非卧床男孩和50名健康年龄匹配的男孩的下肢肌肉中的肌内脂质含量、肌肉损伤/炎症和收缩面积。为了评估每种MR指标对疾病进展的敏感性，将每年或每6个月对所有DMD男孩进行一次重新评价。此外，我们将MR指标的变化与疾病进展的标准指标（如肌肉力量和功能能力的丧失）相关联。使用MRI/MRS，我们还将检查开始皮质类固醇治疗对骨骼肌特征和组成的影响。最后，我们将存款永生化的成纤维细胞从仔细表征DMD男孩参与这项研究中建立的组织库。我们预计，本提案中开发和验证的MR技术将适用于广泛的肌营养不良症和其他神经肌肉疾病的临床试验。此外，磁共振表征可以作为一个强大的工具，以进一步推进我们的肌营养不良症的发病机制的理解，并帮助指导未来的试验设计。 公共卫生相关性：该项目的目标是开发一种方法来观察新疗法是否能有效纠正杜氏肌营养不良症（DMD）男孩肌肉中的疾病过程，而无需进行肌肉活检。我们在DMD和肢带型肌营养不良的小鼠模型中有证据表明，磁共振成像可用于跟踪疾病进展和监测治疗干预的有效性。我们将把过去的小鼠研究扩展到患有DMD的男孩。

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.