Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

描述(申请人提供)：本提案的总体目标是验证非侵入性磁共振成像(MRI)和波谱(MRS)在监测疾病进展方面的潜力，并作为Duchenne肌营养不良症(DMD)临床试验的替代结果衡量标准。DMD是最具破坏性的遗传相关神经肌肉疾病之一，其特征是Dstrophin的缺失，导致进行性肌肉无力、行走能力丧失和过早死亡。尽管肌营养不良患者的预后很差，但一直缺乏治疗干预措施，临床试验的结果衡量标准仅限于肌肉功能和生活质量的测量、肌肉破裂的血清生物标记物和侵入性肌肉活检。需要其他非侵入性的、对肌肉结构和成分变化敏感的量化结果指标，以促进有希望的新干预措施从临床前研究快速转化为临床试验。因此，这项建议的目标是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。本研究采用多点研究设计，结合MRI和MRS技术，对100例DMD患儿和50例年龄匹配的健康男童的下肢肌肉中的肌内脂肪含量、肌肉损伤/炎症反应和收缩面积进行检测。为了评估每一项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每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，例如肌肉力量和功能能力的丧失。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，我们将把参与这项研究的DMD男孩的永生化成纤维细胞保存在已建立的组织仓库中。我们预计，在这项建议中开发和验证的磁共振技术将适用于广泛的肌肉营养不良和其他神经肌肉疾病的临床试验。此外，MR定性可能成为进一步加深我们对肌营养不良发病机制的理解的有力工具，并有助于指导未来试验的设计。 公共卫生相关性：这个项目的目标是开发一种方法来观察新的治疗方法是否有效地纠正了患有杜氏肌营养不良症(DMD)的男孩的肌肉疾病过程，而不需要进行肌肉活组织检查。我们在DMD和肢体带状肌营养不良的小鼠模型中都有证据表明，磁共振成像可以用于跟踪疾病进展和监测治疗干预的有效性。我们将把过去的老鼠研究扩展到患有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.