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.
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.
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