Duchenne muscular dystrophy (DMD) is a rare and devastating disease with no cure affecting 1 in 4700 male births. DMD results in loss of ambulation, respiratory failure, cardiomyopathy (CM), and premature death. CM is the leading cause of death in DMD, but CM progression is variable. Currently, there are no genetic, blood, or imaging biomarkers that can predict high- or low-risk cardiovascular phenotype. More importantly, there are no established cardiac outcome measures. Novel, targeted therapeutics are necessary to treat DMD CM, but this knowledge gap makes clinical trials challenging. A better understanding of CM disease progression is critical to improve clinical trial efficiency. To address these obstacles, we propose a rigorous, prospective, serial evaluation in the largest cohort of DMD patients with complete cardiovascular phenotyping. This study will assess serum and imaging markers of fibrosis as surrogate biomarkers of disease progression and ultimately mortality. It will leverage the DMD Cardiac Consortium (created as part of the PIs R56), which has standardized cardiac MRI and skeletal muscle protocols for the assessment of DMD progression. We will combine this prospective evaluation with a comprehensive assessment of genetic polymorphisms performed using DNA collected from the largest DMD registry. The central hypothesis of this proposal is that imaging and blood biomarkers detect subclinical myocardial fibrosis with potential for use as surrogate biomarkers of CM in DMD. We further hypothesize genotyping in a large sample size of DMD patients can determine the impact of genetic polymorphisms on DMD CM progression.
Aim 1 will collect DNA using the largest DMD registry to discover genetic variants that determine DMD CM severity.
Aim 2 will identify serum biomarkers that characterize DMD CM disease severity.
Aim 3 will define the longitudinal progression of DMD CM in the current era and determine serum and imaging measures of myocardial fibrosis that herald a subsequent change in cardiac function. The proposed studies will include four of the larger cardiac muscular dystrophy centers in the country and will create the largest cohort of DMD patients with rigorous cardiovascular phenotyping. The consortium has been constructed to allow additional sites to join in order to foster the larger collaborative efforts necessary to achieve meaningful results in this rare disease. This project directly addresses the goals of the funding mechanism to characterize the natural history of rare diseases, identify genotype and phenotype subpopulations, and develop clinical outcome measures. These results will have clinical relevance for other similar diseases, including Becker muscular dystrophy and female mutation carriers. The innovation of this grant is the integration of genetic polymorphisms with imaging and blood biomarkers to identify surrogate biomarkers of cardiovascular disease. The ability to readily test novel and targeted therapies is crucial for lengthening and improving the quality of life in boys and men with DMD.

Public Health Relevance

Heart dysfunction is now the leading cause of death in patients with Duchenne muscular dystrophy (DMD). The central objectives of this proposal are to combine genetic differences with blood and imaging markers to help predict development of significant heart dysfunction and scar. These aims have the potential to decrease the size and cost of therapeutic clinical trials for DMD heart disease, speeding up the adoption of new therapies and improving quality of life in boys and men with DMD.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1)
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Jillapalli, Devanand
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Vanderbilt University Medical Center
United States
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