Novel Insights and Treatment of Duchenne Muscular Dystrophy-Associated Cardiomyopathy

By Pradeep P.A. Mammen, M.D.

Associate Professor of Internal Medicine
Co-Director, UT Southwestern Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder resulting from mutations within the dystrophin gene. Loss of dystrophin leads to progressive skeletal muscle wasting and cardiomyopathy. In 2020, advanced cardiomyopathy is the primary mode of death in DMD patients, despite the application of standard-of-care heart failure therapies. Over the past six years, our group at UT Southwestern has made several novel observations regarding DMD-associated cardiomyopathy.

During the 2020 AHA Scientific Sessions, our group presented a series of studies that have further expanded our understanding of DMD-associated cardiomyopathy, including a collaborative project with PhaseBio Inc. in which we have discovered a potentially novel treatment to prevent the development of a cardiomyopathy in these patients. The studies we presented were:

1. The development of DMD-associated cardiomyopathy is associated with maladaptive left atrial remodeling that may predispose DMD patients to increased episodes of atrial arrhythmias.
2. A majority of DMD female carrier patients develop left ventricular (LV) dilation and depressed LV ejection fraction prior to the development of cardiac symptoms. These results highlight the need to screen all DMD carriers by cardiac MRI and to monitor these patients closely.
3. Using a novel small molecule developed by PhaseBio Inc. that augments vasoactive intestinal peptide signaling within cardiomyocytes (PB1046), we demonstrated in mdx/Utrn+/- mice, a murine model of DMD, that PB1046 prevented myocardial fibrosis and deterioration of LV function.

Collectively, these data enhance our understanding of DMD-associated cardiomyopathy and open up a potentially novel approach to the prevention of the disease. Our ongoing research is being done in parallel with the groundbreaking work from Dr. Eric Olson’s group at UT Southwestern on the use of genome editing as a novel treatment for DMD patients in the future. Also collectively, the work being forged at the UT Southwestern Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center will pave the way for future therapies for both DMD and DMD-carrier patients. The future is truly promising.

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Twitter: @MammenPradeep