Duchenne Muscular Dystrophy-Related Cardiomyopathy: Beyond Dystrophin Deficiency in Skeletal Muscle


Pre-Clinical Research

Poster Number: S34


Luca Caputo, PhD, Sanford Burnham Prebys Medical Discovery Institute, Chiara Nicoletti, Sanford Burnham Prebys, Jimmy Massenet, PhD, Sanford Burnham Prebys Medical Discovery Institute, Jeffrey S Chamberlain, MD, University of Washington School of Medicine, Lorenzo Puri, MD, Children's National Medical Center

Duchenne Muscular Dystrophy (DMD) is a neuromuscular disease caused by mutations that impair dystrophin (Dys) expression in skeletal muscles as well as other cell types. While impaired function and loss of skeletal myofibers lead to progressive body paralysis and respiratory failure, the current leading cause of DMD patient death is cardiomyopathy. Cardiomyopathy is also observed in patients of Becker muscle dystrophy (BMD) – representing the leading cause of death – and in approximately 10 to 20% of mother carriers of DMD and BMD.

To understand the molecular cell-autonomous pathogenic events causing the onset of DMD-cardiomyopathies and if/how they differs from alterations in DMD-skeletal muscles, we performed parallel differentiation of iPSCs into induced Cardiomyocytes (iCM) and induced Skeletal Muscles (iSkM) of healthy hIPSCs and the isogenic DMD hIPSCs line – DMD∆8/9 to understand cell type-specific epigenome and transcriptome alterations of DMD patients. To understand whether current pre-/clinical approaches are able to revert DMD alterations to the “healthy” status we either delivered μDys using a lentiviral system or differentiated DMDr∆6/9 – a line in which dystrophin reading frame is restored – and differentiate them into iCM and iSkM to analyze the epigenetic landscape and transcriptional output.

We identified common and as well tissue specific chromatin and transcriptomic pathogenic alteration in DMD derived iCMs or iSkM. These results will lead to the definition of additional therapeutic approaches to treat DMD-cardiomyopathies.