Complete restoration of multiple dystrophin isoforms in genetically corrected Duchenne muscular dystrophy patient–derived cardiomyocytes

INTRODUCTION Duchenne muscular dystrophy (DMD) is one of the most common and severe inherited neuromuscular disorders, affecting 1 in 3,500 newborn males. DMD is caused by mutations in the dystrophin gene encoding a key structural protein of the dystrophin glycoprotein complex, which connects the contracting cytoskeletal machinery of skeletal and cardiac muscle fibers to the extracellular matrix scaffold.1 The absence of dystrophin in DMD patients causes a broad spectrum of physical consequences, eventually leading to a premature death.2 Approximately 20% of deaths are the result of cardiomyopathies and/or cardiac conduction abnormalities. The improvement in treatments of respiratory muscle disease allowed an increased life span of patients affected by DMD. Consequently, cardiomyopathies (which are present in ~90% of DMD patients) are emerging as a major cause of morbidity and mortality.3 In addition, many experimental therapies have mainly focused on skeletal muscle, aiming at the restoration of dystrophin expression in myofibers, and have failed to improve cardiac function.4 The derivation of DMD patient–specific cardiomyocytes (CMs) and the correction of their genetic defect could provide a valuable cell source for in vitro modeling and for studying DMD-related cardiac dysfunctions, in addition to potentially representing a significant advancement toward an effective therapy for DMD-associated cardiomyopathies. The efficient reprogramming technology pioneered by Yamanaka and colleagues5 opened the perspective of deriving large numbers of disease-specific human cells in vitro. Human induced pluripotent stem (hiPS) cells are recently emerging as an ideal cell source for the generation of clinically relevant cardiac disease models.6 Several recent studies demonstrate how hiPS cell– derived CMs can be used for modeling the pathological phenotype of inherited cardiac disorders, such as the LEOPARD syndrome,7 type 1 and 2 long QT syndrome,8–10 catecholaminergic polymorphic ventricular tachycardia,11 arrhythmogenic right ventricular dysplasia/cardiomyopathy,12 and the dilated cardiomyopathy.13 However, to our knowledge, CMs from DMD patient–derived hiPS cells have never been obtained so far. Disease-specific hiPS cell–derived CMs could represent a platform for studying in vitro the pathological dystrophic phenotype and for testing and validating the therapeutic approaches and their efficiency in restoring the normal phenotype.14 In addition, it has been recently demonstrated that hiPS cell–derived CMs can efficiently integrate in injured hearts of a guinea pig,15 providing a proof of principle for the application of these cells in regenerative medicine aiming at the treatment of cardiac dysfunctions. In the perspective of a therapeutic application, the genetic defect of CMs derived from inherited disease–specific hiPS cells should be corrected before these cells are reengrafted in the patient.