UC Irvine

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Dilated cardiomyopathy is the leading cause of death in DMD patients. Smaller variants of dystrophin, called microdystrophins, amenable to packaging into adeno-associated virus (AAV), have been shown to be effective in improving skeletal muscle function in animal models. However, the functional benefit of these microdystrophins in the DMD heart remains unclear. To determine the efficacy of microdystrophin gene therapy, we compared three microdystrophin variants in DMD cardiomyocytes (CMs) differentiated from human induced pluripotent stem cells (iPSCs). We used three DMD lines of different genetic backgrounds and benchmarked against controls expressing full-length dystrophin. We also tested a dystrophin variant, minidystrophin, which is larger than the microdystrophins. Our results show that microdystrophins partially rescue disease phenotypes; however, the results are variable among genetic backgrounds. Global transcriptional profiling revealed that gene therapy altered the disease signatures of DMD iPSC-CMs. Minidystrophin significantly improved cell viability of DMD CMs in two of three lines of different genetic backgrounds. Minidystrophin also reduced arrhythmic events in one genetic background. Our findings suggest that the delivery of larger dystrophin variants may be more beneficial to delaying the onset of cardiac complications.