Abstract
Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, presents a multifaceted challenge that affects both skeletal muscle function and cardiomyocyte homeostasis, causing progressive degeneration and life-threatening cardiac complications by adolescence. Current treatments fail to prevent poor prognoses, and while FDA-approved therapies show promise in targeting dystrophin restoration, including RNA-based approaches and microdystrophin gene therapy, clinical evidence supporting their efficacy remains limited. Substantial challenges persist, particularly in achieving effective cardiac targeting, ensuring long-term safety and developing scalable treatments. Alternative therapies addressing muscle and cardiac pathophysiology are being explored alongside dystrophin-based approaches. DMD treatment is increasingly focusing on heart targeting with optimized cardiac-specific delivery strategies. Human-induced pluripotent stem cells (hiPSCs) enable DMD modelling, bridging pathophysiology and clinical phenotypes. DMD patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs) serve as in vitro models for disease mechanisms and therapy, with 3D cardiac models, either self-organizing (spheroids) or moulded, expanding on hiPSC-CMs to reflect cell interactions and myocardial tissue architecture. Advanced methods like 2D cell sheets, patches and engineered 3D human cardiac models show potential for improving cell engraftment and functional recovery in injured hearts, but their direct therapeutic application in DMD remains speculative due to extensive muscle mass loss; the complexity of cardiac and skeletal muscle interactions; and unresolved challenges related to cell integration, maturation and long-term function. Considering the premature state of cell-based therapies in this complex disease, current DMD treatment efforts focus on genetic approaches. Progress will likely depend on combining dystrophin-restoring strategies with therapies targeting disease mechanisms and improving cardiac delivery.