For families navigating Duchenne muscular dystrophy, gene therapy has represented one of the most hopeful frontiers in modern medicine — yet this NEJM correspondence raises a critical safety signal that the field cannot afford to dismiss. The intersection of therapeutic promise and cardiac risk demands immediate scrutiny from clinicians, regulators, and patients alike.
This correspondence published in the New England Journal of Medicine reports cardiotoxic effects observed in patients with Duchenne muscular dystrophy (DMD) following adeno-associated virus (AAV)-based gene therapy delivering a truncated microdystrophin construct. Despite confirmed microdystrophin expression — the intended therapeutic endpoint demonstrating successful gene delivery and protein production — some patients exhibited clinically meaningful cardiac adverse events. The findings suggest that expression of the therapeutic protein does not guarantee cardiac safety, and that the myocardium may respond adversely to either the viral vector, the immune response it triggers, or the microdystrophin construct itself.
This report arrives at a pivotal moment in the AAV gene therapy landscape. The FDA approval of delandistrogene moxeparvovec (Elevidys) in 2023 generated significant momentum, but post-market surveillance has already prompted regulatory scrutiny. AAV-mediated cardiac toxicity is not unique to DMD therapies — high-dose AAV delivery has raised myocarditis concerns across multiple neuromuscular programs. What makes this particularly complex in DMD is that the heart is already a primary target organ of dystrophin deficiency, making it exceptionally difficult to distinguish gene-therapy-induced cardiomyopathy from disease progression. The apparent paradox — detectable microdystrophin yet cardiac deterioration — challenges the assumption that protein restoration is both necessary and sufficient for therapeutic benefit. This is an incremental but consequential safety signal, reinforcing that long-term cardiac monitoring must be embedded as a standard-of-care requirement for all AAV-treated DMD patients, and that microdystrophin expression alone is an insufficient surrogate for clinical cardiac safety.