Gene Therapy for Cardiomyopathy: Tools, Targets, and Trials

Cardiomyopathy remains a leading cause of heart failure-related morbidity and mortality, driven by diverse genetic architectures that include monogenic variants, oligogenic interactions, and polygenic risk. Rapid advances in genomic medicine and vector engineering have positioned cardiac gene therapy as a transformative therapeutic approach. Adeno-associated virus-mediated gene replacement for hypertrophic, dilated, and arrhythmogenic cardiomyopathies has transitioned into early-phase clinical trials, with emerging data providing promising signals of myocardial transgene expression and improvements in circulating biomarkers such as NT-proBNP (N-terminal pro-B-type natriuretic peptide). Genome-editing platforms-including CRISPR-mediated base editing and prime editing-offer the potential for durable variant correction without introducing double-stranded breaks. Yet, major translational challenges remain, including strategies to bypass liver uptake to ensure high-efficiency transduction of cardiomyocytes, overcoming delivery constraints, including the cargo size of adeno-associated virus vectors, addressing toxicities, and establishing adequate immunosuppressive regimens. Novel strategies such as direct antegrade and retrograde coronary infusion, capsid engineering, split-intein dual-adeno-associated virus systems, miniaturization of CRISPR-related proteins, and nonviral nanoparticles are underway. As first-in-human cardiomyopathy gene therapy trials begin to define safety, dosing, and vector tropism in the failing human heart, the field is entering an inflection point where genomic diagnosis, molecular correction, and phenotype-guided delivery can converge into precision heart failure therapeutics. This review highlights current progress, emerging platforms, and scientific hurdles that must be overcome to realize a new era of potentially curative, mechanism-directed therapy for inherited and acquired cardiomyopathies.