Base editing effectively prevents the early-onset hypertrophic cardiomyopathy in Mybpc3 mutant mice

Pathogenic variants in MYBPC3 (myosin-binding protein C3) are the leading cause of genetic hypertrophic cardiomyopathy (HCM). Currently, there is no specific and effective treatment for this disease. Base editing is an emerging modality for treating monogenic diseases; however, its effect on MYBPC3 cardiomyopathy remains unexplored.Mybpc3R946X/R946X mice developed early-onset left ventricular hypertrophy, systolic dysfunction, ventricular dilatation, and arrythmias. exABEmax inefficiently corrected the Mybpc3R946X mutation. In contrast, exABE8e increased the efficiency by 3.6-fold and retained low level off-target editing. In vivo administration of exABE8e efficiently corrected Mybpc3R946X mutation in cardiomyocytes and prevented heart function decline, hypertrophic cardiomyopathy, and ventricular dysfunction. The therapeutic efficacy of exABE8e-mediated gene correction surmounted AAV-mediated Mybpc3 gene replacement.Our study unveiled the immense potential of base editing to treat fatal inherited cardiomyopathies and opened a new avenue for the therapeutic managements of inherited cardiac diseases.