Connexin43 as a Gene Therapy To Circumvent Arrhythmogenic Cardiomyopathy

Abstract

There has been limited focus on interventions that can therapeutically alter arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), a fatal cardiac disease of the desmosomal (mechanical) cell-cell junction. The desmosome is an important target for intervention as its dysregulation is associated with severe cardiac structural alterations, which facilitate myocardial failure, cardiac arrhythmias and premature death. We exploited human models of ARVD/C, to uncover molecular alterations that underlie its diverse cardiac presentation and to reveal potential interventional targets. We showcase the ability of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes to recapitulate classic disease variations in desmosomal structural defects and to reveal connexin43 loss as a molecular predictor of disease severity within ARVD/C hearts in a donor-specific manner. Genetic restoration of full-length connexin43 in ARVD/C hiPSC derived cardiomyocytes in vitro was sufficient to rescue cardiac physiological deficits and increase the transcriptional expression of desmosomal genes. Interestingly, in vivo cardiac-specific connexin43 gene therapy in mice harboring desmosomal structural alterations associated with end-stage ARVD/C was sufficient to prolong lifespan and restore cardiac desmosomal proteins. These data establish connexin43 as a viable downstream target of ARVD/C and provide evidence for non-canonical functions for connexin43, classically associated with electrical function, in the mechanical modulation of cell-cell junctions. These findings also have broad implications in exploiting connexin43 as a therapeutic target in advanced diseases associated with underlying structural defects but also in better understanding the biological actions of connexin43 therapeutics within current ongoing clinical trials.