Cardiac AAV9:PKP2 Gene Therapy Reduces Ventricular Arrhythmias, Reverses Adverse Remodeling, and Reduces Mortality in a Mouse Model of ARVC

Abstract Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease. Mutations in desmosome gene Plakophilin-2 (PKP2) account for 45% of ARVC cases and result in reduced gene expression. Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. We demonstrated that a single-dose cardiac AAV9:PKP2 gene delivery effectively prevented disease development before overt cardiomyopathy and attenuated disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. These results indicate that cardiac AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.