Overexpression of Wild-Type TMEM43 Improves Cardiac Function in Arrhythmogenic Right Ventricular Cardiomyopathy Type 5

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is the most aggressive type of ARVC, caused by a fully penetrant missense mutation (p.S358L) in TMEM43 (transmembrane protein 43). Pathologically, the disease is characterized by dilation of the cardiac chambers and fibrofatty replacement of the myocardium, which results in heart failure and sudden cardiac death. Current therapeutic options are limited, and no specific therapies targeting the primary cause of the disease have been proposed. METHODS: We investigated whether overexpression of wild-type (WT) TMEM43 could overcome the detrimental effects of the mutant form. We used transgenic mouse models overexpressing either WT or mutant (S358L) TMEM43 to generate a double transgenic mouse line overexpressing both forms of the protein. In addition, we explored if systemic delivery of a codon-optimized self-complementary adeno-associated virus bearing WT-TMEM43 could improve disease progression assessed by ECG and echocardiography. RESULTS: Double transgenic mice overexpressing both WT and mutant TMEM43 forms showed delayed ARVC5 onset, improved cardiac contraction, and reduced ECG abnormalities compared with mice expressing S358L-TMEM43. In addition, cardiomyocyte death and myocardial fibrosis were reduced, with an overall increase in survival. Finally, we demonstrated that a single systemic administration of an adeno-associated virus carrying codon-optimized WT-TMEM43 prevents ventricular dysfunction and ECG abnormalities induced by S358L-TMEM43. CONCLUSIONS: Overexpression of WT-TMEM43 improves the pathological phenotype in a mouse model of ARVC5. Adeno-associated virus-mediated delivery of WT-TMEM43 offers a promising and specific therapy for patients suffering from this highly lethal disease. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT05885412, NCT06109181, and NCT06228924.