Modified mRNA Treatment Restores Cardiac Function in Desmocollin-2-Deficient Mouse Models of Arrhythmogenic Right Ventricular Cardiomyopathy.

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by irregular rhythms and right ventricular dysplasia. Sequence variations in desmosomal protein-encoding genes are linked to ARVC development. Effective treatments for ARVC are lacking. Whereas mRNA-based therapies have shown efficacy in humans, their therapeutic potential for inherited cardiomyopathies remains unclear. Whole-exome sequencing identified a novel <i>DSC2</i> sequence variation causing autosomal recessive ARVC in a Chinese family with consanguineous marriage. Mouse models with <i>Dsc2</i> sequence variation knock-in and constitutive knock-out were generated and analyzed using echocardiography and histology. Transcriptomic and biochemical analyses were conducted to explore ARVC mechanisms. Dsc2 mRNA delivered by intracardiac or transcoronary injection was assessed as a treatment for ARVC in <i>Dsc2</i> knock-out mice. In addition, effects of Dsc2 mRNA were examined in a transverse aortic constriction mouse model with noninherited right ventricular systolic dysfunction. <i>Dsc2</i>-deficient mice exhibited right ventricular dilation and dysfunction, mimicking human disease. Transcriptomic analysis identified <i>Myl7</i> as the most downregulated gene in the right ventricles of <i>Dsc2</i>-deficient mice, and its restoration by adeno-associated virus 9 rescued heart function. Dsc2 mRNA delivery, with or without lipid nanoparticle encapsulation, normalized heart size and function in <i>Dsc2</i>-deficient mice. Reduced <i>DSC2</i> and <i>MLC2a</i> expression was also noted in patients with noninherited dilated cardiomyopathy and in mice with transverse aortic constriction. A single dose of mRNA provided therapeutic effects lasting 2 to 3 months before declining. Our study reveals novel mechanisms of ARVC caused by <i>DSC2</i> loss of function, supported by human and mouse data. Loss of <i>Myl7</i> contributes to reduced cardiac contractility in ARVC and dilated cardiomyopathy with right ventricular systolic dysfunction. Dsc2 mRNA treatment demonstrated significant therapeutic potential in ARVC and transverse aortic constriction models, providing a basis for future clinical applications.