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

作者：Yan Zou, Jing Lü, Zhipeng Lian, Jianguo Jia, Juan Shen, Qifu Li, Jennifer Ming Jen Wong, Kejia Jin, Wendi Yan, Xin-yue Ren, Yang Zhang, Chenxing Huang, Huanjie Yang, Feng Huang, Jun Li, Junyu Zhai, Yamei Xu, Xialian Xu, Hang Yu, Yi Jin, Hui Gong, Jinzhong Lin, Junbo Ge, Yuxiang Dai · 发表于：Circulation · 年份：2025 · DOI：10.1161/circulationaha.124.072340 · 被引用次数：11 · 研究领域：Cardiovascular Effects of Exercise、Cardiomyopathy and Myosin Studies、Cardiac tumors and thrombi

BACKGROUND: 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. METHODS: Whole-exome sequencing identified a novel DSC2 sequence variation causing autosomal recessive ARVC in a Chinese family with consanguineous marriage. Mouse models with Dsc2 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 Dsc2 knock-out mice. In addition, effects of Dsc2 mRNA were examined in a transverse aortic constriction mouse model with noninherited right ventricular systolic dysfunction. RESULTS: Dsc2 -deficient mice exhibited right ventricular dilation and dysfunction, mimicking human disease. Transcriptomic analysis identified Myl7 as the most downregulated gene in the right ventricles of Dsc2 -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 functio...