Base editing effectively prevents early-onset severe cardiomyopathy in Mybpc3 mutant mice
Shuo Wu, Ping Yang, Zilong Geng, Yige Li, Zhizhao Guo, Yingmei Lou, Shasha Zhang, Junhao Xiong, Huan Hu, Xiaoling Guo, William T. Pu, Yan Zhang, Dan Zhu, Bing Zhang
Abstract
Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder featured by left ventricular (LV) hypertrophy and cardiac dysfunction with an estimated global morbidity of 1:200–1:500. 1 HCM has severe clinical manifestations including heart failure, arrhythmia, sudden cardiac death and stroke. Myosin-binding protein C3 ( MYBPC3 ) mutations account for more than 40% pathogenic variants causing HCM. 2 Homozygous or compound heterozygous truncating variants of MYBPC3 are leading genetic causes of fetal and childhood-onset HCM characterized by heart failure and life-threatening ventricular arrhythmias. 3 Currently available medications fail to rescue these infants. Base editing is a form of genome editing that enables direct conversion of individual nucleotides at specific genomic sites, without introducing a double-strand DNA break. 4 , 5 Over the last few years, base editing has emerged as a powerful technology to change or generate genetic variants in a wide range of mitotic and postmitotic cells. 6 , 7 , 8