GSE211005
Precise genomic editing of a pathogenic RBM20 mutation rescues dilated cardiomyopathy
Mutations in RNA binding motif protein 20 (RBM20) are a common cause of dilated cardiomyopathy (DCM). Many RBM20 mutations cluster within an arginine/serine rich (RS-rich) domain, resulting in mis-localization of RBM20 to ribonucleoprotein granules within the cytoplasm, abnormal splicing of cardiac genes, and cardiomyocyte dysfunction. We used adenine base editing (ABE) and prime editing to correct pathogenic p.R634Q and p.R636S mutations in the RS-rich domain in human isogenic induced pluripotent stem cell-derived cardiomyocytes. We also created humanized Rbm20R636Q mutant mice, which succumbed to severe cardiac dysfunction, heart failure and premature death.  Systemic delivery of ABE components by adeno-associated virus in these mice restored cardiac function and extended life span. These findings demonstrate the potential of precise correction of genetic mutations as a promising therapeutic approach for DCM. Overall design: We analyzed the transcriptome of single cardiac nulcei from the 6-month old heart of the following genotypes: WT, RBM20 homozygous mutation, RBM20 heterzygous mutation, and RBM20 homozygous mutation with gene editing correction.