Base Editing Correction of a Hypertrophic Cardiomyopathy-Causing MYH7 Mutation in Human Cardiomyocytes and Humanized Mice

The most common form of genetic heart disease is hypertrophic cardiomyopathy (HCM), which is caused by mutations in cardiac sarcomeric genes and leads to abnormal heart muscle thickening. Complications of HCM include heart failure, arrhythmia, and sudden cardiac death. The dominant-negative c.1208 G>A (p.R403Q) mutation in b-myosin (MYH7) is a common and well-studied mutation that leads to increased cardiac contractility and HCM onset. Here we identify an adenine base editor (ABE) and single-guide RNA system that can efficiently correct this human pathogenic mutation with minimal off-target and bystander editing. We show that delivery of base editing components rescues pathological manifestations of HCM in iPSC-cardiomyocytes derived from HCM patients and in a humanized mouse model of HCM. Our findings demonstrate the use of base editing to treat inherited cardiac diseases and prompt the further development of ABE-based therapies to correct a variety of monogenic mutations causing cardiac disease. Overall design: The objective of this study was to determine whether base editing correction of a pathogenic HCM-causing mutation could prevent the onset of HCM pathological features in human cardiomyocytes and a humanized mouse model. In a humanized mouse model containing the mutation Myh6 R403Q, a dual AAV9 system was used to deliver the base editing components to cardiomyocytes and changes in heart function, dimensions, and transcriptomics were measured. CM nuclei were collected from WT, HCM mice, and ABE-treated HCM mice and transcriptomes were profiled by RNA-seq