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The most common form of genetic heart disease is hypertrophic cardiomyopathy (HCM), which is caused by variants 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.1208G>A (p.R403Q) pathogenic variant (PV) in β-myosin (MYH7) is a common and well-studied PV that leads to increased cardiac contractility and HCM onset. In this study we identify an adenine base editor and single-guide RNA system that can efficiently correct this human PV with minimal bystander editing and off-target editing at selected sites. We show that delivery of base editing components rescues pathological manifestations of HCM in induced pluripotent stem cell cardiomyocytes derived from patients with HCM and in a humanized mouse model of HCM. Our findings demonstrate the potential of base editing to treat inherited cardiac diseases and prompt the further development of adenine base editor-based therapies to correct monogenic variants causing cardiac disease. Adenine base editing successfully corrected a MYH7 pathogenic variant that causes hypertrophic cardiomyopathy in human cardiomyocytes and a mouse model of the disease, highlighting the potential of the approach to correct monogenic variants causing cardiac disease.
The thickening of the heart muscle associated with hypertrophic cardiomyopathy leads to arrhythmia, heart failure and sudden cardiac death. The disease often goes undiagnosed, and heart transplantation is the only known treatment. Researchers have been working on a therapy using base editing to correct one of the mutations causing HCM. In this latest study, their target was a mutation in the myosin heavy chain 7 (MYH7) gene. MYH7 encodes β-myosin heavy chain, a motor ATPase that incorporates into heart muscle filaments and affects their contractions. Moreover, the pathogenic G-to-A mutation in the MYH7 gene studied is responsible for a severe, early-onset form of Crohn's disease. The team used the CRISPR-Cas 9 system to correct the MYH7 mutation in induced pluripotent stem cells derived from MHC patients, achieving extremely high editing efficiencies of up to 99%, with little or no off-target. The next step will be to obtain more data in a large animal model and make this potential therapy as safe as possible.