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Updated: Aug 9, 2025
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Base editing correction of hypertrophic cardiomyopathy in human cardiomyocytes and humanized mice
Andreas C Chai1,2, Miao Cui1,2, Francesco Chemello1,2
1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Insights
Researchers developed a base editing system to correct a common genetic mutation causing hypertrophic cardiomyopathy (HCM). This approach shows promise for treating inherited heart conditions by fixing the underlying genetic defect.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Gene Therapy
Background:
- Hypertrophic cardiomyopathy (HCM) is a prevalent genetic heart disease driven by sarcomeric gene variants, leading to heart muscle thickening.
- HCM complications include heart failure, arrhythmia, and sudden cardiac death.
- The MYH7 gene's c.1208G>A (p.R403Q) variant is a common cause of HCM, increasing cardiac contractility.
Purpose of the Study:
- To identify and characterize an adenine base editor system for correcting the p.R403Q pathogenic variant in the MYH7 gene.
- To evaluate the efficacy and specificity of the base editing system in correcting the HCM-causing variant.
- To assess the therapeutic potential of base editing in preclinical models of HCM.
Main Methods:
- Development of an adenine base editor and single-guide RNA system targeting the c.1208G>A variant.
- In vitro validation of base editing efficiency and assessment of bystander and off-target editing.
- In vitro correction of the variant in patient-derived induced pluripotent stem cell cardiomyocytes.
- In vivo testing in a humanized mouse model of HCM.
Main Results:
- The developed base editing system efficiently corrected the pathogenic p.R403Q variant in MYH7.
- Minimal bystander and off-target editing were observed at selected sites.
- Base editing component delivery rescued pathological manifestations of HCM in iPSC-derived cardiomyocytes and a humanized mouse model.
Conclusions:
- Adenine base editing offers a potential therapeutic strategy for correcting the MYH7 p.R403Q variant.
- This approach demonstrates significant potential for treating inherited cardiac diseases caused by monogenic variants.
- Further development of base editor-based therapies is warranted for inherited cardiac conditions.
Abstract:
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.
