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Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice
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Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice
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Journal Article
Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice
2023
Overview
Dominant missense pathogenic variants in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure and sudden cardiac death. In this study, we assessed two different genetic therapies—an adenine base editor (ABE8e) and a potent Cas9 nuclease delivered by AAV9—to prevent disease in mice carrying the heterozygous HCM pathogenic variant myosin R403Q. One dose of dual-AAV9 vectors, each carrying one half of RNA-guided ABE8e, corrected the pathogenic variant in ≥70% of ventricular cardiomyocytes and maintained durable, normal cardiac structure and function. An additional dose provided more editing in the atria but also increased bystander editing. AAV9 delivery of RNA-guided Cas9 nuclease effectively inactivated the pathogenic allele, albeit with dose-dependent toxicities, necessitating a narrow therapeutic window to maintain health. These preclinical studies demonstrate considerable potential for single-dose genetic therapies to correct or silence pathogenic variants and prevent the development of HCM.
Two approaches using an adenine base editor and a Cas9 nuclease prevented the development of hypertrophic cardiomyopathy in mice carrying a pathogenic mutation on the
Myh6
gene, highlighting the potential of single-dose genetic therapies for the treatment of cardiac disease.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Adenine
/ Animals
/ Atria
/ Biomedical and Life Sciences
/ Cardiomyopathy, Hypertrophic
/ Editing
/ Genomes
/ Mice
/ Mutation
/ Myosin
/ Nuclease
/ RNA
