Genome editing prevents hypertrophic cardiomyopathy in mice

By Neha MathurFeb 19 2023Reviewed by Danielle Ellis, B.Sc. In a recent study published in the journal Nature Medicine, researchers pursued one-time cures for hypertrophic cardiomyopathy . They used a previously constructed murine model of HCM, designated as R403Q-129SvEv, to evaluate two different genetic therapies, as follows:ii) a potent Cas9 nuclease delivered by an adeno-associated virus vector.

Background Genetics & Genomics eBook Compilation of the top interviews, articles, and news in the last year. Download a free copy Though rare, HCM, a primary myocardial genetic disorder, causes left ventricular hypertrophy that increases myocardial fibrosis. Subsequently, it increases the risk of heart failure, stroke, and sudden cardiac arrest. It arises from the dominant missense allele that alters the contractile protein cardiac myosin heavy chain in humans.

About the study 129SvEv mice harboring one R403Q mimic key features of human HCM, including LVH. In the present study, researchers used these mice, carrying a heterozygous missense residue R403Q in their α-cardiac Myh6, to study treatment effects on cardiac morphology. They used female R403Q-129SvEv mice to examine gene editing efficiencies. Furthermore, the team evaluated different strategies to edit or silence the HCM allele in R403Q mice for HCM prevention.

Further, the researchers noted that the intra-thoracic delivery of AAV9-encoding small interfering RNAs in 129SvEv mice selectively silenced the mutant transcript by 25%. Moreover, its effect prevented the emergence of LVH for six months before waning. AAV9 delivery of RNA-guided Cas9 nuclease effectively inactivated the pathogenic allele, albeit with dose-dependent deleterious effects on contractile function, indicating the availability of a narrow therapeutic window. HCM patients have over 250 myosin missense residues and multiple pathogenic variant alleles. Thus, designing a single-variant correction approach for HCM treatment is challenging.

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