Editing the trajectory of hypertrophic cardiomyopathy.

Abstract

The genetic code can be coldly tyrannical when it leads a single nucleotide change to alter an individual’s life trajectory. In hypertrophic cardiomyopathy (HCM), dominant pathogenic variants (PVs) in sarcomere genes cause ventricular muscle thickening, hypercontractility, diastolic dysfunction, cardiac fibrosis, and the risk of life-threatening arrhythmias. With a prevalence as high as 1 in 500 individuals [1] , HCM imposes considerable medical and economic costs. Despite advances in genetic diagnosis and an improved understanding of its molecular pathogenesis, HCM remains incurable and can progress to heart failure, cardiac transplantation, and premature death. Although small molecules that target HCM’s underlying pathogenic mechanisms have begun to enter clinical use [2] , it is likely that cures will require therapies that correct the underlying genetic lesions. The advent of efficient gene editing technologies has opened the door to therapies that correct causative HCM variants. Recent studies published in the February 2023 issue of Nature Medicine by the Olson (Chai et al. [3] ) and Seidman (Reichart et al. [4] ) groups have established proof-of-concept that precise and efficient gene editing can be achieved in postnatal mammalian cardiomyocytes and prevent HCM in experimental disease models. Dominant PVs in