Ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease

Abstract

CRISPR-Cas9 gene editing is emerging as a prospective therapy for genomic mutations. However, current editing approaches are directed primarily toward relatively small cohorts of patients with specific mutations. Here, we describe a cardioprotective strategy potentially applicable to a broad range of patients with heart disease. We used base editing to ablate the oxidative activation sites of CaMKIIδ, a primary driver of cardiac disease. We show in cardiomyocytes derived from human induced pluripotent stem cells that editing the CaMKIIδ gene to eliminate oxidation-sensitive methionine residues confers protection from ischemia/reperfusion (IR) injury. Moreover, CaMKIIδ editing in mice at the time of IR enables the heart to recover function from otherwise severe damage. CaMKIIδ gene editing may thus represent a permanent and advanced strategy for heart disease therapy.

Editing away heart disease

Ischemia-reperfusion injury, tissue damage that occurs after oxygen deprivation, can be observed after a variety of insults, including common ones such as heart attack or stroke. A key protein that plays a role in this damage is calcium calmodulin-dependent protein kinase IIδ (CaMKIIδ). Lebek et al . found that targeting CaMKIIδ using CRISPR-Cas9 gene editing was a viable intervention to protect the heart tissue from ischemia-reperfusion damage in mouse models. Injecting gene editing reagents soon after ischemia exposure was sufficient for the mice to recover from severe heart damage, suggesting that it may not be too late to intervene after a heart attack happens. —YN

Abstract

Removing oxidative activation sites in CaMKIIδ by base editing sustains heart function after ischemia-reperfusion injury.