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

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 <i>CaMKIIδ</i> gene to eliminate oxidation-sensitive methionine residues confers protection from ischemia/reperfusion (IR) injury. Moreover, <i>CaMKIIδ</i> editing in mice at the time of IR enables the heart to recover function from otherwise severe damage. <i>CaMKIIδ</i> gene editing may thus represent a permanent and advanced strategy for heart disease therapy.