Ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease.
Simon LebekFrancesco ChemelloXurde M CaraviaWei TanHui LiKenian ChenLin XuNing LiuRhonda Bassel-DubyEric N OlsonPublished in: Science (New York, N.Y.) (2023)
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.
Keyphrases
- crispr cas
- genome editing
- induced pluripotent stem cells
- pulmonary hypertension
- endothelial cells
- left ventricular
- hydrogen peroxide
- copy number
- oxidative stress
- type diabetes
- stem cells
- gene expression
- genome wide
- atrial fibrillation
- bone marrow
- dna methylation
- skeletal muscle
- cell therapy
- high glucose
- mesenchymal stem cells
- radiofrequency ablation
- catheter ablation
- high fat diet induced