Ablation of CaMKIId oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease
成果类型：
Article
署名作者：
Lebek, Simon; Chemello, Francesco; Caravia, Xurde M.; Tan, Wei; Li, Hui; Chen, Kenian; Xu, Lin; Liu, Ning; Bassel-Duby, Rhonda; Olson, Eric N.
署名单位：
University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Regensburg; University of Texas System; University of Texas Southwestern Medical Center
刊物名称：
SCIENCE
ISSN/ISSBN：
0036-10299
DOI：
10.1126/science.ade1105
发表日期：
2023-01-13
页码：
179-185
关键词：
摘要：
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 CaMKIId, a primary driver of cardiac disease. We show in cardiomyocytes derived from human induced pluripotent stem cells that editing the CaMKII6 gene to eliminate oxidation-sensitive methionine residues confers protection from ischemia/reperfusion (IR) injury. Moreover, CaMKII6 editing in mice at the time of IR enables the heart to recover function from otherwise severe damage. CaMKII6 gene editing may thus represent a permanent and advanced strategy for heart disease therapy.