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 CaMKIId gene to eliminate oxidation-sensitive methionine residues confers protection from ischemia/reperfusion (IR) injury. Moreover, CaMKIId editing in mice at the time of IR enables the heart to recover function from otherwise severe damage. CaMKIId gene editing may thus represent a permanent and advanced strategy for heart disease therapy.
Ablation of CaMKIId oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease / Lebek S.; Chemello F.; Caravia X.M.; Tan W.; Li H.; Chen K.; Xu L.; Liu N.; Bassel-Duby R.; Olson E.N.. - In: SCIENCE. - ISSN 0036-8075. - ELETTRONICO. - 379:6628(2023), pp. 179-185. [10.1126/science.ade1105]
Ablation of CaMKIId oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease
Chemello F.;
2023
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 CaMKIId, a primary driver of cardiac disease. We show in cardiomyocytes derived from human induced pluripotent stem cells that editing the CaMKIId gene to eliminate oxidation-sensitive methionine residues confers protection from ischemia/reperfusion (IR) injury. Moreover, CaMKIId editing in mice at the time of IR enables the heart to recover function from otherwise severe damage. CaMKIId gene editing may thus represent a permanent and advanced strategy for heart disease therapy.File | Dimensione | Formato | |
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Ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing as a therapy for cardiac disease.pdf
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