Lebek, Simon and Caravia, Xurde M. and Straub, Leon G. and Alzhanov, Damir and Tan, Wei and Li, Hui and McAnally, John R. and Chen, Kenian and Xu, Lin and Scherer, Philipp E. and Liu, Ning and Bassel-Duby, Rhonda and Olson, Eric N. (2024) CRISPR-Cas9 base editing of pathogenic CaMKIIδ improves cardiac function in a humanized mouse model. JOURNAL OF CLINICAL INVESTIGATION, 134 (1): e175164. ISSN 0021-9738, 1558-8238
Full text not available from this repository. (Request a copy)Abstract
Cardiovascular diseases are the most common cause of worldwide morbidity and mortality, highlighting the necessity for advanced therapeutic strategies. Ca2+/calmodulin-dependent protein kinase II8 (CaMKII8) is a prominent inducer of various cardiac disorders, which is mediated by 2 oxidation-sensitive methionine residues within the regulatory domain. We have previously shown that ablation of CaMKII8 oxidation by CRISPR-Cas9 base editing enables the heart to recover function from otherwise severe damage following ischemia/reperfusion (IR) injury. Here, we extended this therapeutic concept toward potential clinical translation. We generated a humanized CAMK2D knockin mouse model in which the genomic sequence encoding the entire regulatory domain was replaced with the human sequence. This enabled comparison and optimization of two different editing strategies for the human genome in mice. To edit CAMK2D in vivo, we packaged the optimized editing components into an engineered myotropic adeno-associated virus (MyoAAV 2A), which enabled efficient delivery at a very low AAV dose into the humanized mice at the time of IR injury. CAMK2D-edited mice recovered cardiac function, showed improved exercise performance, and were protected from myocardial fibrosis, which was otherwise observed in injured control mice after IR. Our findings identify a potentially effective strategy for cardioprotection in response to oxidative damage.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | KINASE-II; HYPERTROPHIC CARDIOMYOPATHY; GENOMIC DNA; ACTIVATION; MUSCLE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Dec 2025 06:30 |
| Last Modified: | 09 Dec 2025 06:30 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65164 |
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