Key result
In vivo CRISPR/Cas9 corrects ~4% of mutations and alleviates cardiac dysfunction in an HCM rat model.
Why the study?
MYBPC3 variants are a major cause of HCM, and this study investigated whether in vivo CRISPR/Cas9 genome editing could rescue the phenotype in an HCM rat model.
Does CRISPR/Cas9-mediated homology-directed repair improve cardiac function and phenotype in a rat model of MYBPC3-mutant hypertrophic cardiomyopathy?
Does CRISPR/Cas9-mediated homology-directed repair improve cardiac function and phenotype in a rat model of MYBPC3-mutant hypertrophic cardiomyopathy?
In vivo CRISPR/Cas9-mediated homology-directed repair partially corrected a MYBPC3 mutation, restored protein expression, and improved cardiac function in a rat model of hypertrophic cardiomyopathy.
Premature for clinical use in HCM; hypothesis-generating in rats and leaves open translation to larger models.
Variants in myosin-binding protein C3 ( MYBPC3 ) gene are a main cause of hypertrophic cardiomyopathy (HCM), accounting for 30–40% of the total number of HCM cases. Gene editing represents a potential permanent cure for HCM. The aim of this study was to investigate whether genome editing of MYBPC3 using the CRISPR/Cas9 system in vivo could rescue the phenotype of rats with HCM. We generated a rat model of HCM (“1098hom”) that carried an Mybpc3 premature termination codon mutation (p.W1098x) discovered in a human HCM pedigree. On postnatal day 3, the CRISPR/Cas9 system was introduced into rat pups by a single dose of AAV9 particles to correct the variant using homology-directed repair (HDR). Analysis was performed 6 months after AAV9 injection. The 1098hom rats didn’t express MYBPC3 protein and developed an HCM phenotype with increased ventricular wall thickness and diminished cardiac function. Importantly, CRISPR HDR genome editing corrected 3.56% of total mutations, restored MYBPC3 protein expression by 2.12%, and normalized the HCM phenotype of 1098hom rats. Our work demonstrates that the HDR strategy is a promising approach for treating HCM associated with MYBPC3 mutation, and that CRISPR technology has great potential for treating hereditary heart disease.
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Nie et al. (2022) studied Hypertrophic cardiomyopathy (n=27). CRISPR/Cas9 homology-directed repair (HDR) via AAV9 vs. Control AAV9 (BbsI-donor-AAV9 + SpCas9-AAV9) was evaluated on Precise HDR editing efficiency (correction of total mutations). In vivo CRISPR/Cas9 homology-directed repair corrected 3.56% of total mutations, restored MYBPC3 protein expression, and alleviated cardiac hypertrophy and dysfunction in a rat model of HCM.
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