Mini-dCas13X-mediated RNA editing for the treatment of hypertrophic cardiomyopathy

Hypertrophic Cardiomyopathy (HCM) is an inherited heart disease triggered by asingle mutation in the region coding for the myocardial sarcomeric proteins. Thesevariants lead to abnormally increased contractile function of the heart muscle andenergy consumption, which significantly increases the risk of arrhythmia and heartfailure. Particularly, pathogenic variants of the MYH7 gene have been identifiedin approximately 20% of patients with HCM, with the c.1208G>A pathogenic variantis a common and well-studied one. Unlike the heritable changes caused by DNA baseediting, RNA base editing technology shows the potential for a safer treatmentthan traditional methods by reversibly correcting mutant RNA transcripts. In thisstudy, we have constructed the humanized mouse mouse of HCM, utilized a higherediting efficiency, smaller nuclease proteins, and lower off-target efficiency RNAsingle-base editor for correct the mutation and restore functional in the heart.We then investigated the therapeutic potential of RNA single-base editor using HCMpatient-derived iPSC. Our research aims to explores and develops effective genetherapies for HCM, this finding can provide ideas for further study of thetreatment and drug development for HCM.