RYR2 and catecholaminergic polymorphic ventricular tachycardia 1: AAV9-SaCas9-mediated editing targeted mutant RYR2R4496C in the heart, achieving ~41% editing efficiency in cardiomyocytes. Treated mice exhibited significant reduction in ventricular arrhythmias during epinephrine/caffeine challenge (0/7 treated vs. 7/8 control; p = 0.0014). Restored Ca2+ handling was observed with decreased spontaneous Ca2+ waves and normalized Ca2+ transients. No significant off-target editing detected in vivo, and no adverse effects noted. This study offers first in vivo demonstration of safe, effective CRISPR-mediated RYR2 repair in a CPVT1 model.