The phospholamban (PLN) gene regulates calcium homeostasis in cardiomyocytes by inhibiting the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a). A PLN founder mutation identified in Greek and Dutch populations is linked to severe dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Patients often exhibit low-voltage ECGs, ventricular arrhythmias, and progressive heart failure, typically by their fourth decade, though some carriers remain asymptomatic. This mutation disrupts calcium handling, induces metabolic dysfunction, and promotes protein aggregation in cardiomyocytes. Current treatments manage symptoms, prevent sudden cardiac death, or involve heart transplantation in advanced cases. This study aimed to develop an AAV-based prime editing (PE) strategy to correct the PLN mutation in human iPSC-derived cardiomyocytes and humanized PLN mice. Screening four pegRNAs with various nicking gRNAs and Cas9 variants yielded correction efficiencies up to 30%, identifying the most promising PE tools. A dual AAV-PE system incorporating optimized components achieved 10-13% mutation correction in patient-derived cardiomyocytes.In vivo, AAV9-PE vectors were administered to humanized PLN mice and evaluated after five weeks using a stress-induced arrhythmia protocol. The intervention reduced pathogenic PLN expression and significantly decreased arrhythmic events compared to controls.These findings demonstrate the potential of dual AAV-PE for targeted PLN mutation correction and associated cardiac dysfunction mitigation. Ongoing studies in humanized porcine PLN models aim to expand its translational applications.