CRISPR/Cas9-Based Gene Editing for Correcting Inherited Channelopathies

Abstract

Inherited cardiac channelopathies, including long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia, are major causes of arrhythmic morbidity and sudden cardiac death in young individuals. Current therapies, such as pharmacologic agents, implantable cardioverter-defibrillators, and lifestyle modifications, reduce risk but fail to correct the underlying genetic substrate, creating an urgent need for curative strategies. CRISPR/Cas9 genome editing has emerged as a transformative platform with the potential to directly repair pathogenic variants. Recent advances in base and prime editing, together with novel viral and nonviral delivery platforms, have enabled precise correction of disease-causing mutations in preclinical models. Proof-of-concept studies using animal models and patient-derived iPSC-cardiomyocytes demonstrate restoration of electrophysiologic stability, suppression of arrhythmias, and durable functional benefit. Nevertheless, translational challenges remain, including off-target effects, delivery barriers, immune responses, scalability, and ethical considerations. Ongoing innovations-such as engineered nucleases, improved delivery vectors, immunogenicity mitigation strategies, and integration of artificial intelligence for personalized guide design-are expected to accelerate clinical translation. This review synthesizes current knowledge on CRISPR-based strategies for inherited channelopathies, highlighting both the promise and limitations of gene editing as a path toward durable, disease-modifying therapies capable of preventing sudden cardiac death.

Keywords: Brugada syndrome; CRISPR/Cas9; adeno-associated virus; base editing; catecholaminergic polymorphic ventricular tachycardia; gene editing; induced pluripotent stem cells; inherited cardiac channelopathies; long QT syndrome; prime editing.