Emerging Gene Therapies for Inherited Arrhythmia Syndromes

Inherited arrhythmia syndromes predispose to malignant arrhythmic events, including cardiac arrest and sudden cardiac death, which can be particularly catastrophic in young and otherwise healthy individuals. Despite considerable progress in clinical management in recent decades, the therapeutic options for many conditions remain limited and often expose patients to significant side effects that impair quality of life. There is therefore a pressing need for more effective and better-tolerated therapies. Owing to the predominantly monogenic nature of these diseases, and in light of the remarkable advances in molecular biology over the past two decades, gene therapies offer unprecedented potential by directly targeting the molecular determinants of arrhythmogenesis. In this review, we discuss advances in nucleic acid-based therapies for inherited cardiac arrhythmias, highlighting preclinical successes-some already progressing to first-in-class clinical trials-as well as the existing limitations. In light of accumulating preclinical evidence, we also discuss the impact of heterogeneous cardiac transduction/transfection by gene therapy vectors for arrhythmia treatment, a critical yet underexplored concept that carries theoretical concerns for pro-arrhythmia, but may also offer therapeutic opportunities. Finally, we briefly review future directions for the field, including the development of nucleic acid-based therapeutics for more prevalent arrhythmic disorders, such as post-myocardial infarction ventricular tachycardia and atrial fibrillation.