Gene therapy for cardiac arrhythmias

Cardiac arrhythmias are a major cause of morbidity and mortality worldwide. Existing treatments (electronic pacemakers, implantable cardioverter-defibrillators, antiarrhythmic drugs, and catheter ablation) manage symptoms without correcting the underlying molecular defects, and carry substantial limitations. Gene therapy using adeno-associated virus (AAV) vectors offers a fundamentally different approach: durable, targeted modulation of cardiac electrical function at its molecular source.
This thesis advances AAV gene therapy for cardiac arrhythmias from vector design through therapeutic proof of concept. A systematic comparison of AAV6, AAV9, and engineered MyoAAV variants across cellular, tissue, and whole-heart models identifies AAV6 as the serotype best suited for local cardiac delivery and shows that simple screening assays reliably predict in vivo performance, providing a framework for rational vector selection in future work. Two biological pacemaker strategies are then evaluated: sustained AAV-mediated TBX18 expression clarifies the limits of transcription-factor-based reprogramming, whereas AAV6-HCN4t establishes a robust, β-adrenergic-responsive alternative with clear translational potential for congenital complete heart block. Turning to ventricular tachyarrhythmias, SCN10A-short (S10s), a compact modulator of the cardiac sodium current, is shown to restore conduction and prevent life-threatening arrhythmias, overcoming the size constraints that have long limited sodium-channel gene therapy.
Together, these studies define an integrated preclinical foundation for AAV gene therapies targeting both bradyarrhythmias and tachyarrhythmias, and move the field closer to clinical translation.