Regulation of Sodium/Calcium Homeostasis by BacNav Gene Therapy Rescues Cardiac Dysfunction in Chronic Heart Failure

Despite continued progress, therapies to augment contractile function and prevent arrhythmias in patients with heart disease remain limited. Here, we present a two-pronged gene therapy approach whereby simultaneous augmentation of peak Na+ current and Ca2+ transient amplitude in cardiomyocytes (CMs) effectively alleviates pathogenesis of heart failure. Specifically, using in vitro engineered tissue models of neonatal rat CMs, ex vivo adult mouse CMs, and in silico rabbit CMs, we show that expression of prokaryotic Na+ channels (BacNav) dose-dependently enhances Ca2+ transient amplitude and contractility of CMs by modulating the activity of the Na+/Ca2+ exchanger and increasing sarcoplasmic reticulum Ca2+ stores. In vivo, AAV9-mediated BacNav therapy rescues contractile deficit and prevents arrhythmias in a pressure-overload induced model of chronic heart failure in mice. BacNav therapy also confers protective effects on pressure-overload induced dysregulation of the cardiac transcriptome. We further establish the safety of long-term systemic delivery of AAV9-BacNav in mice. Collectively, these studies support the translational promise of BacNav gene delivery as a novel therapy for electrical and contractile dysfunction in heart failure.