Regulation of sodium/calcium homeostasis by BacNagene therapy rescues cardiac dysfunction in chronic heart failure.

Abstract

Despite continued progress, therapies to augment contractile function and prevent arrhythmias in patients with heart failure remain limited. Here, we present a two-pronged gene therapy approach that simultaneously augments peak Nacurrent and Catransient amplitude in cardiomyocytes (CMs) to alleviate heart failure pathogenesis. Using in vitro engineered neonatal rat heart tissues, ex vivo adult mouse CMs, and in silico rabbit CMs, we show that expression of prokaryotic Nachannels (BacNa) dose-dependently enhances Catransients and contractility of CMs by modulating Na/Caexchanger activity and increasing sarcoplasmic reticulum Castores. In mice, adeno-associated virus 9 (AAV9)-mediated BacNatherapy rescues contractile deficit, prevents arrhythmias, and improves transcriptomic dysregulation in a pressure-overload induced model of chronic heart failure. We further establish the safety of long-term systemic delivery of AAV9-BacNain mice. Collectively, these studies support the translational promise of BacNagene delivery as an effective therapy for electrical and contractile dysfunction in heart failure.