At AHA 2025, researchers reported that AAV9‑delivered BacNav, a prokaryotic voltage‑gated sodium channel gene, improved cardiomyocyte calcium handling and contractility and prevented arrhythmias in preclinical heart‑failure models. Ex vivo mouse cardiomyocytes and an in vivo TAC mouse model showed dose‑dependent increases in Ca2+ transient amplitude and rescued contractile function (ΔLVEF −3.5 ± 2.2% treated vs −17.0 ± 2.8% control). Treated mice also exhibited reduced fibrosis and hypertrophy and 0% arrhythmias versus 56% in controls. While promising, these are preclinical results and require further safety and translational studies before clinical use.
AHA 2025: AAV‑delivered BacNav Gene Therapy Restores Contractility and Prevents Arrhythmia in Preclinical Heart‑Failure Models
At AHA 2025, researchers reported that AAV9‑delivered BacNav, a prokaryotic voltage‑gated sodium channel gene, improved cardiomyocyte calcium handling and contractility and prevented arrhythmias in preclinical heart‑failure models. Ex vivo mouse cardiomyocytes and an in vivo TAC mouse model showed dose‑dependent increases in Ca2+ transient amplitude and rescued contractile function (ΔLVEF −3.5 ± 2.2% treated vs −17.0 ± 2.8% control). Treated mice also exhibited reduced fibrosis and hypertrophy and 0% arrhythmias versus 56% in controls. While promising, these are preclinical results and require further safety and translational studies before clinical use.
06:22 AM, 11/12/2025Health
Preclinical data at AHA 2025 suggest BacNav gene therapy could reverse mechanical and electrical dysfunction in HFrEF
At the American Heart Association Scientific Sessions 2025 in New Orleans, investigators presented preclinical findings indicating that a prokaryotic voltage‑gated sodium channel gene (BacNav) delivered by adeno‑associated virus (AAV) can improve both contractile strength and electrical stability in animal models of chronic heart failure (HF). The conference summary highlighted initial results from a rat ischemia–reperfusion model, while detailed mechanistic studies used ex vivo mouse cardiomyocytes and an in vivo mouse transverse aortic constriction (TAC) model of pressure‑overload heart failure.
Rationale
Therapies that simultaneously improve cardiomyocyte contractility and reduce arrhythmia risk remain limited. The investigators proposed that increasing peak Na+ current while augmenting the cardiomyocyte Ca2+ transient could correct the combined electrical and mechanical dysfunction that contributes to heart failure with reduced ejection fraction (HFrEF). A prokaryotic voltage‑gated sodium channel (BacNav) was chosen to test this dual mechanism.
Study design
The team first validated BacNav expression and functional effects ex vivo in adult mouse cardiomyocytes. For in vivo experiments, they used cardiomyocyte‑specific AAV delivery (AAV9) of BacNav in a mouse TAC model. Animals received either AAV‑BacNav or control AAV four weeks after TAC surgery and were followed for 12 weeks. Endpoints at 12 weeks included left ventricular function, arrhythmia susceptibility, histology (fibrosis and hypertrophy) and cardiac transcriptomics.
Key results
- BacNav expression produced dose‑dependent increases in Ca2+ transient amplitude and cardiomyocyte contractility by modulating Na+/Ca2+ channel activity and increasing sarcoplasmic reticulum Ca2+ stores.
- In vivo, AAV9‑mediated BacNav reduced fibrosis and hypertrophy and substantially rescued contractile performance: change in left ventricular ejection fraction (ΔLVEF) was −3.5 ± 2.2% in treated animals versus −17.0 ± 2.8% in controls.
- Arrhythmia incidence fell to 0% in BacNav‑treated mice versus 56% in control animals under pressure‑overload conditions.
- BacNav treatment also mitigated pressure‑overload–induced dysregulation of the cardiac transcriptome, consistent with broader protective effects.
Implications and caveats
These preclinical results support the concept that targeted gene therapy restoring Na+ and Ca2+ handling in cardiomyocytes can be both inotropic and anti‑arrhythmic, offering a potential disease‑modifying approach for HFrEF. If safety and efficacy are confirmed in translational and clinical studies, AAV‑BacNav could become a first‑in‑class genetic therapy for severe HFrEF, with substantial clinical and economic implications.
Important caution: These data are preclinical. Safety concerns (including off‑target expression, immunogenicity of the vector or channel, and long‑term electrophysiologic effects) must be rigorously addressed in additional studies before human trials.
Source: Conference presentation at AHA Scientific Sessions 2025; summary originally published by Pharmaceutical Technology (GlobalData).