At the American Heart Association’s Scientific Sessions 2025 in New Orleans, results were discussed from a study demonstrating the potential use of a prokaryotic voltage-gated sodium channel (BacNav) gene therapy to restore contractile strength and electrical stability in a rat model of chronic ischemia-reperfusion heart failure (HF).
In recent decades, there has been continued progress in research to augment cardiac contractile function and prevent arrhythmias. However, therapies in the space remain limited. The augmentation of peak sodium current and calcium transient amplitude in cardiomyocytes presents a promising avenue to restore electrical and contractile dysfunction in HF. This study hypothesised that the expression of BacNav can simultaneously target sodium and calcium dysregulation in failing cardiomyocytes. Gene therapy has been demonstrated as a strategy for targeting the pathophysiological mechanisms of HF to provide robust inotropic and anti-arrhythmic effects in HF with reduced ejection fraction (HFrEF). Increasingly, gene therapy is being investigated for the treatment of cardiovascular disorders, including HF, and has the potential to correct specific electro-mechanical failures that occur in these conditions. Therapy options in HF are limited to management of the condition in the long-term. As such, gene therapy presents a potential curative option. Key opinion leaders (KOLs) interviewed by GlobalData often reported that they would like to see cardio-metabolic therapies that significantly improve long-term outcomes, alleviate symptoms, and are potentially curative.
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Initially, the functional effects of BacNav expression using ex vivo adult mouse cardiomyocytes were investigated with preclinical evaluations of cardiomyocyte specific adeno-associated virus (AAV)-mediated BacNav therapy conducted in a mouse traverse aortic constriction (TAC) model of chronic HF. AAV-mediated BacNav, or control AAV virus, was administered four weeks post-surgery, and cardiac contractile function was monitored over a 12-week period following TAC, with arrythmia susceptibility, histological outcomes, and transcriptomic changes assessed at the 12-week endpoint.
The study concluded that expression of BacNav dose-dependently enhances Ca2+ transient amplitude and the contractility of cardiomyocytes by modulating the activity of the Na+/Ca2+ voltage-gated channels and increased stores of Ca2+ in the sarcoplasmic reticulum. Compared to control AAV treated animals, in vivo, AAV9-mediated BacNav therapy alleviates fibrotic and hypertrophic changes, rescues contractile deficit (delta left ventricular ejection fraction (LVEF)-3.5±2.2% versus -17.0%±2.8%), and prevents arrhythmias (0% versus 56%) in chronic cardiac pressure overload in mice. BacNav therapy also confers protective effects on pressure-overload induced dysregulation of the cardiac transcriptome.
This preclinical study supports the promise of BacNav gene therapy as a novel therapy for HFrEF by demonstrating an approach whereby the augmentation of both peak Na+ current and Ca2+ transient amplitude in cardiomyocytes alleviates the pathology of HF. GlobalData forecasts that through translational research, if this therapy is efficacious in humans, BacNav gene therapy could open a first-in-class market for disease-modifying genetic interventions in severe HF and create high-value opportunities for hospitals and payers aiming to reduce the burden of HF.
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By GlobalData
