HERG Channel Agonists: A Novel, Substrate-Based Therapeutic Approach for Long QT Syndrome

Long QT Syndrome (LQTS) is a potentially fatal genetic arrhythmia syndrome, characterized by prolongation of ventricular repolarization, which predisposes young and otherwise healthy individuals to sudden cardiac death. Despite quantum leaps in our understanding of LQTS, the mainstay of treatment remains the use of beta-adrenergic blockers, which are aimed at control of the arrhythmic trigger, and which do not modify the QT interval duration. Since the duration of the QT interval is a potent predictor of outcomes, our group championed a substrate-based approach aimed at shortening the duration of the QT interval using mexiletine, a class I antiarrhythmic for treatment of Long QT Syndrome type 3 (LQT3). Currently, mexiletine is indicated as a standard-of-care for all patients with LQT3, suggesting that in principle shortening the QTc interval may be an effective strategy to treat all forms of LQTS. We tested the efficacy and safety of 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA-105574), the most potent HERG1 channel agonist, in different models of LQTS. In Phase One, we successfully developed drug-induced models of type 2, type 3, and type 8 LQTS and used them to investigate the ability of ICA-105574 to safely abbreviate the QT interval in different forms of LQTS. Following the successful preliminary demonstration of efficacy and safety, we exploited the opportunity to study in vivo the effects and safety of ICA-105574 using the first successful knock-in large mammal model of a cardiac channelopathy. Using state-of-the art, clinical grade, ultra-high density mapping of ventricular repolarization, we showed that ICA-105574 significantly reduces the arrhythmogenic gradients of ventricular repolarization identified in our knock-in model of LQTS. These results offer evidence to support the view that development of HERG1 channel agonists, as a novel class of antiarrhythmics, could have clinical application.