Katja Odening

SGV Meeting 2026 · Scientific Programme

CHUV, Lausanne

• 24 November 2026 · 10:15Gene therapies to prevent arrhythmias in cardiac channelopathies – first evidence of feasibility and efficacy in transgenic rabbit models
  Abstract

  The cardiac channelopathies long QT (LQTS) and short QT syndrome (SQTS) are mainly caused by pathogenic variants in the cardiac ion channel genes KCNQ1 or KCNH2, leading to loss-of-function or gain-of-function of KCNQ1/IKs or hERG/IKr currents. These lead to a pathologically prolonged or accelerated cardiac repolarization, respectively, which both predispose the heart to potentially lethal ventricular tachyarrhythmias and sudden cardiac death. Current therapies primarily reduce proarrhythmic triggers or terminate arrhythmias once they occur with an implantable defibrillator, but do not correct the underlying disease mechanisms. Consequently, life-threatening arrhythmias can still occur, underscoring the need for more effective, mechanism-based therapies. We have developed AAV9-based suppression-replacement gene therapy approaches targeting either the mutant KCNQ1 or KCNH2, have delivered them through a cardiac-specific approach via the coronaries, and have tested their efficacy to normalize electrical cardiac function in transgenic rabbit models of LQTS and SQTS. Rabbits are particularly well-suited for this purpose because of pronounced similarities to humans in cardiac electrophysiology, KCNQ1 and KCNH2 sequence, structure and function.

  We could demonstrate that KCNH2-SupRep normalized the shortened QT interval / action potential duration (APD) in SQT1 rabbits (carrying the KCNH2-N588K gain-of-function variant) and that KCNQ1-SupRep normalized the prolonged QT / APD in LQT1 rabbits (carrying the KCNQ1-Y315S loss-of-function variant) in vivo and on the cellular level. Moreover, at the ex vivo whole-heart level, KCNH2-SupRep corrected action potential duration (APD) and resolved the increased apicobasal regional APD heterogeneity observed in untreated (UT)-SQT1 hearts, supporting an antiarrhythmic effect, which was further validated by reduced re-entry formation in silico. At the cellular level, KCNH2-SupRep prolonged APD in cardiomyocytes from SupRep-SQT1 rabbits towards the wild-type levels. Additionally, KCNH2-SupRep normalized IKr in nearly 50% of cardiomyocytes, in line with a 50%–60% suppression of the mutant KCNH2 transcript. Based on these encouraging results, we are currently conducting an IND-enabling preclinical study of KCNH2-SupRep gene therapy in transgenic LQT2 rabbits.