SCN10A-short gene therapy to restore conduction and protect against malignant cardiac arrhythmias

  • Eur Heart J. 2025 May 7;46(18):1747-1762. doi: 10.1093/eurheartj/ehaf053.
Jianan Wang  1 ,  Arie O Verkerk  1  2 ,  Ronald Wilders  1 ,  Yingnan Zhang  3 ,  Kelly Zhang  3 ,  Adityo Prakosa  3 ,  Mathilde R Rivaud  1 ,  E Madelief J Marsman  2 ,  Arie R Boender  1  4 ,  Mischa Klerk  1 ,  Lianne Fokkert  1 ,  Berend de Jonge  1 ,  Klaus Neef  4  5 ,  Osne F Kirzner  4  6 ,  Connie R Bezzina  2 ,  Carol Ann Remme  2 ,  Hanno L Tan  2  4  5 ,  Bastiaan J Boukens  1  7 ,  Harsha D Devalla  1 ,  Natalia A Trayanova  3  8 ,  Vincent M Christoffels  1 ,  Phil Barnett  1 ,  Gerard J J Boink  1  4  9
Affiliations
  • 1. Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands.
  • 2. Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands.
  • 3. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
  • 4. PacingCure B.V., Roetersstraat 35, Amsterdam 1018 WB, The Netherlands.
  • 5. Netherlands Heart Institute, Moreelsepark 1, Utrecht 3511 EP, The Netherlands.
  • 6. Department of Anaesthesiology, Amsterdam University Medical Centers, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
  • 7. Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Universiteitssingel 50, Maastricht 6229 ER, The Netherlands.
  • 8. Alliance for Cardiovascular Diagnostic and Treatment Innovation, Johns Hopkins University, Baltimore, MD 21218, USA.
  • 9. Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
PMID: 39973098 DOI: 10.1093/eurheartj/ehaf053
Abstract

Background and aims: Life-threatening Arrhythmias are a well-established consequence of reduced cardiac sodium current (INa). Gene therapy approaches to increase INa have demonstrated potential benefits to prevent Arrhythmias. However, the development of such therapies is hampered by the large size of sodium channels. In this study, SCN10A-short (S10s), a short transcript encoding the carboxy-terminal domain of the human neuronal Sodium Channel, was evaluated as a gene therapy target to increase INa and prevent Arrhythmias.

Methods: Adeno-associated viral vector overexpressing S10s was injected into wild type and Scn5a-haploinsufficient mice on which patch-clamp studies, optical mapping, electrocardiogram analyses, and ischaemia reperfusion were performed. In vitro and in silico studies were conducted to further explore the effect of S10s gene therapy in the context of human Hearts.

Results: Cardiac S10s overexpression increased cellular INa, maximal action potential upstroke velocity, and action potential amplitude in Scn5a-haploinsufficient cardiomyocytes. S10s gene therapy rescues conduction slowing in Scn5a-haploinsufficient mice and prevented ventricular tachycardia induced by ischaemia-reperfusion in wild type mice. S10s overexpression increased maximal action potential upstroke velocity in human inducible pluripotent stem cell-derived cardiomyocytes and prevented inducible Arrhythmias in simulated human heart models.

Conclusions: S10s gene therapy may be effective to treat cardiac conduction abnormalities and associated Arrhythmias.

Keywords
AAV; Cardiac arrhythmia; Gene therapy; SCN10A; SCN5A; Sodium current.