AAV9-mediated KCNH2 suppression-replacement gene therapy in a transgenic rabbit model of type 1 short QT syndrome
Year: 2025
Type: article
Abstract: BACKGROUND AND AIMS: Type 1 short QT syndrome (SQT1) is a genetic channelopathy caused by gain-of-function variants in KCNH2, resulting in shortened cardiac repolarization and QT intervals, which predispose patients to ventricular arrhythmias and sudden cardiac death. This study aimed to investigate the therapeutic efficacy of KCNH2-specific suppression-and-replacement (KCNH2-SupRep) gene therapy in a transgenic rabbit model of SQT1. METHODS: KCNH2-SupRep was developed by combining a KCNH2-shRNA with its corresponding shRNA-immune KCNH2-cDNA into an AAV9 vector, delivered directly into the aortic root (1 × 1010 vg/kg). Therapeutic efficacy was evaluated in vivo by electrocardiogram, ex vivo by optical mapping, and at cellular levels by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs). RESULTS: In vivo, KCNH2-SupRep normalized the heart rate-corrected QT interval (QTc) in SQT1 rabbits, without affecting repolarization heterogeneity. Ex vivo, KCNH2-SupRep corrected the action potential duration (APD90) and resolved the increased apicobasal APD90 heterogeneity observed in untreated (UT)-SQT1 hearts, supporting an antiarrhythmic effect, which was further validated by reduced re-entry formation in silico. At cellular levels, KCNH2-SupRep prolonged APD90 in VCMs from SupRep-SQT1 rabbits closer to wildtype levels compared with UT- and sham-SQT1. Additionally, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window and normalized IKr in nearly 50% of VCMs, in line with a 50%-60% suppression of the mutant KCNH2 transcript. CONCLUSIONS: This proof-of-concept study is the first to demonstrate the efficacy of gene therapy for SQT1 in a medium-sized animal model. KCNH2-SupRep gene therapy successfully corrected the pathologic phenotype in vivo, ex vivo, and at cellular levels in transgenic SQT1 rabbits.
Source: European Heart Journal
Authors: Saranda Nimani, Sahej Bains, Nicolò Alerni, Balázs Ördög, András Horváth, Lluis Matas, Julien Louradour, Lucilla Giammarino, David J Tester, Olgica Beslac, Ruben Lopez, Stefan Meier, Manuel Egle, Nicolas Christoforou, Miriam Barbieri, Varjany Vashanthakumar, Stefanie Perez-Feliz, Chiara Parodi, Luisana G Garcia Casalta, C S John Kim, Wei Zhou, Dan Ye, Jacqulyn Jurgensen, Michael A Barry, Mariana Bego, Lisa Keyes, Jane Owens, Jason Pinkstaff, Jan Christoph, Manfred Zehender, Michael Brunner, Jordi Heijman, Daniela Casoni, Fabien Praz, Andreas Haeberlin, Gabriel Brooks, Michael J Ackerman, Katja E Odening
Institutions: University of Bern, University Hospital of Bern, Mayo Clinic, Maastricht University Medical Centre, Maastricht University, University of Freiburg, University Medical Center Freiburg, Pfizer (United States), Alexion Pharmaceuticals (United States), University of California, San Francisco, St. Josefskrankenhaus Freiburg, Medical University of Graz
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,922
OpenAlex ID: W4413859300