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SHR Neuro Krebs Kardio Lipid Stoffw Microb
Nimani, S; Bains, S; Alerni, N; Ördög, B; Horváth, A; Matas, L; Louradour, J; Giammarino, L; Tester, DJ; Beslac, O; Lopez, R; Meier, S; Egle, M; Christoforou, N; Barbieri, M; Vashanthakumar, V; Perez-Feliz, S; Parodi, C; Garcia, Casalta, LG; Kim, CSJ; Zhou, W; Ye, D; Jurgensen, J; Barry, MA; Bego, M; Keyes, L; Owens, J; Pinkstaff, J; Christoph, J; Zehender, M; Brunner, M; Heijman, J; Casoni, D; Praz, F; Haeberlin, A; Brooks, G; Ackerman, MJ; Odening, KE.
AAV9-mediated KCNH2 suppression-replacement gene therapy in a transgenic rabbit model of type 1 short QT syndrome.
Eur Heart J. 2025;
Doi: 10.1093/eurheartj/ehaf660
PubMed
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- Co-Autor*innen der Med Uni Graz
- Heijman Jordi
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- Abstract:
- BACKGROUND AND AIMS: Type 1 short QT syndrome (SQT1) is a genetic channelopathy caused by gain-of-function variants in KCNH2. This shortens cardiac repolarization and QT intervals, predisposing 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 (1x1010 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 (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 to 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.