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Published on: March 12, 2013
AAV9-mediated KCNH2 suppression-replacement gene therapy in a transgenic rabbit model of type 1 short QT syndrome
Saranda Nimani1, Sahej Bains2, Nicolò Alerni1
1Translational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern, Bühlplatz 5, Bern 3012, Switzerland.
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.
Insights
Gene therapy effectively treated Type 1 short QT syndrome (SQT1) in rabbits by correcting cardiac repolarization. This KCNH2-SupRep approach offers a potential new treatment for SQT1 patients at risk of sudden cardiac death.
Area of Science:
- Cardiovascular Genetics
- Gene Therapy
- Channelopathies
Background:
- Type 1 short QT syndrome (SQT1) is a life-threatening genetic disorder caused by KCNH2 gain-of-function variants.
- SQT1 leads to shortened cardiac repolarization, increasing the risk of ventricular arrhythmias and sudden cardiac death.
Purpose of the Study:
- To evaluate the therapeutic efficacy of KCNH2-specific suppression-and-replacement (KCNH2-SupRep) gene therapy in a rabbit model of SQT1.
Main Methods:
- KCNH2-SupRep gene therapy was delivered via AAV9 vector into the aortic root of SQT1 rabbits.
- Efficacy was assessed using in vivo ECG, ex vivo optical mapping, and cellular analyses (patch-clamp, calcium imaging, qPCR).
Main Results:
- KCNH2-SupRep normalized QTc intervals and corrected action potential duration (APD90) and heterogeneity in SQT1 rabbits.
- The therapy reduced arrhythmia susceptibility in silico and restored cellular electrophysiology, including IKr current.
- A 50-60% suppression of the mutant KCNH2 transcript was observed.
Conclusions:
- This study demonstrates the first successful gene therapy for SQT1 in a medium-sized animal model.
- KCNH2-SupRep gene therapy effectively corrected the SQT1 phenotype at multiple levels, showing therapeutic potential.
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