TY - JOUR
T1 - KCNQ1 suppression-replacement gene therapy in transgenic rabbits with type 1 long QT syndrome
AU - Bains, Sahej
AU - Giammarino, Lucilla
AU - Nimani, Saranda
AU - Alerni, Nicolo
AU - Tester, David J.
AU - Kim, C. S.John
AU - Christoforou, Nicolas
AU - Louradour, Julien
AU - Horváth, András
AU - Beslac, Olgica
AU - Barbieri, Miriam
AU - Matas, Lluis
AU - Hof, Thomas S.
AU - Lopez, Ruben
AU - Perez-Feliz, Stefanie
AU - Parodi, Chiara
AU - Garcia Casalta, Luisana G.
AU - Jurgensen, Jacqulyn
AU - Barry, Michael A.
AU - Bego, Mariana
AU - Keyes, Lisa
AU - Owens, Jane
AU - Pinkstaff, Jason
AU - Koren, Gideon
AU - Zehender, Manfred
AU - Brunner, Michael
AU - Casoni, Daniela
AU - Praz, Fabien
AU - Haeberlin, Andreas
AU - Brooks, Gabriel
AU - Ackerman, Michael J.
AU - Odening, Katja E.
N1 - Publisher Copyright:
© 2024 The Author(s).
PY - 2024/9/21
Y1 - 2024/9/21
N2 - Background and Aims: Type 1 long QT syndrome (LQT1) is caused by pathogenic variants in the KCNQ1-encoded Kv7.1 potassium channels, which pathologically prolong ventricular action potential duration (APD). Herein, the pathologic phenotype in transgenic LQT1 rabbits is rescued using a novel KCNQ1 suppression-replacement (SupRep) gene therapy. Methods: KCNQ1-SupRep gene therapy was developed by combining into a single construct a KCNQ1 shRNA (suppression) and an shRNA-immune KCNQ1 cDNA (replacement), packaged into adeno-associated virus serotype 9, and delivered in vivo via an intra-aortic root injection (1E10 vg/kg). To ascertain the efficacy of SupRep, 12-lead electrocardiograms were assessed in adult LQT1 and wild-type (WT) rabbits and patch-clamp experiments were performed on isolated ventricular cardiomyocytes. Results: KCNQ1-SupRep treatment of LQT1 rabbits resulted in significant shortening of the pathologically prolonged QT index (QTi) towards WT levels. Ventricular cardiomyocytes isolated from treated LQT1 rabbits demonstrated pronounced shortening of APD compared to LQT1 controls, leading to levels similar to WT (LQT1-UT vs. LQT1-SupRep, P <. 0001, LQT1-SupRep vs. WT, P = ns). Under β-adrenergic stimulation with isoproterenol, SupRep-treated rabbits demonstrated a WT-like physiological QTi and APD90 behaviour. Conclusions: This study provides the first animal-model, proof-of-concept gene therapy for correction of LQT1. In LQT1 rabbits, treatment with KCNQ1-SupRep gene therapy normalized the clinical QTi and cellular APD90 to near WT levels both at baseline and after isoproterenol. If similar QT/APD correction can be achieved with intravenous administration of KCNQ1-SupRep gene therapy in LQT1 rabbits, these encouraging data should compel continued development of this gene therapy for patients with LQT1.
AB - Background and Aims: Type 1 long QT syndrome (LQT1) is caused by pathogenic variants in the KCNQ1-encoded Kv7.1 potassium channels, which pathologically prolong ventricular action potential duration (APD). Herein, the pathologic phenotype in transgenic LQT1 rabbits is rescued using a novel KCNQ1 suppression-replacement (SupRep) gene therapy. Methods: KCNQ1-SupRep gene therapy was developed by combining into a single construct a KCNQ1 shRNA (suppression) and an shRNA-immune KCNQ1 cDNA (replacement), packaged into adeno-associated virus serotype 9, and delivered in vivo via an intra-aortic root injection (1E10 vg/kg). To ascertain the efficacy of SupRep, 12-lead electrocardiograms were assessed in adult LQT1 and wild-type (WT) rabbits and patch-clamp experiments were performed on isolated ventricular cardiomyocytes. Results: KCNQ1-SupRep treatment of LQT1 rabbits resulted in significant shortening of the pathologically prolonged QT index (QTi) towards WT levels. Ventricular cardiomyocytes isolated from treated LQT1 rabbits demonstrated pronounced shortening of APD compared to LQT1 controls, leading to levels similar to WT (LQT1-UT vs. LQT1-SupRep, P <. 0001, LQT1-SupRep vs. WT, P = ns). Under β-adrenergic stimulation with isoproterenol, SupRep-treated rabbits demonstrated a WT-like physiological QTi and APD90 behaviour. Conclusions: This study provides the first animal-model, proof-of-concept gene therapy for correction of LQT1. In LQT1 rabbits, treatment with KCNQ1-SupRep gene therapy normalized the clinical QTi and cellular APD90 to near WT levels both at baseline and after isoproterenol. If similar QT/APD correction can be achieved with intravenous administration of KCNQ1-SupRep gene therapy in LQT1 rabbits, these encouraging data should compel continued development of this gene therapy for patients with LQT1.
KW - AAV9
KW - Gene therapy
KW - KCNQ1
KW - Long QT syndrome
KW - Transgenic LQT1 rabbits
UR - http://www.scopus.com/inward/record.url?scp=85205922435&partnerID=8YFLogxK
U2 - 10.1093/eurheartj/ehae476
DO - 10.1093/eurheartj/ehae476
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AN - SCOPUS:85205922435
SN - 0195-668X
VL - 45
SP - 3751
EP - 3763
JO - European Heart Journal
JF - European Heart Journal
IS - 36
ER -