Evidence map›Paper›PMID 39115049›Full record

ArticleEuropean heart journal2024

KCNQ1 suppression-replacement gene therapy in transgenic rabbits with type 1 long QT syndrome.

Sahej Bains, Lucilla Giammarino, Saranda Nimani, Nicolo Alerni, David J Tester, C S John Kim, Nicolas Christoforou, Julien Louradour, András Horváth, Olgica Beslac and 22 more

Abstract read
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In one paragraph

Article in European heart journal, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

12 citing papers in PubMed.

  1. Review
  2. Mechano-electrical feedback in transgenic rabbit models of long QT syndrome Type 2 and short QT syndrome Type 1.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026
    Article
  3. Article
  4. Review
  5. Gene therapy for cardiac arrhythmias.Nature reviews. Cardiology · 2026
    Review
  6. Gene Therapy for Inherited Cardiac Arrhythmias.Journal of cardiovascular translational research · 2025
    Review
  7. Beneficial action potential duration-shortening effects, but deleterious negative inotropism of IKs-activator docosahexaenoyl glycine in long QT syndrome type 2.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2025
    Article
  8. Review
  9. Predicting the Damaging Potential of UncharacterizedInternational journal of molecular sciences · 2025
    Article
  10. Current and future precision therapy approaches in the long QT syndrome.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025
    Article
  11. Review
  12. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

32 authors.

Sahej BainsDepartments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic and The Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905, USA.ORCID 0000-0002-1357-7656
Lucilla GiammarinoTranslational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland.ORCID 0000-0002-2100-0160
Saranda NimaniTranslational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland.ORCID 0000-0002-9298-3678
Nicolo AlerniTranslational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland.
David J TesterDepartments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic and The Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905, USA.
C S John KimDepartments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic and The Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905, USA.
Nicolas ChristoforouFormerly from the Rare Disease Research Unit, Pfizer Inc., Cambridge, MA, USA.
Julien LouradourTranslational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland.
András HorváthTranslational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland.
Olgica BeslacDepartment of Cardiology, University Hospital Bern, University of Bern, Bern, Switzerland.
Miriam BarbieriTranslational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland.
Lluis MatasTranslational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland.
Thomas S HofTranslational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland.
Ruben LopezTranslational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland.
Stefanie Perez-FelizDepartment of Cardiology, University Heart Center, University Hospital Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.
Chiara ParodiExperimental Surgical Facility, Experimental Animal Center, University of Bern, Bern, Switzerland.
Luisana G Garcia CasaltaExperimental Surgical Facility, Experimental Animal Center, University of Bern, Bern, Switzerland.
Jacqulyn JurgensenDepartment of Virology & Gene Therapy, Vector and Vaccine Engineering Laboratory, Mayo Clinic, Rochester, USA.
Michael A BarryDepartment of Virology & Gene Therapy, Vector and Vaccine Engineering Laboratory, Mayo Clinic, Rochester, USA.
Mariana BegoFormerly from Biomedicine Design, Pfizer Inc., Cambridge, MA, USA.
Lisa KeyesFormerly from Biomedicine Design, Pfizer Inc., Cambridge, MA, USA.
Jane OwensFormerly from the Rare Disease Research Unit, Pfizer Inc., Cambridge, MA, USA.
Jason PinkstaffDrug Safety Research & Development, Pfizer Inc., Cambridge, MA, USA.
Gideon KorenCardiovascular Research Center, Brown University, Providence, USA.
Manfred ZehenderDepartment of Cardiology, University Heart Center, University Hospital Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.
Michael BrunnerDepartment of Cardiology, University Heart Center, University Hospital Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.ORCID 0000-0002-0287-9560
Daniela CasoniExperimental Surgical Facility, Experimental Animal Center, University of Bern, Bern, Switzerland.
Fabien PrazDepartment of Cardiology, University Hospital Bern, University of Bern, Bern, Switzerland.ORCID 0000-0001-5416-165X
Andreas HaeberlinDepartment of Cardiology, University Hospital Bern, University of Bern, Bern, Switzerland.ORCID 0000-0002-9283-0110
Gabriel BrooksFormerly from the Rare Disease Research Unit, Pfizer Inc., Cambridge, MA, USA.
Michael J AckermanDepartments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic and The Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905, USA.ORCID 0000-0002-8011-3333
Katja E OdeningTranslational Cardiology, Department of Cardiology and Department of Physiology, University Hospital Bern, University of Bern, Bühlplatz 5, 3012 Bern, Switzerland.ORCID 0000-0001-6999-841X

Funding

Dr. Scholl FoundationMayo Clinic Center for Individualized Medicine High-Definition TherapeuticsMayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death ProgramPfizer Inc.
6 · The paper itself

Abstract

BACKGROUND AND

aimsType 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.

methodsKCNQ1-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.

resultsKCNQ1-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.

conclusionsThis 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.

Indexed as

Genetic TherapyKCNQ1 Potassium ChannelMyocytes, CardiacRomano-Ward SyndromeAction PotentialsAnimalsAnimals, Genetically ModifiedDisease Models, AnimalElectrocardiographyLong QT SyndromeRabbitsRNA, Small InterferingKCNQ1 Potassium ChannelRNA, Small InterferingAAV9Gene therapyKCNQ1Long QT syndromeTransgenic LQT1 rabbits

Identifiers

PMID39115049
PMCPMC11439107

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.