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Suppression and Replacement Gene Therapy for KCNH2-Mediated Arrhythmias

Sahej Bains1,2, Wei Zhou2, Steven M Dotzler1,2

  • 1Medical Scientist Training Program (S.B., S.M.D.), Mayo Clinic, Rochester, MN.

Circulation. Genomic and Precision Medicine
|October 17, 2022
PubMed
Abstract

Insights

This study introduces KCNH2-SupRep gene therapy, a novel approach for treating KCNH2-mediated arrhythmia syndromes. The therapy successfully corrected both Long QT Syndrome type 2 and Short QT Syndrome type 1 by normalizing cardiac action potential duration.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Gene Therapy

Background:

  • KCNH2 gene variants cause Long QT Syndrome type 2 (LQT2) and Short QT Syndrome type 1 (SQT1).
  • These syndromes result from loss-of-function or gain-of-function mutations in the KCNH2-encoded Kv11.1 potassium channel.
  • The Kv11.1 channel is critical for regulating cardiac action potential.

Purpose of the Study:

  • To develop and evaluate a dual-component gene therapy (KCNH2-SupRep) for KCNH2-mediated arrhythmia syndromes.
  • To assess the efficacy of KCNH2-SupRep in correcting both loss-of-function (LQT2) and gain-of-function (SQT1) KCNH2 variants.
  • To demonstrate proof-of-principle for gene therapy in treating these cardiac conditions.

Main Methods:

  • A single construct, KCNH2-SupRep, was engineered combining KCNH2 short hairpin RNA for suppression and an immune KCNH2 cDNA for replacement.
  • Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with LQT2 and SQT1 variants were generated.
  • Cells were treated with KCNH2-SupRep or control short hairpin RNA (shCT), and action potential duration at 90% repolarization (APD90) was measured.

Main Results:

  • KCNH2-SupRep demonstrated variant-independent correction of both LQT2 and SQT1 phenotypes.
  • For LQT2 variants, KCNH2-SupRep significantly shortened prolonged APD90 to near-normal levels.
  • For the SQT1 variant, KCNH2-SupRep therapeutically prolonged shortened APD90.

Conclusions:

  • KCNH2-SupRep gene therapy offers a potential treatment for LQT2 and SQT1.
  • This study provides the first proof-of-concept for gene therapy correcting both LQT2 and SQT1.
  • The therapy successfully normalized the pathological APD90, addressing the core issue in these arrhythmias.
Keywords:
genetic therapyinduced pluripotent stem cellsion channellong QT syndrome

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