A PAS-targeting hERG1 activator reduces arrhythmic events in Jervell and Lange-Nielsen syndrome patient-derived hiPSC-CMs
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Updated: Jun 3, 2025
High-Throughput Cardiotoxicity Screening Using Mature Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Monolayers
Published on: March 24, 2023
Chiamaka U Ukachukwu1, Eric N Jimenez-Vazquez1, Shreya Salwi1
1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Insights
Targeting the hERG1 potassium channel
Area of Science:
- Cardiovascular Science
- Molecular Cardiology
- Ion Channel Physiology
Background:
- The hERG1 potassium channel is crucial for cardiac repolarization (IKr).
- Prolonged action potential duration (APD) is linked to cardiac diseases, making hERG1 a therapeutic target.
- Existing hERG1 activators often cause off-target and proarrhythmic effects.
Purpose of the Study:
- To investigate the hERG1 PAS domain as a therapeutic target for cardiac arrhythmias.
- To evaluate the antiarrhythmic potential of a PAS-disabling antibody (scFv2.10) in a Long QT Syndrome (LQTS) model.
Main Methods:
- Utilized human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a Jervell and Lange Nielsen (JLN) syndrome patient.
- Assessed the effects of scFv2.10 on IKr, APD, and early afterdepolarizations (EADs).
- Studied hiPSC-CMs with compound heterozygous KCNQ1 mutations characteristic of JLN syndrome.
Main Results:
- JLN hiPSC-CMs exhibited prolonged APD and EADs.
- Disruption of the hERG1 PAS domain with scFv2.10 increased IKr and shortened APD.
- scFv2.10 treatment significantly reduced the incidence of EADs in JLN hiPSC-CMs.
Conclusions:
- The hERG1 PAS domain is a viable therapeutic target for reducing cardiac arrhythmogenic potential.
- Targeting the hERG1 PAS domain offers a novel strategy for treating cardiac electrical dysfunction, including LQTS.
- PAS-disabling antibodies like scFv2.10 show promise for managing cardiac arrhythmias.
Abstract:
The hERG1 potassium channel conducts the cardiac repolarizing current, IKr. hERG1 has emerged as a therapeutic target for cardiac diseases marked by prolonged action potential duration (APD). Unfortunately, many hERG1 activators display off-target and proarrhythmic effects that limit their therapeutic potential. A Per-Arnt-Sim (PAS) domain in the hERG1 N-terminus reduces IKr by slowing channel activation and promoting inactivation. Disrupting PAS activity increases IKr and shortens APD in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We thus hypothesized that the hERG1 PAS domain could represent a therapeutic target to reduce arrhythmogenic potential in a long QT syndrome (LQTS) background. To test this, we measured the antiarrhythmic capacity of a PAS-disabling single-chain variable fragment antibody, scFv2.10, in a hiPSC-CM line derived from a patient with Jervell and Lange Nielsen (JLN) syndrome. JLN is a severe form of LQTS caused by autosomal recessive mutations in KCNQ1. The patient in this study carried compound heterozygous mutations in KCNQ1. Corresponding JLN hiPSC-CMs displayed prolonged APD and early afterdepolarizations (EADs). Disrupting PAS with scFv2.10 increased IKr, shortened APD, and reduced the incidence of EADs. These data demonstrate that the hERG1 PAS domain could serve as a therapeutic target to treat disorders of cardiac electrical dysfunction.
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