Prime-edited isogenic hiPSC-derived cardiomyocyte model of short QT syndrome type 3 reveals electrophysiological phenotypes and differential drug responses.

Authors

Min Woo Kim, Jeong Hwan Park, Myeonghee Lee, Seul-Gi Lee, Jeong-Seop Oh, Shinhye Park, Youngin Jeong, Yoonseo Kim, Hyewon Shin, Jin Kim, C-Yoon Kim, Hyung Min Chung

Published in

Life sciences. Volume 402. Pages 124573. Jul 07, 2026. Epub Jul 07, 2026.

Abstract

Short QT syndrome (SQTS) is a genetically inherited autosomal dominant cardiac channelopathy associated with paroxysmal atrial and ventricular fibrillation, syncope, and sudden cardiac arrest. Although SQTS is a well-known arrhythmogenic disorder, no optimal therapies currently exist due to its rarity and the challenges associated with diagnosis. Rodent models and patient-derived induced pluripotent stem cell (iPSC) models have been used to evaluate potential drug effects, but physiological and genetic variability between species and individuals can limit their fidelity. To address these limitations, we generated an isogenic human iPSC (hiPSC) model by introducing the short QT syndrome type 3 (SQT3)-associated KCNJ2 mutation into a normal hiPSC line using the Prime Editing 7 (PE7) system and differentiating it into cardiomyocytes (CMs). Multi-electrode array (MEA) analysis confirmed shortened field potential duration (FPD), an in vitro correlate of the QT interval as an electrophysiological SQT3 phenotype, validating the model's relevance to SQT3. Quinidine produced a consistent FPD-prolonging effect in the isogenic hiPSC-CMs, recapitulating previous clinical observations in a small number of SQT1 patients and supporting the model's utility as a reliable in vitro surrogate for assessing therapeutic strategies. Additionally, chloroquine, a selected candidate that has not yet been clinically validated, was evaluated and found to prolong FPD and induce irregular spontaneous beats indicative of arrhythmia. Overall, these findings demonstrate the potential of isogenic hiPSC-based platforms for elucidating disease mechanisms in rare genetic arrhythmogenic disorders and advancing the identification of candidate therapeutic agents.

PMID:
42413163
Bibliographic data and abstract were imported from PubMed on 08 Jul 2026.

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