Alleviating the Effects of Short QT Syndrome Type 3 by Allele-Specific Suppression of the KCNJ2 Mutant Allele DOI Open Access
Ronald Wilders

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(24), P. 13351 - 13351

Published: Dec. 12, 2024

Short QT syndrome type 3 (SQTS3 or SQT3), which is associated with life-threatening cardiac arrhythmias, caused by heterozygous gain-of-function mutations in the KCNJ2 gene. This gene encodes pore-forming α-subunit of ion channel that carries inward rectifier potassium current (IK1). These either increase amplitude IK1 attenuate its rectification. The aim present silico study to test extent allele-specific suppression mutant allele can alleviate effects SQT3, as recently demonstrated vitro studies on specific long 1 and 2 short 1. To this end, simulations were carried out two most recent comprehensive models a single human ventricular cardiomyocyte. showed can, at least partially, counteract mutation restore action potential duration for each four SQT3 are known now. We conclude promising technique treatment should be evaluated vivo studies.

Language: Английский

SCN10A-short gene therapy to restore conduction and protect against malignant cardiac arrhythmias DOI Creative Commons
Jianan Wang, Arie O. Verkerk, Ronald Wilders

et al.

European Heart Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Abstract Background and Aims Life-threatening arrhythmias are a well-established consequence of reduced cardiac sodium current (INa). Gene therapy approaches to increase INa have demonstrated potential benefits prevent arrhythmias. However, the development such therapies is hampered by large size channels. In this study, SCN10A-short (S10s), short transcript encoding carboxy-terminal domain human neuronal channel, was evaluated as gene target Methods Adeno-associated viral vector overexpressing S10s injected into wild type Scn5a-haploinsufficient mice on which patch-clamp studies, optical mapping, electrocardiogram analyses, ischaemia reperfusion were performed. vitro in silico studies conducted further explore effect context hearts. Results Cardiac overexpression increased cellular INa, maximal action upstroke velocity, amplitude cardiomyocytes. rescues conduction slowing prevented ventricular tachycardia induced ischaemia-reperfusion mice. velocity inducible pluripotent stem cell-derived cardiomyocytes simulated heart models. Conclusions may be effective treat abnormalities associated

Language: Английский

Citations

2
Modeling the atrioventricular conduction axis using human pluripotent stem cell-derived cardiac assembloids DOI Creative Commons
Jiuru Li, Alexandra Wiesinger,

Lianne Fokkert

et al.

Cell stem cell, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

Citations

8
A novel ionic model for matured and paced atrial-like human iPSC-CMs integrating IKur and I DOI Creative Commons
Sofia Botti, Chiara Bartolucci, Claudia Altomare

et al.

Computers in Biology and Medicine, Journal Year: 2024, Volume and Issue: 180, P. 108899 - 108899

Published: Aug. 5, 2024

This work introduces the first atrial-specific in-silico human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) model, based on a set of phenotype-specific I

Language: Английский

Citations

2
Chronic Mexiletine Administration Increases Sodium Current in Non-Diseased Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes DOI Creative Commons
Giovanna Nasilli, Arie O. Verkerk, Molly O’Reilly

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(6), P. 1212 - 1212

Published: May 29, 2024

A sodium current (INa) reduction occurs in the setting of many acquired and inherited conditions is associated with cardiac conduction slowing increased arrhythmia risks. The channel blocker mexiletine has been shown to restore trafficking mutant channels membrane. However, these studies were mostly performed heterologous expression systems using high concentrations. Moreover, chronic effects on INa a non-diseased cardiomyocyte environment remain unknown. In this paper, we investigated acute therapeutic dose action potential (AP) characteristics human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) healthy individual. Control hiPSC-CMs incubated for 48 h 10 µM or vehicle. Following wash-out mexiletine, patch clamp analysis immunocytochemistry experiments performed. incubation (followed by wash-out) significant increase peak ~75%, without any change voltage dependence (in)activation. This was accompanied AP upstroke velocity, changes other parameters. showed membrane Nav1.5 fluorescence following mexiletine. re-exposure resulted small but duration, density, Importantly, density resulting velocity not counteracted re-administration drug. conclusion, administration clinically relevant concentration increases hiPSC-CMs, likely enhancing channels. Our findings identify as strategy enhance and/or conduction.

Language: Английский

Citations

1
A novel ionic model for matured and paced atrial–like hiPSC–CMs integratingIKurandIKCacurrents DOI Creative Commons
Sofia Botti, Chiara Bartolucci, Claudia Altomare

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 15, 2024

Abstract Human induced pluripotent stem cells–derived cardiomyocytes have revolutionized the field of regenerative medicine, offering unparalleled potential for in–vitro modeling normal and pathological human cardiomyocytes. The ability to produce cardiac myocytes in abundance has opened new avenues drug efficacy safety testing, as well study conditions such atrial fibrillation, a familial disorder. development fibrillation is influenced by ion channel mutations, genetic variants, other risk factors. Stem cells derived hold promise personalized they share heritage donor. While mathematical models focused on immature phenotypes, primarily relied system stiff ordinary differential equations. Computational diseased tissue presents an opportunity evaluate drugs patient-specific manner, thereby improving therapeutic targets ablation techniques. Previous studies categorized cell phenotypes based action morphology, yet classification criteria remains ambiguous. This work introduces first atrial-specific in–silico model ionic currents, leveraging experimental data provided Altomare et al. It begins summarizing baseline electrophysiological descriptions atrial–specific additional currents. Model parameter tuning was performed through automatic optimization techniques ensure realistic shape expedite adjustment process. resulting validated against rate dependence current blocking data. In summary, represents significant step forward understanding electrophysiology medicine treating like fibrillation. offers tools evaluation, improvement, deeper comprehension phenotypes. Author summary since their discovery 2006, leading Nobel Prize 2012. kind can give rise different types specific cells, Differentiated offer unlimited supply studying heart disease conditions, aiding patient–specific testing helping explore pathogenic mechanisms behind cardiomyopathies, including Atrial common condition, with same donor, are ideal treatments. Recent advances produced currents from focusing forms enabling virtual testing. However, previous did not capture characteristics. We decided create introduce this atrial–like these using novel Thus, we describe tune parameters technique, validate model’s accuracy simulating potentials blockage. research paves way better conditions.

Language: Английский

Citations

0
Alleviating the Effects of Short QT Syndrome Type 3 by Allele-Specific Suppression of the KCNJ2 Mutant Allele DOI Open Access
Ronald Wilders

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(24), P. 13351 - 13351

Published: Dec. 12, 2024

Short QT syndrome type 3 (SQTS3 or SQT3), which is associated with life-threatening cardiac arrhythmias, caused by heterozygous gain-of-function mutations in the KCNJ2 gene. This gene encodes pore-forming α-subunit of ion channel that carries inward rectifier potassium current (IK1). These either increase amplitude IK1 attenuate its rectification. The aim present silico study to test extent allele-specific suppression mutant allele can alleviate effects SQT3, as recently demonstrated vitro studies on specific long 1 and 2 short 1. To this end, simulations were carried out two most recent comprehensive models a single human ventricular cardiomyocyte. showed can, at least partially, counteract mutation restore action potential duration for each four SQT3 are known now. We conclude promising technique treatment should be evaluated vivo studies.

Language: Английский

Citations

0