Elena Matsa
Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes
Matsa, Elena; Dixon, James E.; Medway, Christopher; Georgiou, Orestis; Patel, Minal J.; Morgan, Kevin; Kemp, Paul J.; Staniforth, Andrew; Mellor, Ian; Denning, Chris
Authors
James E. Dixon
Christopher Medway
Orestis Georgiou
Minal J. Patel
Kevin Morgan
Paul J. Kemp
Andrew Staniforth
IAN MELLOR IAN.MELLOR@NOTTINGHAM.AC.UK
Assistant Professor
CHRIS DENNING chris.denning@nottingham.ac.uk
Professor of Stem Cell Biology
Abstract
Aims Long-QT syndromes (LQTS) are mostly autosomal-dominant congenital disorders associated with a 1:1000 mutation frequency, cardiac arrest, and sudden death. We sought to use cardiomyocytes derived from human-induced pluripotency stem cells (hiPSCs) as an in vitro model to develop and evaluate gene-based therapeutics for the treatment of LQTS. Methods and results We produced LQTS-type 2 (LQT2) hiPSC cardiomyocytes carrying a KCNH2 c.G1681A mutation in a IKr ion-channel pore, which caused impaired glycosylation and channel transport to cell surface. Allele-specific RNA interference (RNAi) directed towards the mutated KCNH2 mRNA caused knockdown, while leaving the wild-type mRNA unaffected. Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K+ currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations). Conclusions These findings provide in vitro evidence that allele-specific RNAi can rescue diseased phenotype in LQTS cardiomyocytes. This is a potentially novel route for the treatment of many autosomal-dominant-negative disorders, including those of the heart. © 2013 The Author.
Citation
Matsa, E., Dixon, J. E., Medway, C., Georgiou, O., Patel, M. J., Morgan, K., …Denning, C. (2014). Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes. European Heart Journal, 35(16), 1078-1087. https://doi.org/10.1093/eurheartj/eht067
Journal Article Type | Article |
---|---|
Acceptance Date | Feb 7, 2013 |
Online Publication Date | Mar 6, 2013 |
Publication Date | Apr 21, 2014 |
Deposit Date | Apr 15, 2014 |
Publicly Available Date | Mar 28, 2024 |
Journal | European Heart Journal |
Print ISSN | 0195-668X |
Electronic ISSN | 1522-9645 |
Publisher | Oxford University Press |
Peer Reviewed | Peer Reviewed |
Volume | 35 |
Issue | 16 |
Pages | 1078-1087 |
DOI | https://doi.org/10.1093/eurheartj/eht067 |
Keywords | iPS cells, Long-QT syndrome, Arrhythmia, Electrophysiology, Gene therapy |
Public URL | https://nottingham-repository.worktribe.com/output/713897 |
Publisher URL | http://eurheartj.oxfordjournals.org/content/early/2013/03/06/eurheartj.eht067.full |
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Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/
Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0
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