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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


Elena Matsa

James E. Dixon

Christopher Medway

Orestis Georgiou

Minal J. Patel

Professor of Human Genomics and Molecular Genetics

Paul J. Kemp

Andrew Staniforth

Assistant Professor

Professor of Stem Cell Biology


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.


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.

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 Apr 15, 2014
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
Keywords iPS cells, Long-QT syndrome, Arrhythmia, Electrophysiology, Gene therapy
Public URL
Publisher URL
Copyright Statement Copyright information regarding this work can be found at the following address:


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