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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

Authors

Elena Matsa

James E. Dixon

Christopher Medway

Orestis Georgiou

Minal J. Patel

Kevin Morgan

Paul J. Kemp

Andrew Staniforth

Ian Mellor

Chris Denning

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.

Journal Article Type Article
Publication Date Mar 6, 2013
Journal European Heart Journal
Print ISSN 0195-668X
Electronic ISSN 0195-668X
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Institution Citation Matsa, E., Dixon, J. E., Medway, C., Georgiou, O., Patel, M. J., Morgan, K., …Denning, C. (2013). Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes. European Heart Journal, doi:10.1093/eurheartj/eht067
DOI https://doi.org/10.1093/eurheartj/eht067
Keywords iPS cells, Long-QT syndrome, Arrhythmia, Electrophysiology, Gene therapy
Publisher URL http://eurheartj.oxfordjournals.org/content/early/2013/03/06/eurheartj.eht067.full
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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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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