Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes
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 gen...
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| Format: | Article |
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Oxford University Press
2013
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| Online Access: | https://eprints.nottingham.ac.uk/2664/ |
| _version_ | 1848790843769487360 |
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| author | Matsa, Elena Dixon, James E. Medway, Christopher Georgiou, Orestis Patel, Minal J. Morgan, Kevin Kemp, Paul J. Staniforth, Andrew Mellor, Ian Denning, Chris |
| author_facet | Matsa, Elena Dixon, James E. Medway, Christopher Georgiou, Orestis Patel, Minal J. Morgan, Kevin Kemp, Paul J. Staniforth, Andrew Mellor, Ian Denning, Chris |
| author_sort | Matsa, Elena |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T18:19:04Z |
| format | Article |
| id | nottingham-2664 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T18:19:04Z |
| publishDate | 2013 |
| publisher | Oxford University Press |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-26642020-05-04T16:36:07Z https://eprints.nottingham.ac.uk/2664/ 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 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. Oxford University Press 2013-03-06 Article PeerReviewed Matsa, Elena, Dixon, James E., Medway, Christopher, Georgiou, Orestis, Patel, Minal J., Morgan, Kevin, Kemp, Paul J., Staniforth, Andrew, Mellor, Ian and Denning, Chris (2013) Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes. European Heart Journal . ISSN 0195-668X iPS cells Long-QT syndrome Arrhythmia Electrophysiology Gene therapy http://eurheartj.oxfordjournals.org/content/early/2013/03/06/eurheartj.eht067.full doi:10.1093/eurheartj/eht067 doi:10.1093/eurheartj/eht067 |
| spellingShingle | iPS cells Long-QT syndrome Arrhythmia Electrophysiology Gene therapy Matsa, Elena Dixon, James E. Medway, Christopher Georgiou, Orestis Patel, Minal J. Morgan, Kevin Kemp, Paul J. Staniforth, Andrew Mellor, Ian Denning, Chris Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes |
| title | Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes |
| title_full | Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes |
| title_fullStr | Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes |
| title_full_unstemmed | Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes |
| title_short | Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes |
| title_sort | allele-specific rna interference rescues the long-qt syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes |
| topic | iPS cells Long-QT syndrome Arrhythmia Electrophysiology Gene therapy |
| url | https://eprints.nottingham.ac.uk/2664/ https://eprints.nottingham.ac.uk/2664/ https://eprints.nottingham.ac.uk/2664/ |