Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10451/47091 |
Resumo: | © The Author(s) 2017. Open Access. This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
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Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia© The Author(s) 2017. Open Access. This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.β-Thalassemia is one of the most common inherited anemias, with no effective cure for most patients. The pathophysiology reflects an imbalance between α- and β-globin chains with an excess of free α-globin chains causing ineffective erythropoiesis and hemolysis. When α-thalassemia is co-inherited with β-thalassemia, excess free α-globin chains are reduced significantly ameliorating the clinical severity. Here we demonstrate the use of CRISPR/Cas9 genome editing of primary human hematopoietic stem/progenitor (CD34+) cells to emulate a natural mutation, which deletes the MCS-R2 α-globin enhancer and causes α-thalassemia. When edited CD34+ cells are differentiated into erythroid cells, we observe the expected reduction in α-globin expression and a correction of the pathologic globin chain imbalance in cells from patients with β-thalassemia. Xenograft assays show that a proportion of the edited CD34+ cells are long-term repopulating hematopoietic stem cells, demonstrating the potential of this approach for translation into a therapy for β-thalassemia.This work was supported by grants to D.R.H. by the UK Medical Research Council (grant number MC_UU_12025/ unit programme MC_UU_12009/4) and the NIHR Oxford Biomedical Research Center. S.M. is a Commonwealth Scholar, funded by the UK government.Springer NatureRepositório da Universidade de LisboaMettananda, SachithFisher, Chris A.Hay, DeborahBadat, MohsinQuek, LynnClark, KevinHublitz, PhilipDownes, DamienKerry, JonGosden, MatthewTelenius, JelenaSloane-Stanley, Jackie A.Faustino, PaulaCoelho, AndreiaDoondeea, JessicaUsukhbayar, BatchimegSopp, PaulSharpe, Jacqueline A.Hughes, Jim R.Vyas, PareshGibbons, Richard J.Higgs, Douglas R.2021-03-26T12:23:49Z20172017-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/47091engNat Commun. 2017 Sep 4;8(1):42410.1038/s41467-017-00479-72041-1723info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:49:44Zoai:repositorio.ul.pt:10451/47091Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:59:10.154584Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia |
title |
Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia |
spellingShingle |
Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia Mettananda, Sachith |
title_short |
Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia |
title_full |
Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia |
title_fullStr |
Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia |
title_full_unstemmed |
Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia |
title_sort |
Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia |
author |
Mettananda, Sachith |
author_facet |
Mettananda, Sachith Fisher, Chris A. Hay, Deborah Badat, Mohsin Quek, Lynn Clark, Kevin Hublitz, Philip Downes, Damien Kerry, Jon Gosden, Matthew Telenius, Jelena Sloane-Stanley, Jackie A. Faustino, Paula Coelho, Andreia Doondeea, Jessica Usukhbayar, Batchimeg Sopp, Paul Sharpe, Jacqueline A. Hughes, Jim R. Vyas, Paresh Gibbons, Richard J. Higgs, Douglas R. |
author_role |
author |
author2 |
Fisher, Chris A. Hay, Deborah Badat, Mohsin Quek, Lynn Clark, Kevin Hublitz, Philip Downes, Damien Kerry, Jon Gosden, Matthew Telenius, Jelena Sloane-Stanley, Jackie A. Faustino, Paula Coelho, Andreia Doondeea, Jessica Usukhbayar, Batchimeg Sopp, Paul Sharpe, Jacqueline A. Hughes, Jim R. Vyas, Paresh Gibbons, Richard J. Higgs, Douglas R. |
author2_role |
author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
dc.contributor.author.fl_str_mv |
Mettananda, Sachith Fisher, Chris A. Hay, Deborah Badat, Mohsin Quek, Lynn Clark, Kevin Hublitz, Philip Downes, Damien Kerry, Jon Gosden, Matthew Telenius, Jelena Sloane-Stanley, Jackie A. Faustino, Paula Coelho, Andreia Doondeea, Jessica Usukhbayar, Batchimeg Sopp, Paul Sharpe, Jacqueline A. Hughes, Jim R. Vyas, Paresh Gibbons, Richard J. Higgs, Douglas R. |
description |
© The Author(s) 2017. Open Access. This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017 2017-01-01T00:00:00Z 2021-03-26T12:23:49Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/47091 |
url |
http://hdl.handle.net/10451/47091 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Nat Commun. 2017 Sep 4;8(1):424 10.1038/s41467-017-00479-7 2041-1723 |
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info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Springer Nature |
publisher.none.fl_str_mv |
Springer Nature |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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