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Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia

2017-09-04Journal article Open access
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dc.contributor.authorMettananda, Sachith
dc.contributor.authorFisher, Chris A.
dc.contributor.authorHay, Deborah
dc.contributor.authorBadat, Mohsin
dc.contributor.authorQuek, Lynn
dc.contributor.authorClark, Kevin
dc.contributor.authorHublitz, Philip
dc.contributor.authorDownes, Damien
dc.contributor.authorKerry, Jon
dc.contributor.authorGosden, Matthew
dc.contributor.authorTelenius, Jelena
dc.contributor.authorSloane-Stanley, Jackie A.
dc.contributor.authorFaustino, Paula
dc.contributor.authorCoelho, Andreia
dc.contributor.authorDoondeea, Jessica
dc.contributor.authorUsukhbayar, Batchimeg
dc.contributor.authorSopp, Paul
dc.contributor.authorSharpe, Jacqueline A.
dc.contributor.authorHughes, Jim R.
dc.contributor.authorVyas, Paresh
dc.contributor.authorGibbons, Richard J.
dc.contributor.authorHiggs, Douglas R.
dc.date.accessioned2017-09-15T13:56:06Z
dc.date.available2017-09-15T13:56:06Z
dc.date.issued2017-09-04
dc.description.abstractβ-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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNat Commun. 2017 Sep 4;8(1):424. doi: 10.1038/s41467-017-00479-7pt_PT
dc.identifier.doi10.1038/s41467-017-00479-7pt_PT
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/10400.18/4791
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherNature Publishing Grouppt_PT
dc.relation.publisherversionhttps://www.nature.com/articles/s41467-017-00479-7pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectSteam Cellspt_PT
dc.subjectBeta-thalassemiapt_PT
dc.subjectAlpha-thalassemiapt_PT
dc.subjectTherapy for β-thalassemiapt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectDoenças Raraspt_PT
dc.subjectRegulação Génicapt_PT
dc.subjectEdição do Genomapt_PT
dc.subjectCRISPR/Cas9pt_PT
dc.subjectTratamento beta-talassémiapt_PT
dc.subjectGlobinaspt_PT
dc.subjectTerapia Génicapt_PT
dc.subjectHemoglobinopatiaspt_PT
dc.subjectTalassémiaspt_PT
dc.titleEditing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemiapt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue1pt_PT
oaire.citation.startPage424pt_PT
oaire.citation.titleNature Communicationspt_PT
oaire.citation.volume8pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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