Highly efficient editing of the β-globin gene in patient-derived hematopoietic stem and progenitor cells to treat sickle cell disease

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dc.citation.firstpage7955
dc.citation.issueNumber15
dc.citation.journalTitleNucleic Acids Research
dc.citation.lastpage7972
dc.citation.volumeNumber47
dc.contributor.authorPark, So Hyun
dc.contributor.authorLee, Ciaran M.
dc.contributor.authorDever, Daniel P.
dc.contributor.authorDavis, Timothy H.
dc.contributor.authorCamarena, Joab
dc.contributor.authorSrifa, Waracharee
dc.contributor.authorZhang, Yankai
dc.contributor.authorPaikari, Alireza
dc.contributor.authorChang, Alicia K.
dc.contributor.authorPorteus, Matthew H.
dc.contributor.authorSheehan, Vivien A.
dc.contributor.authorBao, Gang
dc.date.accessioned2019-11-14T17:52:23Z
dc.date.available2019-11-14T17:52:23Z
dc.date.issued2019
dc.description.abstractSickle cell disease (SCD) is a monogenic disorder that affects millions worldwide. Allogeneic hematopoietic stem cell transplantation is the only available cure. Here, we demonstrate the use of CRISPR/Cas9 and a short single-stranded oligonucleotide template to correct the sickle mutation in the β-globin gene in hematopoietic stem and progenitor cells (HSPCs) from peripheral blood or bone marrow of patients with SCD, with 24.5 ± 7.6% efficiency without selection. Erythrocytes derived from gene-edited cells showed a marked reduction of sickle cells, with the level of normal hemoglobin (HbA) increased to 25.3 ± 13.9%. Gene-corrected SCD HSPCs retained the ability to engraft when transplanted into non-obese diabetic (NOD)-SCID-gamma (NSG) mice with detectable levels of gene correction 16–19 weeks post-transplantation. We show that, by using a high-fidelity SpyCas9 that maintained the same level of on-target gene modification, the off-target effects including chromosomal rearrangements were significantly reduced. Taken together, our results demonstrate efficient gene correction of the sickle mutation in both peripheral blood and bone marrow-derived SCD HSPCs, a significant reduction in sickling of red blood cells, engraftment of gene-edited SCD HSPCs in vivo and the importance of reducing off-target effects; all are essential for moving genome editing based SCD treatment into clinical practice.
dc.identifier.citationPark, So Hyun, Lee, Ciaran M., Dever, Daniel P., et al.. "Highly efficient editing of the β-globin gene in patient-derived hematopoietic stem and progenitor cells to treat sickle cell disease." <i>Nucleic Acids Research,</i> 47, no. 15 (2019) Oxford University Press: 7955-7972. https://doi.org/10.1093/nar/gkz475.
dc.identifier.digitalgkz475
dc.identifier.doihttps://doi.org/10.1093/nar/gkz475
dc.identifier.urihttps://hdl.handle.net/1911/107682
dc.language.isoeng
dc.publisherOxford University Press
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/),
dc.titleHighly efficient editing of the β-globin gene in patient-derived hematopoietic stem and progenitor cells to treat sickle cell disease
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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