Gene correction for SCID-X1 in long-term hematopoietic stem cells

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dc.citation.articleNumber1634en_US
dc.citation.journalTitleNature Communicationsen_US
dc.citation.volumeNumber10en_US
dc.contributor.authorPavel-Dinu, Maraen_US
dc.contributor.authorWiebking, Volkeren_US
dc.contributor.authorDejene, Beruh T.en_US
dc.contributor.authorSrifa, Warachareeen_US
dc.contributor.authorMantri, Sruthien_US
dc.contributor.authorNicolas, Carmencita E.en_US
dc.contributor.authorLee, Ciaranen_US
dc.contributor.authorBao, Gangen_US
dc.contributor.authorKildebeck, Eric J.en_US
dc.contributor.authorPunjya, Nirajen_US
dc.contributor.authorSindhu, Camilleen_US
dc.contributor.authorInlay, Matthew A.en_US
dc.contributor.authorSaxena, Niveditaen_US
dc.contributor.authorDeRavin, Suk Seeen_US
dc.contributor.authorMalech, Harryen_US
dc.contributor.authorRoncarolo, Maria Graziaen_US
dc.contributor.authorWeinberg, Kenneth I.en_US
dc.contributor.authorPorteus, Matthew H.en_US
dc.contributor.orgBioengineeringen_US
dc.date.accessioned2019-12-12T17:25:40Zen_US
dc.date.available2019-12-12T17:25:40Zen_US
dc.date.issued2019en_US
dc.description.abstractGene correction in human long-term hematopoietic stem cells (LT-HSCs) could be an effective therapy for monogenic diseases of the blood and immune system. Here we describe an approach for X-linked sSevere cCombined iImmunodeficiency (SCID-X1) using targeted integration of a cDNA into the endogenous start codon to functionally correct disease-causing mutations throughout the gene. Using a CRISPR-Cas9/AAV6 based strategy, we achieve up to 20% targeted integration frequencies in LT-HSCs. As measures of the lack of toxicity we observe no evidence of abnormal hematopoiesis following transplantation and no evidence of off-target mutations using a high-fidelity Cas9 as a ribonucleoprotein complex. We achieve high levels of targeting frequencies (median 45%) in CD34+ HSPCs from six SCID-X1 patients and demonstrate rescue of lymphopoietic defect in a patient derived HSPC population in vitro and in vivo. In sum, our study provides specificity, toxicity and efficacy data supportive of clinical development of genome editing to treat SCID-Xl.en_US
dc.identifier.citationPavel-Dinu, Mara, Wiebking, Volker, Dejene, Beruh T., et al.. "Gene correction for SCID-X1 in long-term hematopoietic stem cells." <i>Nature Communications,</i> 10, (2019) Springer Nature: https://doi.org/10.1038/s41467-019-09614-y.en_US
dc.identifier.digitals41467-019-09614-yen_US
dc.identifier.doihttps://doi.org/10.1038/s41467-019-09614-yen_US
dc.identifier.urihttps://hdl.handle.net/1911/107894en_US
dc.language.isoengen_US
dc.publisherSpringer Natureen_US
dc.rightsThis article is licensed under a Creative Commons Attribution 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 Creative Commons 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.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleGene correction for SCID-X1 in long-term hematopoietic stem cellsen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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