CRISPR-based gene editing enables FOXP3 gene repair in IPEX patient cells

dc.contributor.authorGoodwin, M.
dc.contributor.authorLee, E.
dc.contributor.authorLakshmanan, U.
dc.contributor.authorShipp, S.
dc.contributor.authorFroessl, L.
dc.contributor.authorBarzaghi, F.
dc.contributor.authorPasserini, L.
dc.contributor.authorNarula, M.
dc.contributor.authorSheikali, A.
dc.contributor.authorLee, Ciaran M.
dc.contributor.authorBao, G.
dc.contributor.authorBauer, C. S.
dc.contributor.authorMiller, H. K.
dc.contributor.authorGarcia-Lloret, M.
dc.contributor.authorButte, M. J.
dc.contributor.authorBertaina, A.
dc.contributor.authorShah, A.
dc.contributor.authorPavel-Dinu, M.
dc.contributor.authorHendel, A.
dc.contributor.authorPorteus, M.
dc.contributor.authorRoncarolo, M. G.
dc.contributor.authorBacchetta, R.
dc.contributor.funderNational Institute of Allergy and Infectious Diseasesen
dc.contributor.funderCalifornia Institute for Regenerative Medicineen
dc.contributor.funderStanford Universityen
dc.contributor.funderSutardja Foundation, United Statesen
dc.contributor.funderCancer Prevention and Research Institute of Texasen
dc.contributor.funderAgency for Science, Technology and Researchen
dc.date.accessioned2021-01-15T13:00:16Z
dc.date.available2021-01-15T13:00:16Z
dc.date.issued2020-05-06
dc.date.updated2021-01-15T12:32:02Z
dc.description.abstractThe prototypical genetic autoimmune disease is immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, a severe pediatric disease with limited treatment options. IPEX syndrome is caused by mutations in the forkhead box protein 3 (FOXP3) gene, which plays a critical role in immune regulation. As a monogenic disease, IPEX is an ideal candidate for a therapeutic approach in which autologous hematopoietic stem and progenitor (HSPC) cells or T cells are gene edited ex vivo and reinfused. Here, we describe a CRISPR-based gene correction permitting regulated expression of FOXP3 protein. We demonstrate that gene editing preserves HSPC differentiation potential, and that edited regulatory and effector T cells maintain their in vitro phenotype and function. Additionally, we show that this strategy is suitable for IPEX patient cells with diverse mutations. These results demonstrate the feasibility of gene correction, which will be instrumental for the development of therapeutic approaches for other genetic autoimmune diseases.en
dc.description.sponsorshipNational Institute of Allergy and Infectious Diseases (R21 AI123896); California Institute for Regenerative Medicine (DISC2-09526); Stanford University (1110504-308-DHBTC; Stanford NIH-NCATS-CTSA, UL1 TR001085; 1182084-100-DHDEZ; Masters of Science in Medicine scholarship); Sutardja Foundation, United States (1198779-101-GHFBB); Cancer Prevention and Research Institute of Texas (RR140081 and RR170721)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleideaaz0571en
dc.identifier.citationGoodwin, M., Lee, E., Lakshmanan, U., Shipp, S., Froessl, L., Barzaghi, F., Passerini, L., Narula, M., Sheikali, A., Lee, C. M., Bao, G., Bauer, C. S., Miller, H. K., Garcia-Lloret, M., Butte, M. J., Bertaina, A., Shah, A., Pavel-Dinu, M., Hendel, A., Porteus, M., Roncarolo, M. G. and Bacchetta, R. (2020) 'CRISPR-based gene editing enables FOXP3 gene repair in IPEX patient cells', Science Advances, 6(19), eaaz0571 (17pp). doi: 10.1126/sciadv.aaz0571en
dc.identifier.doi10.1126/sciadv.aaz0571en
dc.identifier.endpage17en
dc.identifier.issn2375-2548
dc.identifier.issued19en
dc.identifier.journaltitleScience Advancesen
dc.identifier.startpage1en
dc.identifier.urihttps://hdl.handle.net/10468/10924
dc.identifier.volume6en
dc.language.isoenen
dc.publisherAmerican Association for the Advancement of Scienceen
dc.rights© 2020, The Authors. Some rights reserved. Exclusive licensee: American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).en
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/en
dc.subjectIPEX syndromeen
dc.subjectForkhead box protein 3 geneen
dc.subjectFOXP3en
dc.subjectImmune regulationen
dc.subjectGene correctionen
dc.titleCRISPR-based gene editing enables FOXP3 gene repair in IPEX patient cellsen
dc.typeArticle (peer-reviewed)en
Files
Original bundle
Now showing 1 - 3 of 3
Loading...
Thumbnail Image
Name:
eaaz0571.full.pdf
Size:
1.6 MB
Format:
Adobe Portable Document Format
Description:
Published Version
Loading...
Thumbnail Image
Name:
aaz0571_SM.pdf
Size:
1.52 MB
Format:
Adobe Portable Document Format
Description:
Supplementary Materials
Loading...
Thumbnail Image
Name:
aaz0571_Table_S3.xlsx
Size:
39.02 KB
Format:
Microsoft Excel XML
Description:
Table S3
License bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
license.txt
Size:
2.71 KB
Format:
Item-specific license agreed upon to submission
Description: