CRISPR-based gene editing enables gene repair in IPEX patient cells.
Authors
Goodwin, MLee, 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
Bacchetta, R
Issue Date
2020-05-06Keywords
GENETICSAUTO-IMMUNE DISEASES
GENE EDITING
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Science advancesDOI
10.1126/sciadv.aaz0571PubMed ID
32494707Abstract
The 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.Item Type
ArticleLanguage
enEISSN
2375-2548ae974a485f413a2113503eed53cd6c53
10.1126/sciadv.aaz0571
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