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CRISPR-based gene editing enables gene repair in IPEX patient cells.
Goodwin, M Lee, E Lakshmanan, U Shipp, S Froessl, L Barzaghi, F Passerini, L Narula, M Sheikali, A Lee, C M
Goodwin, M
Lee, E
Lakshmanan, U
Shipp, S
Froessl, L
Barzaghi, F
Passerini, L
Narula, M
Sheikali, A
Lee, C M
Advisors
Editors
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Departments
Date
06/05/2020
Date Submitted
Keywords
GENETICS
AUTO-IMMUNE DISEASES
GENE EDITING
AUTO-IMMUNE DISEASES
GENE EDITING
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Subject Mesh
Planned Date
Start Date
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Principal Investigators
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eaaz0571.full.pdf
Adobe PDF, 1.6 MB
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Abstract
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.
Language
en
Citation
ISSN
eISSN
2375-2548
ISBN
DOI
10.1126/sciadv.aaz0571
PMID
32494707