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

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.

• Authors: M Goodwin, E Lee, U Lakshmanan, S Shipp, L Froessl, F Barzaghi, L Passerini, M Narula, A Sheikali, C M Lee, G Bao, C S Bauer, H K Miller, M Garcia-Lloret, M J Butte, A Bertaina, A Shah, M Pavel-Dinu, A Hendel, M Porteus, M G Roncarolo, R Bacchetta
• Journal: Science advances (Sci Adv) Vol. 6 Issue 19 Pg. eaaz0571 (05 2020) ISSN: 2375-2548 [Electronic] United States
• PMID: 32494707 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 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).

Chemical References

• FOXP3 protein, human
• Forkhead Transcription Factors

Topics

• Child
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Editing
• Genetic Diseases, X-Linked (genetics, therapy)
• Humans
• Mutation
• Phenotype
• T-Lymphocytes, Regulatory