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

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. PorteusM. G. Roncarolo, R. Bacchetta

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


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.

Original languageEnglish
Article numbereaaz0571
JournalScience advances
Issue number19
StatePublished - May 2020

Bibliographical note

Funding Information:
We gratefully acknowledge the support from several grants and awards, including the NIH NIAID (R21 AI123896), the CIRM (DISC2-09526), the Stanford SPARK (1110504-308-DHBTC), and the Sutardja Foundation (1198779-101-GHFBB), and the Cancer Prevention and Research Institute of Texas to G.B. (RR140081 and RR170721), in addition to a donation from an anonymous donor to the Stanford Center for Genetic Immune Diseases (CGID) for immunological studies on the patient samples. M.G. thanks the Stanford University for the tremendous support, including the Stanford Maternal and Child Health Research Institute (MCHRI) Postdoctoral Award (Stanford NIH-NCATS-CTSA, UL1 TR001085) and the Stanford University Office of the Dean Postdoctoral Award (1182084-100-DHDEZ). E.L. received funding support from the Agency for Science, Technology and Research, Singapore and the Stanford Masters of Science in Medicine scholarship.

Publisher Copyright:
Copyright © 2020 The Authors,


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