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Therapeutic gene editing of T cells to correct CTLA-4 insufficiency

Fox, Thomas Andrew; Houghton, Benjamin Christopher; Petersone, Lina; Waters, Erin; Edner, Natalie Mona; McKenna, Alex; Preham, Olivier; ... Morris, Emma Catherine; + view all (2022) Therapeutic gene editing of T cells to correct CTLA-4 insufficiency. Science Translational Medicine , 14 (668) , Article eabn5811. 10.1126/scitranslmed.abn5811. Green open access

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Abstract

Heterozygous mutations in CTLA-4 result in an inborn error of immunity with an autoimmune and frequently severe clinical phenotype. Autologous T cell gene therapy may offer a cure without the immunological complications of allogeneic hematopoietic stem cell transplantation. Here, we designed a homology-directed repair (HDR) gene editing strategy that inserts the CTLA-4 cDNA into the first intron of the CTLA-4 genomic locus in primary human T cells. This resulted in regulated expression of CTLA-4 in CD4+ T cells, and functional studies demonstrated CD80 and CD86 transendocytosis. Gene editing of T cells isolated from three patients with CTLA-4 insufficiency also restored CTLA-4 protein expression and rescued transendocytosis of CD80 and CD86 in vitro. Last, gene-corrected T cells from CTLA-4-/- mice engrafted and prevented lymphoproliferation in an in vivo murine model of CTLA-4 insufficiency. These results demonstrate the feasibility of a therapeutic approach using T cell gene therapy for CTLA-4 insufficiency.

Type: Article
Title: Therapeutic gene editing of T cells to correct CTLA-4 insufficiency
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/scitranslmed.abn5811
Publisher version: https://doi.org/10.1126/scitranslmed.abn5811
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10158526
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