Therapeutic gene editing of T cells to correct CTLA-4 insufficiency.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 36288278.
- Also identified by DOI 10.1126/scitranslmed.abn5811 and PMC identifier 7617859.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Heterozygous mutations in <i>CTLA-4</i> 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 <i>CTLA-4</i> cDNA into the first intron of the <i>CTLA-4</i> genomic locus in primary human T cells. This resulted in regulated expression of CTLA-4 in CD4<sup>+</sup> 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 <i>CTLA-4</i><sup>-/-</sup> 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.
Medical subject headings
- T-Lymphocytes
- Lymphocyte Activation