| Autor: |
Thomas Andrew Fox, Benjamin Christopher Houghton, Lina Petersone, Erin Waters, Natalie Mona Edner, Alex McKenna, Olivier Preham, Claudia Hinze, Cayman Williams, Adriana Silva de Albuquerque, Alan Kennedy, Anne Maria Pesenacker, Pietro Genovese, Lucy Sarah Kate Walker, Siobhan Oisin Burns, David Michael Sansom, Claire Booth, Emma Catherine Morris |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Science translational medicine. 14(668) |
| ISSN: |
1946-6242 |
| Popis: |
Heterozygous mutations inCTLA-4result 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 theCTLA-4cDNA into the first intron of theCTLA-4genomic 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 fromCTLA-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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
