2026-07-23T22:58:32Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/97892025-05-08T10:45:12Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Pino-Barrio, Maria José
author
Giménez, Yari
author
Villanueva, Mariela
author
Hildenbeutel, Marcus
author
Sánchez-Domínguez, Rebeca
author
Rodriguez Perales, Sandra
author
Pujol, Roser
author
Surrallés, Jordi
author
Río, Paula
author
Cathomen, Toni
author
Mussolino, Claudio
author
Bueren, Juan Antonio
author
Navarro, Susana
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Instituto de Salud Carlos III
funder
Comunidad de Madrid (España)
funder
Federal Ministry of Education & Research (Alemania)
2020-04-28T14:49:51Z
2020-04-28T14:49:51Z
2020-04-24
Sci Rep. 2020 ;10(1):6997.
10.1038/s41598-020-63971-z
2045-2322
2045-2322
Scientific reports
32332829
http://hdl.handle.net/20.500.12105/9789
The promising ability to genetically modify hematopoietic stem and progenitor cells by precise gene editing remains challenging due to their sensitivity to in vitro manipulations and poor efficiencies of homologous recombination. This study represents the first evidence of implementing a gene editing strategy in a murine safe harbor locus site that phenotypically corrects primary cells from a mouse model of Fanconi anemia A. By means of the co-delivery of transcription activator-like effector nucleases and a donor therapeutic FANCA template to the Mbs85 locus, we achieved efficient gene targeting (23%) in mFA-A fibroblasts. This resulted in the phenotypic correction of these cells, as revealed by the reduced sensitivity of these cells to mitomycin C. Moreover, robust evidence of targeted integration was observed in murine wild type and FA-A hematopoietic progenitor cells, reaching mean targeted integration values of 21% and 16% respectively, that were associated with the phenotypic correction of these cells. Overall, our results demonstrate the feasibility of implementing a therapeutic targeted integration strategy into the mMbs85 locus, ortholog to the well-validated hAAVS1, constituting the first study of gene editing in mHSC with TALEN, that sets the basis for the use of a new safe harbor locus in mice.
eng
TALEN mediated gene editing in a mouse model of Fanconi anemia
research article
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