2026-04-29T20:47:13Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/97892025-05-08T10:45:12Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc 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 author 2020-04-24 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. 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 TALEN mediated gene editing in a mouse model of Fanconi anemia