2026-04-13T05:56:14Zhttps://recercat.cat/oai/request

oai:recercat.cat:2072/4752562025-07-29T22:51:51Zcom_2072_98col_2072_378192

00925njm 22002777a 4500 dc Lasaga, Miren author Río, Paula author Vilas-Zornoza, Amaia author Planell, Núria author Navarro, Susanna author Alignani, Diego author Fernández-Varas, Beatriz author Mouzo, Daniel author Zubicaray, Josune author Pujol, Roser author Nicoletti, Eileen author Schwartz, Jonathan D. author Sevilla, Julián author Ainciburi, Marina author Ullate-Agote, Asier author Surrallés i Calonge, Jordi author Perona, Rosario author Sastre, Leandro author Prosper, Felipe author Gomez-Cabrero, David author Bueren, Juan A. author Universitat Autònoma de Barcelona author 2023 Clinical trials have shown that lentiviral-mediated gene therapy can ameliorate bone marrow failure (BMF) in non-conditioned Fanconi anemia (FA) patients resulting from the proliferative advantage of corrected FA hematopoietic stem and progenitor cells (HSPC). However, it is not yet known if gene therapy can revert affected molecular pathways in diseased HSPC. Single-cell RNA sequencing was performed in chimeric populations of corrected and uncorrected HSPC co-existing in the BM of gene therapy-treated FA patients. Our study demonstrates that gene therapy reverts the transcriptional signature of FA HSPC, which then resemble the transcriptional program of healthy donor HSPC. This includes a down-regulated expression of TGF-β and p21, typically up-regulated in FA HSPC, and upregulation of DNA damage response and telomere maintenance pathways. Our results show for the first time the potential of gene therapy to rescue defects in the HSPC transcriptional program from patients with inherited diseases; in this case, in FA characterized by BMF and cancer predisposition. Gene therapy restores the transcriptional program of hematopoietic stem cells in Fanconi anemia