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Gene therapy restores the transcriptional program of stem cells in Fanconi anemia

Autores: Lasaga, M.; Rio, P.; Vilas Zornoza, Amaia; Planell, N.; Navarro, S.; Alignani, D.; Fernández-Varas, B.; Mouzo, D.; Zubicaray, J.; Pujol, R. M.; Nicoletti, E.; Schwartz, J. D.; Sevilla, J.; Ainciburu Fernandez, Marina; Ullate Agote, Asier; Surrallés, J.; Perona, R.; Sastre, L.; Prosper Cardoso, Felipe (Autor de correspondencia); Gomez-Cabrero, D. (Autor de correspondencia); Bueren, J. A. (Autor de correspondencia)
Título de la revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN: 0390-6078
Volumen: 108
Número: 10
Páginas: 2652 - 2663
Fecha de publicación: 2023
Resumen:
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-beta 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.
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