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

Miren Lasaga, Paula Río, Amaia Vilas-Zornoza, Nuria Planell, Susana Navarro, Diego Alignani, Beatriz Fernández-Varas, Daniel Mouzo, Josune Zubicaray, Roser M Pujol, Eileen Nicoletti, Jonathan D Schwartz, Julián Sevilla, Marina Ainciburi, Asier Ullate-Agote, Jordi Surrallés, Rosario Perona, Leandro Sastre, Felipe Prosper, David Gomez-CabreroJuan A Bueren

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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 HSPCs, however it is yet unknown if gene therapy can revert affected molecular pathways in diseased HSPCs. Single-cell RNA sequencing was performed in chimeric populations of corrected and uncorrected HSPCs coexisting in the BM of gene therapy treated FA patients. Our study demonstrates that gene therapy reverts the transcriptional signature of FA HSPCs, which then resembles the transcriptional program of healthy donor HSPCs. This includes a downregulated expression of TGF-β and p21, typically upregulated in FA HSPCs, 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.
Original languageEnglish (US)
StatePublished - Apr 6 2023

ASJC Scopus subject areas

  • Hematology


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