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

Bibliographical note

KAUST Repository Item: Exported on 2023-04-10
Acknowledgements: The authors thank Ramón García-Escudero for careful reading of the manuscript and helpful discussions. The authors also thank A. de la Cal for coordinating the delivery of BM samples from patients with FA. The authors are also indebted to the patients with FA, their families and clinicians from the Fundación Anemia de Fanconi. Funding: This work was supported by grants from the European Commission’s Seventh Framework Program (HEALTH-F5-2012-305421) to the EUROFANCOLEN Consortium J.B. and J.Se; from Ministerio de Ciencia, Innovación y Universidades and Fondo Europeo de Desarrollo Regional (RTI2018-097125-B-I00 and PID2021-125077OB-C21 to P.R. and S.N.); from Gobierno de Navarra, Departamento de Desarrollo Económico y Empresarial (AGATA 0011-1411-2020- 000010); from Instituto de Salud Carlos III (ISCIII) and co-financed by FEDER CIBERONC (CB16/12/00489 and CB16/12/00225); Redes de Investigación Cooperativa (TERCEL RD16/0011/0005); “Instituto de Salud Carlos III (ISCIII)/Red Espanola de Terapias Avanzadas RICORS/TERAV” (RD21/0017/0027- Supported by European Union-NextGenerationEU. and from Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid (AvanCell Project; B2017/BMD3692); from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain, grant number PI20/0335 and co-funded by European Regional Development (FEDER) funds. M.A. was supported by a PhD Fellowship from Ministerio de Ciencia, Innovación y Universidades (FPU18/05488). CIBERER and CIBERONC are initiatives of the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional.

ASJC Scopus subject areas

  • Hematology


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