Gene therapy restores the transcriptional program of hematopoietic stem cells in Fanconi anemia
Lasaga, Miren (Universidad Pública de Navarra)
Río, Paula (Instituto de Investigaciones Sanitarias)
Vilas-Zornoza, Amaia (Centro de Investigación Biomédica en Red de Cáncer)
Planell, Nuria (Universidad Pública de Navarra)
Navarro, Susanna (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Alignani, Diego (Universidad de Navarra)
Fernández-Varas, Beatriz (Instituto de Investigaciones Biomédicas "Alberto Sols")
Mouzo, Daniel (Universidad Pública de Navarra)
Zubicaray, Josune (Hospital Infantil Universitario Niño Jesús (Madrid))
Pujol, Roser (Institut d'Investigació Biomèdica Sant Pau)
Nicoletti, Eileen (Rocket Pharmaceuticals Inc.)
Schwartz, Jonathan D. (Rocket Pharmaceuticals Inc.)
Sevilla, Julián (Hospital Infantil Universitario Niño Jesús (Madrid))
Ainciburi, Marina (Centro de Investigación Biomédica en Red de Cáncer)
Ullate-Agote, Asier (Centro de Investigación Biomédica en Red de Cáncer)
Surrallés i Calonge, Jordi (Institut d'Investigació Biomèdica Sant Pau)
Perona, Rosario (Instituto de Salud Carlos III)
Sastre, Leandro (Instituto de Investigaciones Biomédicas "Alberto Sols")
Prosper, Felipe (Centro de Investigación Biomédica en Red de Cáncer)
Gomez-Cabrero, David (King Abdullah University of Science and Technology)
Bueren, Juan A. (Instituto de Investigaciones Sanitarias)
Universitat Autònoma de Barcelona

Date:	2023
Abstract:	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.
Grants:	Agencia Estatal de Investigación RTI2018-097125-B-I00 Agencia Estatal de Investigación PID2021-125077OB-C21 Ministerio de Economía y Competitividad CB16/12/00489 Ministerio de Economía y Competitividad CB16/12/00225 Ministerio de Economía y Competitividad RD16/0011/0005
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Haematologica, Vol. 108 (april 2023) , p. 2652-2663, ISSN 1592-8721

DOI: 10.3324/haematol.2022.282418
PMID: 37021532

12 p, 2.8 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles