TY - JOUR
T1 - Gene therapy restores the transcriptional program of hematopoietic stem cells in Fanconi anemia
AU - Lasaga, Miren
AU - Río, Paula
AU - Vilas-Zornoza, Amaia
AU - Planell, Nuria
AU - Navarro, Susanna
AU - Alignani, Diego
AU - Fernández-Varas, Beatriz
AU - Mouzo, Daniel
AU - Zubicaray, Josune
AU - Pujol, Roser
AU - Nicoletti, Eileen
AU - Schwartz, Jonathan D.
AU - Sevilla, Julián
AU - Ainciburi, Marina
AU - Ullate-Agote, Asier
AU - Surrallés i Calonge, Jordi
AU - Perona, Rosario
AU - Sastre, Leandro
AU - Prosper, Felipe
AU - Gomez-Cabrero, David
AU - Bueren, Juan A.
N1 - Publisher Copyright:
© 2023 Ferrata Storti Foundation Published under a CC BY-NC license.
PY - 2023/10
Y1 - 2023/10
N2 - Clinical trials have shown that lentiviral-mediated gene therapy can ameliorate bone marrow failure (BMF) in nonconditioned 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.
AB - Clinical trials have shown that lentiviral-mediated gene therapy can ameliorate bone marrow failure (BMF) in nonconditioned 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.
UR - http://www.scopus.com/inward/record.url?scp=85173242436&partnerID=8YFLogxK
U2 - 10.3324/haematol.2022.282418
DO - 10.3324/haematol.2022.282418
M3 - Article
C2 - 37021532
AN - SCOPUS:85173242436
SN - 0390-6078
VL - 108
SP - 2652
EP - 2663
JO - Haematologica
JF - Haematologica
IS - 10
ER -
