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

Haematologica. 2023 Oct 1;108(10):2652-2663. doi: 10.3324/haematol.2022.282418.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Marrow Failure Disorders / metabolism
  • Fanconi Anemia* / genetics
  • Fanconi Anemia* / metabolism
  • Fanconi Anemia* / therapy
  • Genetic Therapy / methods
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Pancytopenia* / metabolism
  • Transforming Growth Factor beta / metabolism
  • Up-Regulation

Substances

  • Transforming Growth Factor beta

Grants and funding

Funding: This work was supported by grants from the European Commission’s Seventh Framework Program (HEALTH-F5-2012-305421) to the EUROFANCOLEN Consortium (to JB and JSe); from Ministerio de Ciencia, Innovación y Universidades and Fondo Europeo de Desarrollo Regional (RTI2018-097125-B-I00 and PID2021-125077OB-C21, to PR and SN); 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 n. PI20/0335 and co-funded by European Regional Development (FEDER) funds. MA was supported by a PhD Fellowship from the 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.