Article Dans Une Revue Nature Communications Année : 2025

Severe inflammation and lineage skewing are associated with poor engraftment of engineered hematopoietic stem cells in patients with sickle cell disease

Steicy Sobrino
  • Fonction : Auteur
Laure Joseph
  • Fonction : Auteur
Elisa Magrin
  • Fonction : Auteur
Anne Chalumeau
Nicolas Hebert
Alice Corsia
  • Fonction : Auteur
Adeline Denis
  • Fonction : Auteur
Cécile Roudaut
  • Fonction : Auteur
Clotilde Aussel
  • Fonction : Auteur
Olivia Leblanc
  • Fonction : Auteur
Mégane Brusson
Tristan Felix
Jean-Sebastien Diana
  • Fonction : Auteur
Angelina Petrichenko
Jana El Etri
  • Fonction : Auteur
Auria Godard
Eden Tibi
  • Fonction : Auteur
Sandra Manceau
  • Fonction : Auteur
Jean Marc Treluyer
  • Fonction : Auteur
Fulvio Mavilio
Frederic Bushman
Ambroise Marcais
Martin Castelle
  • Fonction : Auteur
Benedicte Neven
Olivier Hermine
  • Fonction : Auteur
Sylvain Renolleau
Alessandra Magnani
  • Fonction : Auteur
Vahid Asnafi
Pablo Bartolucci
  • Fonction : Auteur
Emmanuelle Six
Michaela Semeraro
  • Fonction : Auteur
Annarita Miccio
Marina Cavazzana

Résumé

Abstract In sickle cell disease (SCD), the β6 Glu→Val substitution in the β-globin leads to red blood cell sickling. The transplantation of autologous, genetically modified hematopoietic stem and progenitor cells (HSPCs) is a promising treatment option for patients with SCD. We completed a Phase I/II open-label clinical trial (NCT03964792) for patients with SCD using a lentiviral vector (DREPAGLOBE) expressing a potent anti-sickling β-globin. The primary endpoint was to evaluate the short-term safety and secondary endpoints included the efficacy and the long-term safety. We report on the results after 18 to 36 months of follow-up. No drug-related adverse events or signs of clonal hematopoiesis were observed. Despite similar vector copy numbers in the drug product, gene-marking in peripheral blood mononuclear cells and correction of the clinical phenotype varied from one patient to another. Single-cell transcriptome analyses show that in the patients with poor engraftment, the most immature HSCs display an exacerbated inflammatory signature (via IL-1 or TNF-α and interferon signaling pathways). This signature is accompanied by a lineage bias in the HSCs. Our clinical data indicates that the DREPAGLOBE-based gene therapy (GT) is safe. However, its efficacy is variable and probably depends on the number of infused HSCs and intrinsic, engraftment-impairing inflammatory alterations in HSCs. Trial: NCT03964792

Dates et versions

hal-05333490 , version 1 (27-10-2025)

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Citer

Steicy Sobrino, Laure Joseph, Elisa Magrin, Anne Chalumeau, Nicolas Hebert, et al.. Severe inflammation and lineage skewing are associated with poor engraftment of engineered hematopoietic stem cells in patients with sickle cell disease. Nature Communications, 2025, 16 (1), pp.3137. ⟨10.1038/s41467-025-58321-4⟩. ⟨hal-05333490⟩
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