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

Steicy Sobrino, Laure Joseph, Elisa Magrin, Anne Chalumeau, Nicolas Hebert, Alice Corsia, Adeline Denis, Cécile Roudaut, Clotilde Aussel, Olivia Leblanc, Mégane Brusson, Tristan Felix, Jean-Sebastien Diana, Angelina Petrichenko, Jana El Etri, Auria Godard, Eden Tibi, Sandra Manceau, Jean Marc Treluyer, Fulvio Mavilio, Frederic D. Bushman, Ambroise Marcais, Martin Castelle, Benedicte Neven, Olivier Hermine, Sylvain Renolleau, Alessandra Magnani, Vahid Asnafi, Wassim El Nemer, Pablo Bartolucci, Emmanuelle Six, Michaela Semeraro, Annarita Miccio and Marina Cavazzana ()
Additional contact information
Steicy Sobrino: Imagine Institute
Laure Joseph: Université Paris Cité
Elisa Magrin: Université Paris Cité
Anne Chalumeau: Imagine Institute
Nicolas Hebert: Laboratory of Excellence LABEX GRex
Alice Corsia: Université Paris Cité
Adeline Denis: Imagine Institute
Cécile Roudaut: Université Paris Cité
Clotilde Aussel: Université Paris Cité
Olivia Leblanc: Université Paris Cité
Mégane Brusson: Imagine Institute
Tristan Felix: Imagine Institute
Jean-Sebastien Diana: Université Paris Cité
Angelina Petrichenko: University of Pennsylvania
Jana El Etri: Imagine Institute
Auria Godard: Labex GR-Ex
Eden Tibi: Université Paris Cité
Sandra Manceau: Université Paris Cité
Jean Marc Treluyer: GH Paris Centre
Fulvio Mavilio: University of Modena and Reggio Emilia
Frederic D. Bushman: University of Pennsylvania
Ambroise Marcais: Université Paris Cité
Martin Castelle: Hôpital Necker Enfants-Malades
Benedicte Neven: Hôpital Necker Enfants-Malades
Olivier Hermine: Université Paris Cité
Sylvain Renolleau: Université Paris Cité
Alessandra Magnani: Université Paris Cité
Vahid Asnafi: Assistance Publique-Hôpitaux de Paris (AP-HP)
Wassim El Nemer: Labex GR-Ex
Pablo Bartolucci: Laboratory of Excellence LABEX GRex
Emmanuelle Six: Imagine Institute
Michaela Semeraro: GH Paris Centre
Annarita Miccio: Imagine Institute
Marina Cavazzana: Université Paris Cité

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract In sickle cell disease (SCD), the β6Glu→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

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-58321-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58321-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-58321-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().