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

In sickle cell disease (SCD), the β6<sup>Glu→Val</sup> 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.

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Publication Details

Journal
Nature Communications
Published
2025-04-01
DOI
https://doi.org/10.1038/s41467-025-58321-4
Citations
11
Primary Topic
Hemoglobinopathies and Related Disorders
Type
article
Field-Weighted Citation Impact
17.88

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article

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

Bénédicte Neven, Sylvain Renolleau, Annarita Miccio, Marina Cavazzana et al.
11 citations
Nature Communications
Hemoglobinopathies and Related Disorders
17.88
article

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

Bénédicte Neven, Sylvain Renolleau, Annarita Miccio, Marina Cavazzana, Adeline Denis, Fulvio Mavilio, Anne Chalumeau, Elisa Magrin, Frederic D. Bushman, Michaëla Semeraro, Eden Tibi, Auria Godard, Pablo Bartolucci, Mégane Brusson, Alessandra Magnani, Alice Corsia, Vahid Asnafi, Steicy Sobrino, Nicolas Hebert, Sandra Manceau, Olivia Leblanc, Jean‐Sébastien Diana, Martin Castelle, Tristan Félix, Olivier Hermine, Wassim El Nemer, Emmanuelle Six, Ambroise Marçais, Jean‐Marc Tréluyer, Angelina Petrichenko, Laure Joseph, Cécile Roudaut, Clotilde Aussel, Jana El Etri
article en
11 citations

Abstract

In sickle cell disease (SCD), the β6<sup>Glu→Val</sup> 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.

Nature CommunicationsVol. 16(1)
University of Modena and Reggio Emilia (IT), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Paris-Est Créteil (FR), Université Paris Cité (FR), Aix-Marseille Université (FR), Sorbonne Paris Cité (FR), Assistance Publique – Hôpitaux de Paris (FR), Groupe Hospitalier Cochin - Port-Royal, Hôtel-Dieu, Broca - La Collégiale (FR), Établissement Français du Sang (FR), Institut Mondor de Recherche Biomédicale (FR), Institut des Maladies Génétiques Imagine (FR), University of Pennsylvania (US)
Institut des maladies génétiques Imagine, European Commission, Agence Nationale de la Recherche, Etablissement Français du Sang, HORIZON EUROPE Framework Programme
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Hemoglobinopathies and Related Disorders
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