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<p>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</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月1日

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  • 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,
  • Marina Cavazzana

摘要

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