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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 \u03b2-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-\u03b1 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. 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