SingleSevere inflammation and lineage skewing is associated with poor engraftment of engineered hematopoietic stem cells in patients with sickle cell disease (bulk RNAseq)

ABSTRACT: In sickle cell disease (SCD), the ?6Glu?Val substitution in the ?-globin chain leads to sickle hemoglobin (HbS) polymerization and red blood cell (RBC) sickling. Transplantation of autologous, genetically modified hematopoietic stem and progenitor cells (HSPCs) represents a promising therapeutic option for patients lacking a compatible donor. We previously designed a new lentiviral vector (DREPAGLOBE LV) expressing a potent anti-sickling ?AS3 globin and demonstrated its safety and efficacy in SCD patient cells (PMID: 1508458). In vitro and in vivo preclinical studies demonstrated the safety and efficacy of a gene therapy (GT) protocol based on the efficient transduction of plerixafor-mobilized SCD HSPCs by the DREPAGLOBE LV. We therefore initiated a Phase I/II open label clinical trial for severe SCD patients. Here, for the 4 treated patients, we report the follow-up of 8 to 33 months. No drug-related adverse events or signs of clonal hematopoiesis were observed. Despite the similar VCN in the drug product, gene marking in peripheral blood mononuclear cells (PBMCs) was variable and as a consequence the correction of the clinical phenotype. These results pinpoint the difficulty to estimate the gene marking, self-renewal and engraftment potential of hematopoietic stem cells (HSCs) in the grafts. Therefore, we performed a transcriptomic analysis at single cell level for studying the pathophysiological mechanisms underlying SCD HSCs dysfunction. This analysis unraveled in the most immature HSCs in the two patients with partial loss of corrected cells, an exacerbated inflammatory signature through IL1-signaling pathways or TNF? and interferon. This was accompanied respectively by a lineage bias of HSCs. Overall, these clinical data indicate a variable efficacy of the DREPAGLOBE GT treatment, which likely depends on the number of infused HSCs and the intrinsic inflammatory alterations of genetically modified HSCs in SCD patients reducing their engraftment capability. Transcriptomic analysis of HSPCs and evaluation of the bone marrow niche in SCD patients will aid in defining critical parameters for achieving successful outcomes in future GT clinical trials for SCD.

ORGANISM(S): Homo sapiens (human)

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PROVIDER: S-BSST1257 | biostudies-other |

REPOSITORIES: biostudies-other