Base Editing of HBG1 and HBG2 Promoters for Sickle Cell Disease - PubMed
19 hours ago
- #fetal hemoglobin
- #base editing
- #sickle cell disease
- Ristoglogene autogetemcel (risto-cel) uses base-edited CD34+ hematopoietic stem and progenitor cells to target HBG1/HBG2 promoters and inhibit BCL11A binding, switching hemoglobin production from sickle hemoglobin (HbS) to fetal hemoglobin (HbF).
- In a phase 1-2 study of 31 sickle cell disease patients aged 12-35 with ≥4 severe vaso-occlusive crises in the previous 2 years, after myeloablative conditioning, a single infusion of risto-cel led to neutrophil engraftment at median 17.5 days and platelet engraftment at 19 days.
- At 6 months, mean on-target edited alleles were 67.4%, mean HbF exceeded 60% of total hemoglobin, and HbS was below 40%, maintained during follow-up, with no severe vaso-occlusive crises reported >60 days post-transfusion.
- Adverse events included grade ≥3 events in 87% and serious events in 39% of patients, with one death from idiopathic pneumonia syndrome, but treatment showed durable HbF expression and HbS reduction.
- Results support further investigation of risto-cel for sickle cell disease treatment, indicating potential efficacy in preventing severe crises and altering hemoglobin profiles.