Base Editing of HBG1 and HBG2 Promoters for Sickle Cell Disease

BACKGROUND: promoters and inhibit BCL11A binding without altering BCL11A expression, yielding a switch in hemoglobin production from sickle hemoglobin (HbS) to antisickling fetal hemoglobin (HbF). METHODS: viable CD34+ cells per kilogram of body weight). The primary efficacy end point was freedom from severe vaso-occlusive crises for 12 consecutive months, starting later than 60 days after the last red-cell transfusion. This interim analysis was unplanned; here, we describe safety, editing, engraftment, and hemoglobin production and the number of severe vaso-occlusive crises starting later than 60 days after the last red-cell transfusion. RESULTS: A total of 31 patients received risto-cel and were followed for a mean of 6.6 months (range, 0.3 to 20.4). A median of one cycle (range, one to five) was required for stem-cell collection. Neutrophil engraftment occurred at a median of 17.5 days, and platelet engraftment at a median of 19 days. One patient died from idiopathic pneumonia syndrome. All 31 patients had at least one adverse event, 27 (87%) had an adverse event of grade 3 or higher, and 12 (39%) had a serious adverse event. At 6 months, the mean fraction of on-target edited alleles in peripheral blood was 67.4%, the mean HbF as a fraction of total hemoglobin was more than 60%, and the HbS as a fraction of total hemoglobin was less than 40% (among 13 patients); these levels were maintained throughout follow-up. No investigator-reported severe vaso-occlusive crises occurred later than 60 days after the last red-cell transfusion. CONCLUSIONS: Treatment with risto-cel was followed by rapid engraftment and durable expression of HbF and reduction in HbS. These data support further investigation of risto-cel to treat sickle cell disease. (Funded by Beam Therapeutics; BEACON ClinicalTrials.gov number, NCT05456880.).