03457nam a2200337 4500 ESSALUD 20260903142036.0 ta t pe ||||| |||| 00| 0 spa d BMG eng Gupta, Ashish O. Autor 54539 Base editing of HBG1 and HBG2 promoters for sickle cell disease páginas: 1824-1835 Background: Sickle cell disease is characterized by chronic hemolytic anemia and recurrent severe vaso-occlusive crises. Ristoglogene autogetemcel (risto-cel) includes autologous CD34+ hematopoietic stem and progenitor cells that have been base-edited to target the HBG1 and HBG2 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: In this phase 1–2 study, we enrolled patients 12 to 35 years of age with sickle cell disease who had had at least four severe vaso-occlusive crises in the 2 years before enrollment. After myeloablative conditioning with pharmacokinetically guided administration of busulfan, patients received a single infusion of risto-cel (at a dose of ≥3.0×106 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. MEDICINA DEL ADOLESCENTE 5533 ANEMIA 7417 ENFERMEDADES INFANTILES 53890 GENÉTICA GENERAL 54107 HEMATOLOGÍA 7422 ONCOLOGÍA GENERAL 54224 CÉLULAS MADRE 42759 Sharma, Akshay 54540 Frangoul, Haydar 54541 Kanter, Julie 54542 Mapara, Markus Y. 54543 Dalal, Jignesh 54544 Alavi, Asif 54545 22717 22676 Massachusetts NEJM Group NEJM015 The New England Journal of Medicine ESSALUD 0028-4793 ARTICULOS 2026-08-31 sqb 22925 22925