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001			ESSALUD
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040			_aBMG
041			_aeng
100			_aGupta, Ashish O. _eAutor _954539
245			_aBase editing of HBG1 and HBG2 promoters for sickle cell disease
300			_apáginas: 1824-1835
520			_aBackground: 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.
650			_aMEDICINA DEL ADOLESCENTE _95533
650			_aANEMIA _97417
650			_aENFERMEDADES INFANTILES _953890
650			_aGENÉTICA GENERAL _954107
650			_aHEMATOLOGÍA _97422
650			_aONCOLOGÍA GENERAL _954224
650			_aCÉLULAS MADRE _942759
700			_aSharma, Akshay _954540
700			_aFrangoul, Haydar _954541
700			_aKanter, Julie _954542
700			_aMapara, Markus Y. _954543
700			_aDalal, Jignesh _954544
700			_aAlavi, Asif _954545
773	0		_022717 _922676 _dMassachusetts NEJM Group _oNEJM015 _tThe New England Journal of Medicine _wESSALUD _x0028-4793
942			_cARTICULOS _e2026-08-31 _zsqb
999			_c22925 _d22925