Base Editing of HBG1 and HBG2 Promoters for Sickle Cell Disease

作者：Ashish O. Gupta, Akshay Sharma, Haydar Frangoul, J Kanter, Markus Y. Mapara, Jignesh Dalal, Asif Alavi, Jennifer Jaroscak, Ernesto Ayala, John F. DiPersio, Edward D. Ziga, Mary Eapen, Stacey Rifkin-Zenenberg, Alex C. Minella, Yinzhong Chen, Sarah Chesler, Srikanth Ambati, Thomas S. Bowman, Bahru Habtemariam, Marcelyne Joseney-Antoine, Priya S. Chockalingam, Ling Lin, Sunita Goyal, Amy Simon, Alexis A. Thompson, Matthew M. Heeney · 发表于：New England Journal of Medicine · 年份：2026 · DOI：10.1056/nejmoa2504835 · 被引用次数：18 · 研究领域：Hemoglobinopathies and Related Disorders、Neurological diseases and metabolism、Neurogenetic and Muscular Disorders Research

BackgroundSickle 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). MethodsIn 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. ResultsA 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...