Base Editing of Gamma-Globin Promoters Increases Fetal Hemoglobin in Sickle Cell Disease

Sickle cell disease is a monogenic hemoglobinopathy defined by chronic hemolytic anemia and recurrent vaso-occlusive crises, which are painful episodes caused by sickle-shaped red blood cells obstructing the microvasculature [1, 2, 3]. While hydroxyurea remains a standard therapy, its clinical utility is often limited by poor adherence and inadequate prevention of cumulative organ damage [4, 5]. Allogeneic hematopoietic stem cell transplantation, a procedure that replaces a patient's bone marrow with healthy donor cells, provides a curative option but is restricted by the scarcity of human leukocyte antigen matched donors and the risk of graft versus host disease [1, 2]. Recent strategies utilize ex vivo gene editing to induce fetal hemoglobin, a form of hemoglobin typically absent after infancy, by targeting the BCL11A erythroid-specific enhancer or the gamma-globin promoters [6, 7, 8]. A recent phase 1-2 study of risto-cel evaluated a base editing therapy, a technology that chemically converts one DNA base pair into another without causing double-strand breaks. The researchers demonstrated that 31 patients achieved mean fetal hemoglobin levels exceeding 60% and remained free of severe vaso-occlusive crises during follow-up, suggesting a potential pathway to functionally cure the disease without relying on donor availability [9].