Clinical base editing for β-hemoglobinopathies across different genetic backgrounds.

Abstract

β-Hemoglobinopathies are monogenic disorders. We previously applied a transformer base editor (tBE) to reactivate fetal hemoglobin (HbF) expression, and five Chinese transfusion-dependent β-thalassemia (TDT) patients achieved transfusion independence. However, the applicability of tBE to sickle cell disease (SCD) and genetically different TDT populations remained unknown. Here, we show a four-patient descriptive report from three trials, including one African SCD patient and three TDT patients carrying mutations common in South and Southeast Asia. All patients achieve hematopoietic recovery, and red blood cell transfusions are discontinued in all cases. After more than 12 months of follow-up, all patients show durable editing, sustained high-level pan-cellular HbF expression, and transfusion independence. No vaso-occlusive episodes occur in the SCD patient. No off-target mutations, malignancies, or deaths are observed. These initial results support the feasibility of applying tBE to treat SCD and the reported TDT genotypes, warranting broader evaluation across diverse populations. ClinicalTrials.gov identifiers are as follows: NCT06328764, NCT06065189, and NCT06565026.