Abstract

β-Thalassaemia is caused by reduced or absent production of β-haemoglobin 1 , 2 , 3 , 4 . Previously, we performed laboratory-scale electroporation of CD34 + haematopoietic stem and progenitor cells from patients with β-thalassaemia using a transformer base editor 5 , 6 . The aim was to target the binding motif of the transcription repressor BCL11A in the HBG1 and HBG2 promoters 7 to reactivate fetal haemoglobin (HbF) production. Here we present results of a phase 1 clinical trial (ClinicalTrials.gov identifier: NCT06024876) of five patients who received autologous CD34 + cells modified using a transformer base editor at clinical scale (CS-101). With a median follow-up of 23.0 months after CS-101 infusion, the median times to neutrophil and platelet engraftment were 16 days and 25 days, respectively. Moreover, all patients had stopped red blood cell transfusions, with a median time to the last transfusion of 18 days after CS-101 infusion. The mean total haemoglobin and HbF concentrations were 12.4 ± 1.0 and 11.5 ± 0.9 g dl –1 , respectively, at month 3 after infusion. These levels remained at similar or higher levels throughout the follow-up period, which indicated rapid haematopoietic reconstitution. The adverse events of CS-101 were generally consistent with those of busulfan myeloablative conditioning and autologous haematopoietic stem and progenitor cell transplantation. No deaths or cancer occurrences were reported. In summary, CS-101 can lead to rapid and sustained increases in both total haemoglobin and HbF levels, which resulted in early and enduring transfusion independence.

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