β-Thalassaemia is caused by reduced or absent production of β-haemoglobin. Previously, we performed laboratory-scale electroporation of CD34haematopoietic stem and progenitor cells from patients with β-thalassaemia using a transformer base editor. The aim was to target the binding motif of the transcription repressor BCL11A in the HBG1 and HBG2 promotersto 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 CD34cells 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, 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. 1-4 + 5,6 7 + -1
CRISPR Gene Editing