CRISPR-Cas12a Gene Editing of HBG1 and HBG2 Promoters to Treat Sickle Cell Disease

BACKGROUND: promoters to reactivate fetal hemoglobin production for the treatment of sickle cell disease. METHODS: We conducted a phase 1-2, multicenter, open-label, single-group study involving patients with severe sickle cell disease who were 12 to 50 years of age and had had at least two severe vaso-occlusive events per year in the previous 2 years. The patients received a single infusion of reni-cel after myeloablative conditioning with busulfan. The patients were monitored for engraftment, hemoglobin-related measures, allelic editing levels, vaso-occlusive events, and adverse events over a 24-month period. The study was terminated early on the basis of the sponsor's reassessment of clinical development priorities. Results of an analysis that was not prespecified are reported. RESULTS: As of October 29, 2024, a total of 28 patients with severe sickle cell disease had been treated with reni-cel. The median duration of follow-up was 9.5 months (range, 0.7 to 25.2). Among 27 patients who had neutrophil and platelet engraftment by the data-cutoff date, neutrophil engraftment occurred after a median of 23 days (range, 14 to 29), and platelet engraftment occurred after a median of 25 days (range, 17 to 51). At month 6, among 18 patients with at least 6 months of available data, the mean (±SD) total hemoglobin level (9.8±1.7 g per deciliter at baseline) had increased to 13.8±1.9 g per deciliter, and the mean percentage of fetal hemoglobin (2.5±2.5% at baseline) had increased to 48.1±3.2%; both measures were maintained at or above these values thereafter. One patient had two severe vaso-occlusive events after infusion. Adverse events were consistent with those that occur after myeloablative busulfan-based conditioning and autologous hematopoietic stem-cell transplantation. CONCLUSIONS: Treatment with reni-cel led to normalization of the total hemoglobin level and an increase in the percentage of fetal hemoglobin, with no vaso-occlusive events occurring in 27 of 28 patients after infusion. These results support further investigation of this gene-editing approach in the treatment of severe sickle cell disease. (Funded by Editas Medicine; RUBY ClinicalTrials.gov number, NCT04853576.).