Investigational CRISPR Gene Editing Therapy Shows Early Promise in SCD, Beta-Thalassemia

Findings from two small, phase 1–2 clinical trials suggest that an investigational gene-editing therapy may increase fetal hemoglobin levels, which could eliminate vaso-occlusive events in patients with sickle cell disease (SCD) and enable transfusion independence in patients with transfusion-dependent beta-thalassemia (TDT). Both studies were published this month in the New England Journal of Medicine.

The therapy, renizgamglogene autogedtemcel (reni-cel; Editas Medicine), is a CRISPR–Cas12a gene-edited autologous hematopoietic stem-cell product designed to increase fetal hemoglobin (HbF) production. It works by disrupting BCL11A binding sites in the HBG1 and HBG2 promoters to reactivate fetal hemoglobin expression.

In a phase 1–2 study of 28 patients with severe SCD, treatment with reni-cel was associated with increases in both total hemoglobin and fetal hemoglobin levels. Among 18 patients with at least six months of follow-up, mean hemoglobin increased from 9.8 g/dL at baseline to 13.8 g/dL, while mean fetal hemoglobin increased from 2.5% to 48.1%. Notably, 27 of 28 patients experienced no vaso-occlusive events following infusion during the observation period. Neutrophil and platelet engraftment occurred at a median of 23 and 25 days, respectively. Adverse events were consistent with those expected following myeloablative conditioning with busulfan and autologous transplantation.

A separate phase 1–2 study evaluated reni-cel in nine patients with TDT. All patients achieved transfusion independence by their last follow-up visit, including six with at least 12 months of follow-up. Total hemoglobin levels exceeded 12 g/dL and HbF levels exceeded 11 g/dL between months 6 and 18. All patients achieved neutrophil and platelet engraftment within 42 days. Reported adverse events were consistent with conditioning-related toxicity, although one patient experienced prolonged lymphopenia attributed to reni-cel.

Both trials were terminated early following a sponsor reassessment of development priorities, and the reported analyses were not prespecified. However, the authors concluded that these findings support continued investigation of CRISPR–Cas12a gene editing as a potential disease-modifying approach for SCD and TDT.