Two studies published concurrently in The New England Journal of Medicine report early clinical activity for the same CRISPR–Cas12a gene-editing therapy, renizgamglogene autogedtemcel (reni-cel), across severe sickle cell disease and transfusion-dependent β-thalassemia—demonstrating a shared therapeutic strategy with disease-specific clinical benefit.
Rabi Hanna, MD, a member of Case CCC's Developmental Therapeutics Program, served as first author on the sickle cell study and second author on the β-thalassemia study.
Both trials used Cas12a-mediated editing to disrupt BCL11A binding sites in the HBG1 and HBG2 promoters, reactivating fetal hemoglobin (HbF) production—a strategy that functionally compensates for defective β-globin. Patients in both cohorts underwent myeloablative conditioning with busulfan followed by infusion of autologous, gene-edited hematopoietic stem cells, with engraftment and safety profiles observed across both studies.
In sickle cell disease, 28 patients were treated with reni-cel. Among 18 patients with at least six months of follow-up, mean hemoglobin increased from 9.8 g/dL to 13.8 g/dL and mean HbF rose to approximately 48%. Clinically, 27 of 28 patients experienced no vaso-occlusive events following treatment. In β-thalassemia, all nine treated patients became transfusion-free at last follow-up, with sustained hemoglobin levels above 12 g/dL and durable HbF expression. Despite the smaller cohort size, the consistency of response across both diseases reinforces the mechanistic strength of HbF reactivation.
Adverse events in both studies were largely attributable to myeloablative conditioning and stem-cell transplantation rather than the gene-editing platform itself. Although both trials were terminated early due to sponsor reprioritization, the concordant outcomes across two distinct indications provide a compelling signal for further development.
These findings by Hanna and his collaborators highlight the translational potential of CRISPR-based genome editing—particularly Cas12a—as a platform for durable, cell-based therapies, with implications for targeting regulatory elements and reprogramming gene expression in oncologic contexts.