CRISPR Gene Therapy for Sickle Cell Disease

Source: Hanna R, Frangoul H, Pineiro L, et al. CRISPR-Cas12a gene editing of HBG1 and HBG2 promoters to treat sickle cell disease. N Engl J Med. 2026;394(13):1281-1291; doi: 10.1056/NEJMoa2415550.Investigators from multiple institutions conducted a study to assess the efficacy and safety of Renizgamglogene autogedemcel (reni-cel) in the treatment of adolescents and adults with sickle cell disease. Reni-cel is an investigational, clustered regularly interspaced short palindromic repeats (CRISPR)-Cas12a, gene-edited autologous stem-cell therapy, designed to alter the BCL11a binding sites in the HBG1 and HBG2 promoters. HBG1 and HBG2 promote gamma-globin production, and BCL11A is a transcription factor that represses their function. The goal of the therapy is to promote production of fetal hemoglobin. Study participants were patients 12–50 years old with sickle cell disease and a history of ≥2 severe vaso-occlusive events per year in the previous 2 years who were enrolled at 24 sites in North America. For the treatment, autologous CD34+ hematopoietic stem and progenitor cells (HSPC) were collected by apheresis. Reni-cel was manufactured from the HSPCs with use of a engineered AsCas12a nuclease. After the patient underwent myeloablative conditioning, they received an infusion of reni-cel. The main study outcomes included neutrophil and platelet engraftment, hemoglobin levels after treatment, fetal hemoglobin percentage, occurrence of severe vaso-occlusive events, and adverse events. Although it was planned to enroll 45 participants, the sponsor terminated the study early because of changing priorities. Because of this, the analysis was limited to patients who received reni-cel before study termination.A total of 28 participants had received reni-cel treatment prior to study termination. The age of study patients ranged from 18 to 41, with a median age of 26 years. In the 2 years prior to enrollment, the mean number of severe vaso-occlusive events per participant was 4.6 ±2.6. The median duration of follow-up after receiving reni-cel was 9.5 months. The median time from treatment until neutrophil and platelet engraftment was 23 and 25 days, respectively, in 27 patients with engraftment at the time of data collection cutoff. At enrollment, the mean hemoglobin level in the 28 participants was 9.8 ±1.7 g/dL. In 18 patients with data on hemoglobin 6 months after treatment, mean levels were 13.8 ±1.9 g/dL. The mean percentage of fetal hemoglobin increased from 2.5% ±2.5% at baseline to 48.1% ±3.2%, 4 months following treatment. Among the 28 participants, 1 patient had 2 severe vaso-occlusive events during follow-up. All participants reported at least 1 adverse event after reni-cel infusion, including febrile neutropenia in 39%, stomatitis in 39%, and mucosal inflammation in 36%. Infections such as pneumonia and sepsis also occurred.The authors conclude that reni-cel infusion in adolescents and adults with sickle cell disease led to increased hemoglobin levels associated with an increase in the percentage of fetal hemoglobin and no severe vaso-occlusive events in 27 of 28 treated patients during limited follow-up.Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Sickle cell disease affects about 100,000 US persons.1 Around 6 months of age, production of hemoglobins (Hb) switch from fetal (HbF, αα/γγ globin chains) to adult (HbA, αα/ββ globin chains). In infants with sickle cell mutations on the β-globin genes, production of HbS arises instead of HbA. HbS polymerizes when deoxygenated resulting in life-long hemolysis, vaso-occlusive episodes and organ damage.2 Higher HbF% has been associated with lower disease severity in children with sickle cell disease who take oral hydroxyurea, or those who co-inherit hereditary persistence of HbF.3 (See AAP Grand Rounds. 2025;54[5]:56.)4Amelioration of vaso-occlusive episodes, stroke prevention and stabilization of lung disease has become possible with allogeneic hematopoietic stem cell transplantation (HSCT) from unaffected donors.5 However, <20% of patients with sickle cell disease have an HLA-matched sibling, and <50% have an HLA-matched unrelated donor in the registry.2 Post-HSCT risks include graft versus host disease and graft rejection.5Gene therapy is a type of HSCT that requires chemotherapy, infusion of ex-vivo, gene-modified, autologous stem cells, and prolonged recovery with monitoring.5 The CRISPR gene therapy in this study disrupts the BCL11A repressor to allow production of the γ globin gene promoters and raise HbF%. Although these are promising results at <1 year of follow-up, the company manufacturing this CRISPR has stopped production and is no longer enrolling patients with SCD. The Cure Sickle Cell Initiative is trying to standardize data collection to help institutions make gene therapy accessible, safe, efficient, and effective.6Infusion of CRISPR/Cas12a gene-edited stem cells in patients with sickle cell disease increases fetal hemoglobin and overall hemoglobin within 6 months reducing Vaso-occlusive events.