CRISPR-Based Therapy Targeting BCL11 Shows Clinical Benefit in SCD and Beta-Thalassemia

Treatment with the CRISPR/Cas9 gene-editing therapy CTX001 was associated with successful neutrophil and platelet engraftment in 2 patients with transfusion-dependent β-thalassemia (TDT) and 1 patient with severe sickle cell disease (SCD), according to early results from a phase I/II trial. The therapy also led to long periods of transfusion independence in all 3 patients.

Findings from this study, which were presented at the remotely held 25th European Hematology Association Annual Congress (EHA25 Virtual) by Selim Corbacioglu, MD, of the Regensburg University Hospital in Germany, offer insight into a promising, first-of-its-kind strategy for the management of hemoglobinopathies.

CTX001 is designed to suppress BCL11A, which results in an upregulation of fetal hemoglobin (HbF), Dr. Corbacioglu explained, adding that elevated HbF is associated with decreased disease severity in both thalassemia and SCD. Increases in HbF may reduce or eliminate a patient’s requirement for transfusion and decrease the incidence of vaso occlusive crises (VOCs) in patients with SCD.

Dr. Corbacioglu and colleagues enrolled 2 patients with TDT who had received packed red blood cell (pRBC) transfusions of ≥100 mL/kg per year or ≥10 units per year in the 2 years prior to enrollment. Another patient with severe SCD (defined as ≥2 VOCs per year in the previous 2 years) also was enrolled.

Following mobilization with the granulocyte colony-stimulating factor filgrastim and plerixafor (for TDT) or plerixafor alone (for SCD), the investigators collected CD34-positive hematopoietic stem/progenitor cells by apheresis. Next, they used CRISPR-Cas9 to edit the CD34-positive cells, using a guide RNA specific for BCL11A’s erythroid enhancer region. Patients then received myeloablative conditioning with busulfan, followed by CTX001 infusion on day 1.

Patients were monitored for the following:

  • stem cell engraftment/hematopoietic recovery
  • adverse events (AEs)
  • hemoglobin production
  • hemolysis
  • HbF and F-cell expression
  • pRBC transfusion requirements for TDT
  • VOCs for SCD

After CTX001 infusion, follow-up occurred at 12 months for the participants with TDT and 6 months for the participant with SCD.

The patients with TDT received CTX001 infusions of 17.0×106 cells/kg and 12.3×106 cells/kg. Successful engraftment of neutrophils occurred on days 33 and 36, while engraftment of platelets was achieved on days 37 and 34 post-infusion. In the patient with severe SCD, who received a CTX001 infusion of 3.3×106 cells/kg, successful neutrophil and platelet engraftment was achieved on day 30.

“Clinically meaningful increases in HbF and total Hb were achieved early and maintained,” Dr. Corbacioglu reported. For example, in the patient with TDT and 15-month follow-up, total Hb levels increased from 9.0 g/dL at baseline to 12.7 g/dL, which included an HbF level of 12.4 g/dL. The authors added that this patient has been transfusion free since day 30 following CTX001 infusion. The other patient experienced an Hb increase from 10.1 g/dL to 12.5 g/dL at month 5 – 12.2 g/dL of which was HbF – and remained transfusion free for 3.5 months at last follow-up.

Similarly, in the patient with SCD, total Hb increased from 7.2 g/dL to 11.3 g/dL at 6 months, and HbF levels increased to measure 47.3% of total Hb at 6 months. Again, this patient remained transfusion independent since day 19 after study treatment. Dr. Corbacioglu added that there were no VOCs in this patient during the 6 months following infusion.

Regarding safety, Dr. Corbacioglu reported that “AEs were generally consistent with myeloablation and autologous stem cell transplantation, so [there was] nothing unexpected in these patients.”

The patient with TDT experienced 2 serious AEs, but both events were deemed unrelated to CTX001. The 2 serious AEs – busulfan-associated veno-occlusive liver disease and pneumonia in the presence of neutropenia – resolved.

A total of 3 post-CTX001 infusion serious AEs occurred in the patient with SCD, including sepsis while neutropenic, cholelithiasis, and abdominal pain. All the serious AEs were considered unrelated to CTX001.

The investigators agree that the findings offer a promising new gene therapy option for this patient population, but the study was limited by its small sample size. Dr. Corbacioglu noted that enrollment and manufacturing of CTX001 for TDT and SCD is ongoing, with further dosing planned later in 2020.

The authors report relationships with Vertex Pharmaceuticals and CRISPR Therapeutics, which sponsored the trial.


Corbacioglu S, Cappellini MD, Chapin J, et al. Initial safety and efficacy results with a single dose of autologous CRISPR-CAS9 modified CD34+ hematopoietic stem and progenitor cells in transfusion-dependent B-thalassemia and sickle cell disease. Abstract S280. Presented as part of EHA25 Virtual, June 12, 2020.