CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia

Transfusion-dependent beta-thalassemia (TDT) and sickle cell disease (SCD) are the most common inherited hematologic disorders, affecting approximately 60,000 and 300,000 patients worldwide, respectively. Current therapies, including red blood cell (RBC) transfusion and iron chelation in TDT and transfusion, pain management, and hydroxyurea in SCD, help to manage the disorders but do not address the underlying cause. Drug therapies, such as crizanlizumab and luspatercept, have also helped to reduce the need for transfusion in TDT patients and the incidence of vaso-occlusive episodes in SCD patients. Allogeneic bone marrow transplantation may be a curative option, but finding an appropriate donor is difficult. An association has been observed between elevated levels of fetal hemoglobin and improved morbidity and mortality in these patients. Downregulating BCL11A, a transcription factor that blocks fetal hemoglobin in erythroid cells, may help to increase fetal hemoglobin levels and improve outcomes. Using the CRISPR-Cas9 gene-editing technique, CTX001, an investigational drug, was infused in 2 patients. This article describes the results of infusing CTX001 in 1 patient with TDT and another with SCD. Patients between 18 and 35 years of age were eligible for the trials. Included in 1 trial were patients with beta-thalassemia, who had received transfusions of packed RBC of >= 10 units in the past 2 years. Included in the other trial were patients with documented beta S/beta S or beta S/beta 0 who experienced >= 2 severe vaso-occlusive episodes per year over the past 2 years. Patient 1, a 19-year-old woman with TDT, had received 34 units of packed RBCs in the past 2 years before enrollment. After infusion with CTX001, she was followed for 21.5 months, during which there were high levels of edited alleles in blood and bone marrow. Her baseline fetal hemoglobin level was 0.3 g/dL. Rapid increases in her fetal hemoglobin levels were observed at month 3, 12, and 18 (8.4 g/dL, 12.4 g/dL, and 13.1 g/dL, respectively). Of the 32 adverse events that patient 1 experienced during follow-up, 2 were considered serious: pneumonia with neutropenia and veno-occlusive liver disease. These complications were resolved with treatment on days 28 and 39, respectively. Patient 1 received her last RBC transfusion 30 days after infusion. Her fetal hemoglobin level was normal from month 4 (12.1 g/dL) through month 18. Patient 2, a 33-year-old female with SCD, averaged 7 severe vaso-occlusive episodes per year, annualized over the past 2 years. After infusion with CTX001, she was followed for 16.6 months, during which there were high levels of edited alleles. Her baseline hemoglobin level was 7.2 g/dL. Increases in her hemoglobin levels were seen at months 3 and 15 (10.1 g/dL and 12 g/dL, respectively). Her baseline fetal hemoglobin level was 9.1% and rose to 37.2% at month 3 then 43.2% at month 15. Her baseline sickle hemoglobin level was 74.1% and fell to 32.6% at month 3 then increased to 52.3% at month 15. Of the 114 adverse events that patient 2 experienced during follow-up, 3 were considered serious: sepsis with neutropenia, gallstone formation, and abdominal pain. These complications were resolved with treatment. There were no vaso-occlusive episodes reported in the follow-up after infusion. Patient 2 received her last RBC transfusion 19 days after infusion. In conclusion, CTX001-developed using the CRISPR-Cas9 gene-editing technique-was observed to increase in hemoglobin levels and reduce the need for transfusion in both the TDT and SDC patients. For the SDC patient, no vaso-occlusive episodes were reported.