Inactivation of the BCL11A gene by CRISPR/Cas9 genome editing may be a therapeutic option to cure the most severe type of β thalassemia. An ongoing phase I/II study is evaluating the safety and efficacy of this gene therapy approach in children with transfusion-dependent β thalassemia.

β Thalassemia is a hemolytic disease and one of the most common monogenic disorders. It is caused by defects of the HBB gene leading to a substantial reduction or complete loss of the β globin chains of hemoglobin. Patients who carry defects in both alleles of the HBB gene (β0/β0) require lifelong transfusion therapy and have a severely limited life quality and life expectancy. BCL11A is the transcription factor blocking expression of γ-globin, a component of fetal hemoglobin. Production of fetal hemoglobin (HbF) is normally discontinued after birth. Inactivation of BCL11A can reactivate expression of this functional hemoglobin variant.

The authors of the study published in Nature Medicine transplanted BCL11A-edited autologous hematopoietic stem and precursor cells into two children. One of the children carried the β0/β0 genotype. Both children were clinically well after the treatment, the transplanted cells started to grow and new blood cells were produced. There were no adverse effects that were considered to be related to gene editing. The children showed a sustained activation of HbF synthesis and achieved transfusion independence for more than 18 months after treatment. The researchers also performed single-cell RNA sequencing to analyze gene expression in edited peripheral mononuclear blood cells and did not found no notable side effects of the therapy.