Mutations in the β-globin gene, the essential component of adult hemoglobin (HbA; α2β2), results in either a production of aberrant sickle hemoglobin leading to sickle cell disease or an insufficient β-globin synthesis leading to β-thalassemia. These two major forms of β-hemoglobinopathies cause impaired erythropoiesis and life-threatening anemia. Clinical evidence has suggested that reactivation of fetal γ-globin gene(HBG) expression which is normally silenced after birth by certain genetic mutations can ameliorate the clinical course of β-hemoglobinopathies. There are two major strategies for re-activation of HBG expression: reducing the expression of critical trans-acting repression factors (such as BCL11A) or deletion of inhibitory cis-regulatory elements in the HBG1/2 promoter region.
This study confirmed that efficient editing of the BCL11A binding site on the HBG1 / 2 promoter by CRISPR / Cas9 or single base editing technology can re-open the expression of γ-globin in the cells of β thalassemia patients, and significantly improve the maturation of red blood cells It is expected to become a gene therapy method to cure β thalassemia.
At the same time, this study is the first to demonstrate the feasibility and effectiveness of single-base editor editing technology for the treatment of β-hemoglobinopathy. Subsequent research will further improve the efficiency of single-base editing at this site and provide a safer strategy for clinical applications.