Gene Therapies for Thalassemia

Beta (β)-thalassemia is a genetic hemoglobinopathy that results from defects in β-globin synthesis leading to reduced synthesis or absence of β-globin chains causing impaired production of hemoglobin. The clinical presentation is that of anemia which requires transfusion and multiple downstream sequelae from iron overload. It is estimated that at least 1000 people in the United States have transfusion-dependent β-thalassemia. Betibeglogene autotemcel contains autologous CD34+ hematopoietic stem cells in which functional copies of a modified form of the β-globin gene (βA-T87Q-globin gene) have been added. Once the hematopoietic stem cells reengineered with βA-T87Q are infused, they engraft in the bone marrow and differentiate to produce red blood cells containing βA-T87Q gene that will produce HbAT87Q protein (functional gene therapy-derived hemoglobin) at levels that may eliminate or significantly reduce the need for transfusions. Exagamglogene autotemcel is a cellular gene therapy consisting of autologous CD34+ hematopoietic stem cells edited by CRISPR/Cas9-technology at the erythroid specific enhancer region of the BCL11A gene to reduce BCL11A expression in erythroid lineage cells. After infusion, the edited CD34+ cells engraft in the bone marrow and differentiate to erythroid lineage cells with reduced BCL11A expression. Reduced BCL11A expression results in an increase in γ-globin expression and fetal hemoglobin protein production in erythroid cells.