Gene Therapies for Sickle Cell Disease

Sickle cell disease is a genetic hemoglobinopathy that results from a genetic variant in the HBB gene resulting in the production of dysfunctional hemoglobin which forms polymers in the red blood cells of individuals. The sickled red blood cells have a shorter life span and do not move as freely as normal, round, red blood cells resulting in anemia and vascular obstruction. Recurrent acute pain crises, or vaso-occlusive crises are the most prevalent manifestation of sickle cell disease. It is estimated that there are 100,000 individuals living with sickle cell disease in the United States. Two gene therapies have been approved by the U.S. Food and Drug Administration. Lovotibeglogene autotemcel adds functional copies of a modified βA-globin gene (βA-T87Q-globin) into an individual's hematopoietic stem cell through transduction of autologous CD34+ cells with BB305 lentiviral vector. After infusion, the transduced CD34+ hematopoietic stem cells 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). 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.