Targeting fetal hemoglobin expression to treat β hemoglobinopathies.

Sickle cell disease and β thalassemia are the principal β hemoglobinopathies. The complex pathophysiology of sickle cell disease is initiated by sickle hemoglobin polymerization. In β thalassemia, insufficient β-globin synthesis results in excessive free α globin, ineffective erythropoiesis, and severe anemia. Feta This article examines the pathophysiology of β hemoglobinopathies, the physiology of HbF, intracellular distribution, and the regulation of HbF expression. Inducing high levels of HbF by targeting its regulatory pathways pharmacologically or with cell-based therapeutics provides major clinical benefit and perhaps a 'cure.' Erythrocytes must contain about 10 pg of HbF to 'cure' sickle cell disease. If HbF is the only hemoglobin present, much higher levels are needed to 'cure' β thalassemia. These levels of HbF can be obtained by different iterations of gene therapy. Small molecule drugs that can achieve even modest pancellular HbF concentrations are a major unmet need.