Targeting fetal hemoglobin expression to treat beta hemoglobinopathies

Introduction Sickle cell disease and beta thalassemia are the principal beta hemoglobinopathies. The complex pathophysiology of sickle cell disease is initiated by sickle hemoglobin polymerization. In beta thalassemia, insufficient beta-globin synthesis results in excessive free alpha globin, ineffective erythropoiesis, and severe anemia. Fetal hemoglobin (HbF) prevents sickle hemoglobin polymerization; in beta thalassemia HbF compensates for the deficit of normal hemoglobin. When HbF constitutes about a third of total cell hemoglobin, the complications of sickle cell disease are nearly totally prevented. Similarly, sufficient HbF in beta thalassemia diminishes or prevents ineffective erythropoiesis and hemolysis. Areas covered This article examines the pathophysiology of beta 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.' Expert opinion 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' beta 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.

Automated summary

This article examines the pathophysiology of beta 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.'