DNA hypomethylation therapy for hemoglobin disorders: Molecular mechanisms and clinical applications

SummaryReactivation of fetal hemoglobin (HbF) expression is an important therapeutic option in patients with hemoglobin disorders. In sickle cell disease (SCD), an increase in HbF would interfere with the polymerization of sickle hemoglobin while in β-thalassemia, an increase in γ-globin chain synthesis would decrease non-α:α chain imbalance. Hydroxyurea, an inducer of HbF, is the only currently approved agent for the treatment of patients with moderate and/or severe SCD. However, about one third of patients with SCD do not respond to HU, and in β-thalassemia, the clinical response is unimpressive. The last decade has seen a renewed interest in the use of inhibitors of DNA methylation in the treatment of patients with hemoglobin disorders. In this review, we discuss the role of DNA methylation in γ-globin gene regulation, describe clinical trials with agents that hypomethylate DNA and speculate about the future role of DNA hypomethylation therapy in patients with SCD and β-thalassemia.