When basic science reaches into rational therapeutic design: from historical to novel leads for the treatment of β-globinopathies

Abstract

Purpose of review: β-hemoglobinopathies, such as β-Thalassemias (β-Thal) and sickle cell disease (SCD) are among the most common inherited genetic disorders in humans worldwide. These disorders are characterized by a quantitative (β-Thal) or qualitative (SCD) defects in adult hemoglobin production, leading to anemia, ineffective erythropoiesis and severe secondary complications. Reactivation of the fetal globin genes (γ-globin), making-up fetal hemoglobin (HbF), which are normally silenced in adults, represents a major strategy to ameliorate anemia and disease severity.

Recent findings: Following the identification of the first 'switching factors' for the reactivation of fetal globin gene expression more than 10 years ago, a multitude of novel leads have recently been uncovered.

Summary: Recent findings provided invaluable functional insights into the genetic and molecular networks controlling globin genes expression, revealing that complex repression systems evolved in erythroid cells to maintain HbF silencing in adults. This review summarizes these unique and exciting discoveries of the regulatory factors controlling the globin switch. New insights and novel leads for therapeutic strategies based on the pharmacological induction of HbF are discussed. This represents a major breakthrough for rational drug design in the treatment of β-Thal and SCD.