Fetal Globin Induction—Can It Cure β Thalassemia?

Abstract

Abstract The β thalassemias are one of a few medical conditions in which reactivation of a gene product that is expressed during fetal life can functionally replace a deficiency of essential proteins expressed at a later developmental stage. The fetal globin genes are present and normally integrated in hematopoietic stem cells, and at least one fetal gene appears accessible for reactivation, particularly in β° thalassemia. However, rapid cellular apoptosis from α globin chain precipitation, and relatively low levels of endogenous erythropoietin (EPO) in some β+ thalassemia patients contribute to the anemia in β thalassemia syndromes. In clinical trials, three classes of therapeutics have demonstrated proof-of-principle of this approach by raising total hemoglobin levels by 1–4 g/dL above baseline in thalassemia patients: EPO preparations, short chain fatty acid derivatives (SCFADs), and chemotherapeutic agents. Although thalassemic erythrocytes survive only for a few days, the magnitude of these responses is similar to those induced by rhu-EPO in anemic conditions of normal erythrocyte survival. New oral therapeutic candidates, which stimulate both fetal globin gene expression and erythropoiesis, and combinations of therapeutics with complementary molecular actions now make this gene-reactivation approach feasible to produce transfusion independence in many patients. Development of the candidate therapeutics is hindered largely by costs of drug development for an orphan patient population.