Novel Therapeutic Agents for HbF Induction: A New Era for Treatment of β Thalassemia?

Abstract

Fetal globin is endogenous, normally integrated in hematopoietic stem cells in all humans, and available for reactivation. Inducing expression of fetal globin (γ-globin) gene expression to 60–70% of α globin synthesis produces β-thalassemia trait globin synthetic ratios, and has been shown to reduce anemia to mild levels which do not require regular blood transfusion. Several classes of therapeutics have induced γ-globin expression in β thalassemia patients, raised total hemoglobin levels, and even eliminated transfusion requirements in formerly transfusion-dependent patients, demonstrating proof-of-concept of the approach. However, prior generations of therapeutics were not readily feasible for widespread use. Currently, several recently discovered oral therapeutic candidates are more potent and/ or patientfriendly, requiring low oral doses, have distinct molecular mechanisms of action, and can be used in combination regimens. Tailoring therapeutic regimens to patient subsets stratified for solely β+ or a β0 globin mutation, and for quantitative trait loci (QTL) which modulate HbF and clinical severity, can guide more effective and informative clinical trials. These advancements provide methods for a rational approach to applying fetal globin gene induction in therapeutic regimens suitable for use in diverse thalassemia patient populations world-wide.