Fetal globin gene inducers: novel agents and new potential

Abstract

Inducing expression of endogenous fetal globin (gamma-globin) gene expression to 60-70% of alpha globin synthesis produces beta-thalassemia trait globin synthetic ratios and can reduce anemia to a mild level. Several classes of therapeutics have induced gamma-globin expression in beta-thalassemia patients and subsequently raised total hemoglobin levels, demonstrating proof-of-concept of the approach. Butyrate treatment eliminated transfusion requirements in formerly transfusion-dependent patients with treatment for as long as seven years. However, prior generation inducers were not readily applicable for widespread use. Currently, a novel oral dual-action therapeutic, sodium 2,2-dimethylbutyrate, is in clinical trials, an oral decitabine formulation is under development, and agents with complementary mechanisms of action can be applied in combined regimens. Identification of three major genetic trait loci which modulate clinical severity provides avenues for developing tailored regimens. These refinements offer renewed potential to apply fetal globin induction as a treatment approach in patient-friendly regimens that can be used worldwide.

Figures

Figure 1

Basal levels of fetal hemoglobin (HbF) and endogenous erythropoietin (EPO) in patients with β+- and β0-thalassemia. Values represent the mean baseline levels in the two groups enrolled in a trial of arginine butyrate + erythropoietin.

Figure 2

(A) Representative responses in fetal hemoglobin and (B) Total hemoglobin responses to arginine butyrate (AB) +/− erythropoietin (EPO) in a patient with β+-thalassemia. The combination of the two therapeutics produced the highest rise in total hemoglobin which required both agents; while only Butyrate treatment produced an increase in fetal globin (C) AB treatment rendered a formerly transfusion-dependent a β0/+-thalassemia patient transfusion-independent for 7 years. An initial frequent dose regimen (solid line) and a maintenance pulse regimen, administered 4 nights, twice per month (shown by the dotted line). Addition of EPO to the Butyrate regimen did not produce any added therapeutic benefit in this type of thalassemia patient.

Figure 3

Pharmacokinetic profiles of sodium 2,2-dimethyl butyrate (SDMB) in healthy human volunteers. This therapeutic was administered in single oral doses at 2 mg/kg (○), 5 mg/kg (•), 10 mg/kg (□), and 20 mg/kg (■). The drug was detectable in the plasma after single oral doses with a t1/2 of 9-11 hours.