Fetal globin gene inducers: novel agents and new potential.
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.
Perrine
Susan P
SP
Cancer Center and Hemoglobinopathy-Thalassemia Research Unit, Department of Medicine, Pediatrics, Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, USA. sperrine@bu.edu
Castaneda
Serguei A
SA
Chui
David H K
DH
Faller
Douglas V
DV
Berenson
Ronald J
RJ
Siritanaratku
Noppadol
N
Fucharoen
Suthat
S
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D002087:Butyrates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D000077209:Decitabine; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D009154:Mutation; D040641:Quantitative Trait Loci; D015533:Transcriptional Activation / Q000187:drug effects*; D055542:alpha-Globins / Q000235:genetics / Q000378:metabolism; D017086:beta-Thalassemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D002087:Butyrates; D055542:alpha-Globins; D000077209:Decitabine; D005319:Fetal Hemoglobin; D001374:Azacitidine