Cell signaling pathways involved in drug-mediated fetal hemoglobin induction: Strategies to treat sickle cell disease.
The developmental regulation of globin gene expression has shaped research efforts to establish therapeutic modalities for individuals affected with sickle cell disease and β-thalassemia. Fetal hemoglobin has been shown to block sickle hemoglobin S polymerization to improve symptoms of sickle cell disease; moreover, fetal hemoglobin functions to replace inadequate hemoglobin A synthesis in β-thalassemia thus serving as an effective therapeutic target. In the perinatal period, fetal hemoglobin is synthesized at high levels followed by a decline to adult levels by one year of age. It is known that naturally occurring mutations in the γ-globin gene promoters and distant cis-acting transcription factors produce persistent fetal hemoglobin synthesis after birth to ameliorate clinical symptoms. Major repressor proteins that silence γ-globin during development have been targeted for gene therapy in β-hemoglobinopathies patients. In parallel effort, several classes of pharmacological agents that induce fetal hemoglobin expression through molecular and cell signaling mechanisms have been identified. Herein, we reviewed the progress made in the discovery of signaling molecules targeted by pharmacologic agents that enhance γ-globin expression and have the potential for future drug development to treat the β-hemoglobinopathies.
Department of Pediatrics, Georgia Regents University, Augusta, GA 30912, USA Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA bpace@gru.edu.
Betty S
BS
Pace
Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75083, USA.
Li
L
Liu
Department of Pediatrics, Georgia Regents University, Augusta, GA 30912, USA.
Biaoru
B
Li
Department of Pediatrics, Georgia Regents University, Augusta, GA 30912, USA.
Levi H
LH
Makala
D000375:Aging; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000378:metabolism*; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects*; D017086:beta-Thalassemia / Q000188:drug therapy / Q000378:metabolism
D005319:Fetal Hemoglobin
Fetal hemoglobin; NRF2; cell signaling; p38 MAPK; sickle cell disease; β-hemoglobinopathies