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Learn MoreSickle cell disease (SCD) results from a point mutation in the -globin gene forming hemoglobin S (HbS), which polymerizes in deoxygenated erythrocytes, triggering recurrent painful vaso-occlusive crises and chronic hemolytic anemia. Reactivation of fetal Hb (HbF) expression ameliorates these symptoms of SCD. Nuclear factor (erythroid derived-2)like 2 (Nrf2) is a transcription factor that triggers cytoprotective and antioxidant pathways to limit oxidative damage and inflammation and increases HbF synthesis in CD34+ stem cellderived erythroid progenitors. We investigated the ability of dimethyl fumarate (DMF), a small-molecule Nrf2 agonist, to activate -globin transcription and enhance HbF in tissue culture, murine and primate models. DMF recruited Nrf2 to the -globin promoters and the locus control region of the -globin locus in erythroleukemia cells, elevated HbF in SCD donorderived erythroid progenitors, and reduced hypoxia-induced sickling. Chronic DMF administration in SCD mice induced HbF and increased Nrf2-dependent genes to detoxify heme and limit inflammation. This improved hematological parameters, reduced plasma-free Hb, and attenuated inflammatory markers. Chronic DMF administration to nonanemic primates increased -globin mRNA in BM and HbF protein in red cells. DMF represents a potential therapy for SCD to induce HbF and augment vasoprotection and heme detoxification SOURCE: Suzanne Szak BiogenIdec, Inc.
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