title: HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques.
abstract: The hypoxia-inducible factor (HIF) pathway is crucial in mitigating the deleterious effects of oxygen deprivation. HIF-alpha is an essential component of the oxygen-sensing mechanisms and under normoxic conditions is targeted for degradation via hydroxylation by HIF-prolyl hydroxylases. Several HIF-prolyl hydroxylase inhibitors (PHIs) induced erythropoietin (epo) expression in vitro and in mice, with peak epo expression ranging from 5.6- to 207-fold above control animals. Furthermore, several PHIs induced fetal hemoglobin (HbF) expression in primary human erythroid cells in vitro, as determined by flow cytometry. One PHI, FG-2216, was further tested in a nonhuman primate model without and with chronic phlebotomy. FG-2216 was orally bioavailable and induced significant and reversible Epo induction in vivo (82- to 309-fold at 60 mg/kg). Chronic oral dosing in male rhesus macaques was well tolerated, significantly increased erythropoiesis, and prevented anemia induced by weekly phlebotomy. Furthermore, modest increases in HbF-containing red cells and reticulocytes were demonstrated by flow cytometry, though significant increases in HbF were not demonstrated by high-pressure liquid chromatography (HPLC). HIF PHIs represent a novel class of molecules with broad potential clinical application for congenital and acquired anemias.
authors.affiliation: Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hsieh
authors.forename: N Seth
authors.initials: NS
authors.lastname: Linde
authors.forename: Aisha
authors.initials: A
authors.lastname: Wynter
authors.forename: Mark
authors.initials: M
authors.lastname: Metzger
authors.forename: Carol
authors.initials: C
authors.lastname: Wong
authors.forename: Ingrid
authors.initials: I
authors.lastname: Langsetmo
authors.forename: Al
authors.initials: A
authors.lastname: Lin
authors.forename: Reginald
authors.initials: R
authors.lastname: Smith
authors.forename: Griffin P
authors.initials: GP
authors.lastname: Rodgers
authors.forename: Robert E
authors.initials: RE
authors.lastname: Donahue
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Klaus
authors.forename: John F
authors.initials: JF
authors.lastname: Tisdale
mesh_terms: D000284:Administration, Oral; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D041905:Erythroid Cells / Q000187:drug effects / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism*; D005319:Fetal Hemoglobin / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D000860:Hypoxia; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D010100:Oxygen; D018962:Phlebotomy; D011086:Polycythemia; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012156:Reticulocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D004921:Erythropoietin; D005319:Fetal Hemoglobin; D011393:Procollagen-Proline Dioxygenase; D010100:Oxygen