HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques.
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.
Hsieh
Matthew M
MM
Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Linde
N Seth
NS
Wynter
Aisha
A
Metzger
Mark
M
Wong
Carol
C
Langsetmo
Ingrid
I
Lin
Al
A
Smith
Reginald
R
Rodgers
Griffin P
GP
Donahue
Robert E
RE
Klaus
Stephen J
SJ
Tisdale
John F
JF
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
D004791:Enzyme Inhibitors; D004921:Erythropoietin; D005319:Fetal Hemoglobin; D011393:Procollagen-Proline Dioxygenase; D010100:Oxygen