HIF–prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques
Tóm tắt
The hypoxia-inducible factor (HIF) pathway is crucial in mitigating the deleterious effects of oxygen deprivation. HIF-α 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.
Từ khóa
Tài liệu tham khảo
Ivan, 2001, HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing., Science, 292, 464, 10.1126/science.1059817
Jaakkola, 2001, Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation., Science, 292, 468, 10.1126/science.1059796
Bruick, 2001, A conserved family of prolyl-4-hydroxylases that modify HIF., Science, 294, 1337, 10.1126/science.1066373
Semenza, 2001, HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus., Cell, 107, 1, 10.1016/S0092-8674(01)00518-9
Cook, 1957, Measurement of fetal hemoglobin in newborn infants; correlation with gestational age and intrauterine hypoxia., Pediatrics, 20, 272, 10.1542/peds.20.2.272
Bureau, 1983, Maternal cigarette smoking and fetal oxygen transport: a study of P50, 2,3-diphosphoglycerate, total hemoglobin, hematocrit, and type F hemoglobin in fetal blood., Pediatrics, 72, 22, 10.1542/peds.72.1.22
Versmold, 1976, Oxygen transport in congenital heart disease: influence of fetal hemoglobin, red cell pH, and 2,3-diphosphoglycerate., Pediatr Res, 10, 566, 10.1203/00006450-197606000-00002
Bard, 1994, Hypoxemia and increased fetal hemoglobin synthesis., J Pediatr, 124, 941, 10.1016/S0022-3476(05)83188-9
Bard, 1994, The reactivation of fetal hemoglobin synthesis during anemia of prematurity., Pediatr Res, 36, 253, 10.1203/00006450-199408000-00018
Ballew, 1986, Hematologic evidence of fetal hypoxia among newborn infants at high altitude in Bolivia., Am J Obstet Gynecol, 155, 166, 10.1016/0002-9378(86)90104-3
Reynafarje, 1975, Oxygen transport of hemoglobin in high-altitude animals (Camelidae)., J Appl Physiol, 38, 806, 10.1152/jappl.1975.38.5.806
DeSimone, 1978, Stimulation of fetal hemoglobin synthesis in baboons by hemolysis and hypoxia., Proc Natl Acad Sci U S A, 75, 2937, 10.1073/pnas.75.6.2937
DeSimone, 1981, Genetic relationship between fetal Hb levels in normal and erythropoietically stressed baboons., Br J Haematol, 49, 175, 10.1111/j.1365-2141.1981.tb07213.x
DeSimone, 1982, Maintenance of fetal hemoglobin (HbF) elevations in the baboon by prolonged erythropoietic stress., Blood, 60, 519, 10.1182/blood.V60.2.519.bloodjournal602519
Weinberg, 1995, Low oxygen enhances sickle and normal erythropoiesis and fetal hemoglobin synthesis in vitro., Hemoglobin, 19, 263, 10.3109/03630269509005813
Wood, 1979, Hereditary persistence of fetal haemoglobin (HPFH) and delta beta thalassaemia., Br J Haematol, 43, 509, 10.1111/j.1365-2141.1979.tb03784.x
Bollekens, 1991, Delta beta thalassemia and hereditary persistence of fetal hemoglobin., Hematol Oncol Clin North Am, 5, 399, 10.1016/S0889-8588(18)30422-2
Ivan, 2002, Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor., Proc Natl Acad Sci U S A, 99, 13459, 10.1073/pnas.192342099
Appelhoff, 2004, Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor., J Biol Chem, 279, 38458, 10.1074/jbc.M406026200
Blau, 1993, Fetal hemoglobin in acute and chronic states of erythroid expansion., Blood, 81, 227, 10.1182/blood.V81.1.227.227
Bhanu, 2005, A sustained and pancellular reversal of gamma-globin gene silencing in adult human erythroid precursor cells., Blood, 105, 387, 10.1182/blood-2004-04-1599
Fibach, 1989, Proliferation and maturation of human erythroid progenitors in liquid culture., Blood, 73, 100, 10.1182/blood.V73.1.100.100
Amoyal, 2004, Flow cytometric analysis of fetal hemoglobin in erythroid precursors of beta-thalassemia., Clin Lab Haematol, 26, 187, 10.1111/j.1365-2257.2004.00606.x
Goldberg, 1987, The regulated expression of erythropoietin by two human hepatoma cell lines., Proc Natl Acad Sci U S A, 84, 7972, 10.1073/pnas.84.22.7972
Koury, 1990, Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells., Science, 248, 378, 10.1126/science.2326648
Warnecke, 2003, Activation of the hypoxia-inducible factor-pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors., FASEB J, 17, 1186, 10.1096/fj.02-1062fje
Safran, 2006, Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: assessment of an oral agent that stimulates erythropoietin production., Proc Natl Acad Sci U S A, 103, 105, 10.1073/pnas.0509459103
Siddiq, 2005, Hypoxia-inducible factor prolyl 4-hydroxylase inhibition: a target for neuroprotection in the central nervous system., J Biol Chem, 280, 41732, 10.1074/jbc.M504963200
Fishbane, 2006, Recombinant human erythropoietin: has treatment reached its full potential?, Semin Dial, 19, 1, 10.1111/j.1525-139X.2006.00109.x
Flaharty, 1990, Pharmacokinetics and erythropoietic response to human recombinant erythropoietin in healthy men., Clin Pharmacol Ther, 47, 557, 10.1038/clpt.1990.76
Nwogu, 2001, Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilatation after myocardial infarction., Circulation, 104, 2216, 10.1161/hc4301.097193
Asikainen, 2006, Improved lung growth and function through hypoxia-inducible factor in primate chronic lung disease of prematurity., FASEB J, 20, 1698, 10.1096/fj.06-5887fje
Bernhardt, 2006, Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure., J Am Soc Nephrol, 17, 1970, 10.1681/ASN.2005121302
Lee-Huang, 1984, Cloning and expression of human erythropoietin cDNA in Escherichia coli., Proc Natl Acad Sci U S A, 81, 2708, 10.1073/pnas.81.9.2708
Eschbach, 1987, Correction of the anemia of end-stage renal disease with recombinant human erythropoietin: results of a combined phase I and II clinical trial., N Engl J Med, 316, 73, 10.1056/NEJM198701083160203
Chenuaud, 2004, Autoimmune anemia in macaques following erythropoietin gene therapy., Blood, 103, 3303, 10.1182/blood-2003-11-3845
Gao, 2004, Erythropoietin gene therapy leads to autoimmune anemia in macaques., Blood, 103, 3300, 10.1182/blood-2003-11-3852
Verhelst, 2004, Treatment of erythropoietin-induced pure red cell aplasia: a retrospective study., Lancet, 363, 1768, 10.1016/S0140-6736(04)16302-2
Brill-Almon, 2005, Ex vivo transduction of human dermal tissue structures for autologous implantation production and delivery of therapeutic proteins., Mol Ther, 12, 274, 10.1016/j.ymthe.2005.03.023
Orive, 2005, Long-term expression of erythropoietin from myoblasts immobilized in biocompatible and neovascularized microcapsules., Mol Ther, 12, 283, 10.1016/j.ymthe.2005.04.002
Lippin, 2005, Human erythropoietin gene therapy for patients with chronic renal failure., Blood, 106, 2280, 10.1182/blood-2004-11-4174
Takacs, 2004, The regulated long-term delivery of therapeutic proteins by using antigen-specific B lymphocytes., Proc Natl Acad Sci U S A, 101, 16298, 10.1073/pnas.0405271101
Voutetakis, 2004, Reengineered salivary glands are stable endogenous bioreactors for systemic gene therapeutics., Proc Natl Acad Sci U S A, 101, 3053, 10.1073/pnas.0400136101
Nakano, 2004, Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity, and restores indicators in an in vivo mouse model of anemia of chronic disease., Blood, 104, 4300, 10.1182/blood-2004-04-1631
Saunthararajah, 2004, Clinical studies with fetal hemoglobin-enhancing agents in sickle cell disease., Semin Hematol, 41, 11, 10.1053/j.seminhematol.2004.08.003
Nagel, 1993, F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: a double-blind study., Blood, 81, 9, 10.1182/blood.V81.1.9.9
Fibach, 2003, Mithramycin induces fetal hemoglobin production in normal and thalassemic human erythroid precursor cells., Blood, 102, 1276, 10.1182/blood-2002-10-3096
Cao, 2005, Hydroxamide derivatives of short-chain fatty acid have erythropoietic activity and induce gamma gene expression in vivo., Exp Hematol, 33, 1443, 10.1016/j.exphem.2005.08.007
Fibach, 2006, Effects of rapamycin on accumulation of alpha-, beta- and gamma-globin mRNAs in erythroid precursor cells from beta-thalassaemia patients., Eur J Haematol, 77, 437, 10.1111/j.1600-0609.2006.00731.x
Dover, 1978, Individual variation in the production and survival of F cells in sickle-cell disease., N Engl J Med, 299, 1428, 10.1056/NEJM197812282992603
Rodgers, 1993, Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease., N Engl J Med, 328, 73, 10.1056/NEJM199301143280201