Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis |
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Authors: | Nicole Rainville Edward Jachimowicz Don M Wojchowski |
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Institution: | 1. Maine Medical Center Research Institute, Molecular Medicine Division, Scarborough, ME, USA;2. Tufts University School of Medicine, Boston, MA, USA;3. Maine Medical Center Research Institute, Center of Excellence in Stem &4. Progenitor Cell Biology and Regenerative Medicine, Scarborough, ME 04074, USA +1 207 396 8258;5. wojchd@mmc.org |
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Abstract: | Introduction: Recombinant human erythropoietin (rhEPO) is a first-line therapeutic for the anemia of chronic kidney disease, cancer chemotherapy, AIDS (Zidovudine therapy), and lower-risk myelodysplastic syndrome. However, rhEPO frequently elevates hypertension, is costly, and may affect cancer progression. Potentially high merit therefore exists for defining new targets for anti-anemia agents within erythropoietin (EPO) and EPO receptor (EPOR) regulatory circuits.Areas covered: EPO production by renal interstitial fibroblasts is subject to modulation by several regulators of hypoxia-inducible factor 2a (HIF2a) including Iron Response Protein-1, prolyl hydroxylases, and HIF2a acetylases, each of which holds potential as anti-anemia drug targets. The cell surface receptor for EPO (EPOR) preassembles as a homodimer, together with Janus Kinase 2 (JAK2), and therefore it remains attractive to develop novel agents that trigger EPOR complex activation (activating antibodies, mimetics, small-molecule agonists). Additionally, certain downstream transducers of EPOR/JAK2 signaling may be druggable, including Erythroferrone (a hepcidin regulator), a cytoprotective Spi2a serpin, and select EPOR-associated protein tyrosine phosphatases.Expert opinion: While rhEPO (and biosimilars) are presently important mainstay erythropoiesis-stimulating agents (ESAs), impetus exists for studies of novel ESAs that fortify HIF2a’s effects, act as EPOR agonists, and/or bolster select downstream EPOR pathways to erythroid cell formation. Such agents could lessen rhEPO dosing, side effects, and/or costs. |
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Keywords: | anemia erythroferrone erythroid models erythropoiesis erythropoiesis-stimulating agents erythropoietin erythropoietin receptor hypoxia inducible factors janus kinase 2 prolyl hydroxylases protein tyrosine phosphatases Spi2a |
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