Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

• Published in: Expert opinion on therapeutic targets Vol. 20; no. 3; p. 287
• Main Authors: Rainville, Nicole, Jachimowicz, Edward, Wojchowski, Don M
• Format: Journal Article
• Language: English
• Published: England 03.03.2016
• Subjects: Anemia - drug therapy; Anemia - etiology; Anemia - physiopathology; Animals; Drug Design; Erythropoiesis - drug effects; Erythropoietin - pharmacology; Erythropoietin - therapeutic use; Hematinics - adverse effects; Hematinics - pharmacology; Hematinics - therapeutic use; Humans; Molecular Targeted Therapy; Receptors, Erythropoietin - drug effects; Receptors, Erythropoietin - metabolism; Recombinant Proteins; erythropoietin receptor; hypoxia inducible factors; prolyl hydroxylases; erythroid models; erythropoiesis; Spi2a; anemia; erythroferrone; erythropoiesis-stimulating agents; protein tyrosine phosphatases; erythropoietin; janus kinase 2
• ISSN: 1744-7631
• DOI: 10.1517/14728222.2016.1090975

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. 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. 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.