Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis. (3rd March 2016)

• Record Type: Journal Article
• Authors: Rainville, Nicole; Jachimowicz, Edward; Wojchowski, Don M
• Is Part Of: Expert opinion on therapeutic targets. Volume 20:Number 3(2016:Mar.)
• Page Start: 287
• Page End: 301
• Publication Date: 2016-03-03
• Subjects: anemia -- erythroferrone -- erythroid models -- erythropoiesis -- erythropoiesis-stimulating agents -- erythropoietin -- erythropoietin receptor -- hypoxia inducible factors -- janus kinase 2 -- prolyl hydroxylases -- protein tyrosine phosphatases -- Spi2a; Drugs -- Research -- Periodicals; 615.072
• DOI: 10.1517/14728222.2016.1090975
• Languages: English
• ISSNs: 1744-7631

Abstract

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.