Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

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.

Keywords:

• anemia
• erythroferrone
• erythroid models
• erythropoiesis
• erythropoiesis-stimulating agents
• erythropoietin
• erythropoietin receptor
• hypoxia inducible factors
• janus kinase 2
• prolyl hydroxylases
• protein tyrosine phosphatases
• Spi2a

Acknowledgments

The authors thank Karen Miller for substantial and sustained administrative contributions to manuscript preparation.

Declaration of interest

DM Wojchowski was supported by the National Institutes of Health under grant number NIH R01 HL044491. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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