Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis.
Document Type
Article
Publication Date
2016
Institution/Department
MMCRI
Journal Title
Expert opinion on therapeutic targets
MeSH Headings
Anemia, Animals, Drug Design, Erythropoiesis, Erythropoietin, Hematinics, Humans, Molecular Targeted Therapy, Receptors, Erythropoietin, Recombinant Proteins
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.
ISSN
1744-7631
First Page
287
Last Page
301
Recommended Citation
Rainville, Nicole; Jachimowicz, Edward; and Wojchowski, Don M, "Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis." (2016). MaineHealth Maine Medical Center. 398.
https://knowledgeconnection.mainehealth.org/mmc/398
