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Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

机译：在贫血和红细胞生成失调中靶向EPO和EPO受体途径

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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.
机译：简介：重组人促红细胞生成素（rhEPO）是治疗慢性肾脏疾病，癌症化学疗法，艾滋病（齐多夫定疗法）和低危骨髓增生异常综合征的贫血的一线治疗药物。但是，rhEPO经常会升高高血压，价格昂贵，并可能影响癌症的进展。因此，在促红细胞生成素（EPO）和EPO受体（EPOR）调节回路中定义抗贫血药物的新靶标方面可能存在很高的优势。涵盖的领域：肾间质成纤维细胞产生的EPO受几种缺氧诱导因子2a调节剂的调节。 （HIF2a），包括铁反应蛋白-1，脯氨酰羟化酶和HIF2a乙酰化酶，每种均具有作为抗贫血药物靶标的潜力。 EPO（EPOR）的细胞表面受体与Janus Kinase 2（JAK2）一起预组装为同型二聚体，因此吸引人们开发触发EPOR复合物激活的新型试剂（激活抗体，模拟物，小分子激动剂）仍然具有吸引力。此外，EPOR / JAK2信号传导的某些下游传感器可能是可药物治疗的，包括赤铁酮（铁调素调节剂），具有细胞保护性的Spi2a丝氨酸蛋白酶抑制剂和选择与EPOR相关的蛋白酪氨酸磷酸酶。刺激剂（ESA）的存在促进了新型ESA的研究，这些研究增强了HIF2a的作用，充当EPOR激动剂，和/或支持选择的下游EPOR途径​​形成类红细胞。此类药物可减少rhEPO剂量，副作用和/或成本。

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