Erythropoietin’s Dual Biology: Erythropoietic Hormone and Neuroprotective Cytokine—History, Mechanisms, and Translational Challenges

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Abstract
Human erythropoietin (hEPO) is the principal regulator of erythropoiesis and has been used therapeutically as recombinant hEPO (rhEPO) since 1989. Beyond this hematopoietic role, hEPO is also a tissue-protective cytokine with neurotrophic and neuroprotective activities. Clinically, rhEPO is widely used to treat anemia, although even in that setting its approved labeling carries boxed warnings for an increased risk of death, myocardial infarction, stroke, venous thromboembolism, vascular access thrombosis, and tumor progression or recurrence. Neuroprotective applications, however, require substantially higher and more frequent doses to overcome its limited blood–brain barrier permeability, and at these doses rhEPO produces dose-related adverse effects. Some of these, such as polycythemia and thrombotic events, are attributable to its erythropoietic activity, whereas others, including the excess mortality reported in acute ischemic stroke, remain mechanistically unexplained. This safety profile, together with the absence of benefit on the primary endpoint of three large randomized trials, is the main reason why rhEPO has not been approved for neurodegenerative disorders or neuronal tissue injury, and it has motivated the search for non-erythropoietic hEPO analogues. This review examines the dual biological functions of hEPO and their implications for biopharmaceutical innovation through two complementary cases originating from the Universidad Nacional del Litoral (UNL), Argentina. Zelltek emerged from academic research on recombinant glycoprotein production and developed a manufacturing platform for rhEPO, subsequently commercializing the product and contributing to the development of Argentina’s biopharmaceutical industry. BioSynaptica arose from research into the non-erythropoietic activities of hEPO and is advancing engineered, hyperglycosylated hEPO variants designed to dissociate erythropoietic activity from neuroprotective and other tissue-protective effects. Considered together, these university spin-offs illustrate two distinct translational trajectories arising from the biology of a single molecule: the industrial production of an established therapeutic protein and the preclinical development of engineered candidates targeting unmet medical needs. Their experiences also highlight the complementary roles of academic research, technology transfer, intellectual property, and sustained development efforts in translating biological discoveries into biopharmaceutical innovation.
Funding Information
  • Universidad Nacional del Litoral (SAT No. 356.698/92)
  • BioSynaptica SA

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