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Investigating the regulation of iron homeostasis by erythroferrone and therapeutic applications

Periodic Reporting for period 3 - INVESTIGERFE (Investigating the regulation of iron homeostasis by erythroferrone and therapeutic applications)

Reporting period: 2020-05-01 to 2021-10-31

Iron is essential for most living organisms. As a functional component of red blood cells, iron binds oxygen and ensures the proper transport and storage of oxygen throughout the body. An estimated 1/3 of the worldwide population suffers from anemia, a condition defined as an insufficient amount of circulating red blood cells. Iron deficiency or restricted iron availability for red cells synthesis is a major cause of anemia. On the contrary, excess iron is highly toxic and leads to severe clinical complications. Hepcidin is the central regulator of iron homeostasis. During the recovery from hemorrhage-induced anemia or the anemia that accompanies chronic inflammatory diseases, hepatic synthesis of hepcidin is repressed by the erythroid hormone erythroferrone (ERFE). ERFE regulates the adequate supply of iron supply for new red blood cells synthesis to promote the recovery. At the other end of the spectrum, increased production of ERFE causes iron overload in pathologies associated with ineffective red cell production such as β-thalassemia. However, nothing is known about the molecular mechanism by which ERFE targets hepatocytes to suppress hepcidin expression.
Therefore, delineating the mechanism of hepcidin suppression by ERFE is of high biomedical importance as the pathway could be targeted to develop novel treatments for various forms of anemia. This project will identify the receptor(s) for ERFE and the signal transduction pathways for hepcidin regulation. The potential of ERFE agonists or antagonists to treat iron-restrictive anemias and β-thalassemia will be tested in mice. We will also develop a diagnostic tool to monitor the contrition of ERFE in human pathologies. In parallel, we will examine whether other molecules exert a similar function and could be targeted to combat anemia. Finally, we will establish proof of concept preclinical experiments in murine models of anemia.
Successful completion of this project will lead to the design of new therapeutic approaches for the treatment of anemia which directly answers an unmet need in public health. Indeed, Iron-restrictive anemias affect patients with chronic infections, inflammatory diseases, chronic kidney disease and hematologic and other malignancies. These anemias affect tens of millions of patients worldwide and the current treatments based on EPO and iron administration are largely inefficient but have raised significant safety concerns. The use of ERFE or ERFE agonists has the potential to circumvent the need for EPO and iron to treat anemia. At the other end of the spectrum, increased ERFE concentrations may be responsible for iron overload in β-thalassemia intermedia, a disease affecting at least 100,000 patients worldwide. Iron overload in thalassemia patients is the major cause of morbidity and mortality and is controlled by parenteral or oral chelators but their limitations have highlighted the need for new strategies. Prevention of iron overload by the use of ERFE antagonists would improve the patients’ quality of life and survival. Identification of the receptor and signaling pathway are a prerequisite to envision this possibility.
Since the beginning of the project, we developed an assay to measure ERFE in human serum. We determined that ERFE levels are dramatically elevated in thalassemia and myelodysplastic syndromes (MDS) and could be responsible for the installation of a deleterious iron overload. In MDS, detection of ERFE represents a new biomarker to diagnose the patients and monitor the treatment efficacy. We identified candidate receptor that are currently under investigation. Importantly, we also discovered a previously undescribed critical regulator of iron metabolism.
We discovered a previously undescribed critical regulator of iron metabolism. We will perform an extensive characterization of this new molecule until the end of the project.
The erythroid regulator erythroferrone