Disc Medicine is applying new insights in hepcidin biology

Disc Medicine is developing therapies addressing ineffective red blood cell production in hematologic diseases. Hepcidin is the most promising consensus pathway to address a range of diseases.


Hepcidin, a small peptide hormone produced in the liver, is the master regulator of iron metabolism that when dysregulated is associated with either iron overload or iron deficiency. Both of these conditions can be associated with ineffective red blood cell production, often leading to severe anemia in a range of hematological and non-hematological diseases that can significantly impact lifespan and quality of life.

Disc Medicine is advancing programs to restore hepcidin regulation in high hepcidin and low hepcidin disorders. When hepcidin levels are inappropriately high, reduced iron mobilization can impair red cell formation and lead to anemia. In contrast, when hepcidin levels are inappropriately low, increased iron uptake and mobilization can lead to tissue iron overload and exacerbate anemia.


The hepcidin pathway

Hepcidin regulates the absorption of iron (Fe) in the gut epithelium and transit from storage sites in hepatocytes and macrophages. Hepcidin gene expression is stimulated by binding of BMP-6 to its cognate receptor (BMPR) and co-receptor, hemojuvelin (HJV). Matriptase-2 decreases signaling by proteolytic cleavage of HJV to generate a soluble form (sHJV) that does not transmit the pro-hepcidin signal. Disc Medicine is generating inhibitors of matriptase-2 to prevent HJV cleavage, restore BMPR signaling and elevate hepcidin levels. Monoclonal antibodies directed at HJV are being developed to have the opposite effect, to reduce hepcidin levels.


Hemojuvelin

Hemojuvelin (HJV) is a co-receptor of bone-morphogenic protein signals that lead to increased hepcidin gene expression in hepatocytes. Antagonists of hemojuvelin lead to reductions in hepcidin levels by blocking these signals. Human mutations in HJV lead to substantial reductions in hepcidin levels and cause an early onset form of hereditary hemochromatosis, an iron loading disorder caused by chronic hepcidin suppression. In the context of chronic hepcidin elevation resulting from inflammatory signals, HJV antagonists reduce hepcidin elevations and increase hemoglobin levels.

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Matriptase-2

Matriptase-2 (TMPRSS6) is a serine protease expressed on the surface of hepatocytes that acts as a negative regulator of hepcidin expression by cleaving hemojuvelin from the cell surface. Small molecule inhibitors of matriptase-2 increase hepcidin levels by allowing hemojuvelin to respond to pro-hepcidin signals. Human genetic polymorphisms in TMPRSS6 affect hepcidin expression, iron metabolism, and hemoglobin levels and individuals with polymorphisms that encode for less active matriptase-2 have less severe forms of thalassemia and hemochromatosis.

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