Approaches to modulate levels of hepcidin may provide benefit to people with either iron overload or iron deficiency. Hepcidin, a peptide hormone produced by the liver, is the master regulator of iron balance in humans and other mammals. Hepcidin inhibits transport of iron from cells by binding to the iron channel, ferroportin, which reduces dietary iron absorption and limits release of iron from cells that store iron, such as macrophages. Insufficient levels of hepcidin cause or contribute to iron overload in β-thalassemia and in hereditary hemochromatosis, while excess levels of hepcidin lead to a decline in blood iron levels, as occurs in the anemia of chronic inflammation. Thus, strategies that increase or decrease the effective level of hepcidin could help treat these diseases.
Researchers recently reported the design of smaller forms of hepcidin and tested the ability of these compounds to mimic hepcidin activity and also treat iron overload in mice. These “mini-hepcidins” contain the segment of the hepcidin protein that interacts with ferroportin, and were found to be resistant to degradation by enzymes in the blood. After injection or oral administration to mice, these “mini-hepcidins” were found to lower serum iron levels as effectively as full-length hepcidin and also to lower liver iron levels significantly in an animal model of iron overload. “Mini-hepcidins” offer certain advantages over full-length hepcidin in that they are less expensive to produce, are more stable, and can be administered orally.
In a separate study, scientists assessed the ability of two small compounds (LDN-193189 and HJV.Fc) to block the production of hepcidin in an animal model of anemia of chronic inflammation. Previous research has demonstrated that both LDN-193189 and HJV.Fc block the action of a protein that signals the hepcidin gene to be expressed. By blocking this protein, called bone morphogenetic protein (BMP), the production of hepcidin was effectively blocked. This study provided compelling evidence that both agents reduced hepcidin levels by blocking BMP, allowing iron to become more available for red blood cell production, thereby ameliorating anemia of chronic inflammation in an experimental animal model.
Past investments in basic science research provided the foundation for these two research studies targeting hepcidin levels. Ongoing studies continue to evaluate these and other promising compounds in order to develop effective treatments for iron-related blood disorders.
Preza GC, Ruchala P, Pinon R, et al. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest 121: 4880-4888, 2011.
Theurl I, Schroll A, Sonnweber T, et al. Pharmacologic inhibition of hepcidin expression reverses anemia of chronic
inflammation in rats. Blood 118: 4977-4984, 2011.