Iron-overload disorders, including hereditary hemochromatosis, are typically insidious, causing progressive and sometimes irreversible end-organ injury before clinical symptoms develop. Iron overload in vital organs increases the risk for liver disease (cirrhosis, cancer), heart attack or heart failure, diabetes mellitus, osteoarthrtis, osteoporosis, metabolic syndrome, and other disorders. Iron overload can be inherited or acquired by receiving numerous blood transfusions or consuming high levels of supplemental iron. Routine treatment in an otherwise-healthy person consists of regularly scheduled phlebotomies or iron-chelating agents like deferoxamine. Most types of iron overload are associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Recently, hepcidin agonists have been reported to reduce serum iron levels in mice (Nemeth and Ganz, 2011). However, hepcidin itself is problematic as a therapeutic because of difficulties in production and short plasma half-life. Peptides (termed minihepcidins) containing the ferroportin-binding residues of native hepcidin are more easily produced. While minihepcidins show hepcidin activity in vitro and in vivo, their affinity for ferroportin lags behind that of native hepcidin by a log or more (Preza, 2011). We propose to develop a best-in-class hepcidin fusion protein containing the human Fc. Hepcidin-Fc is expected to have activity equal to or better than hepcidin and have favorable pharmacokinetics with increased plasma half-life permitting once monthly administration.
Iron overload leads to damage to vital organs, including the liver and heart. Hepcidin, a peptide hormone produced by the liver, is the master regulator of iron metabolism. We have developed a hepcidin agonist that will be as effective as hepcidin in the treatment for hemochromatosis and other iron overload disorders, while being more easily produced and having a longer plasma half-life.
