Methods and compositions to regulate hepcidin expression

Abstract

The present invention provides new systems and strategies for the regulation of iron metabolism in mammals. In particular, methods of using agonists and antagonists of TGF-β superfamily members to modulate the expression or activity of hepcidin, a key regulator of iron metabolism, are described. The inventive methods find applications in the treatment of diseases associated with iron overload, such as juvenile hemochromatosis and adult hemochromatosis, and in the treatment of diseases associated with iron deficiency, such as anemia of chronic disease and EPO resistant anemia in end-stage of renal disease. The present invention also relates to screening tools and methods for the development of novel drugs and therapies for treating iron metabolism disorders.

1 .- 102 . (canceled) 
     
     
         103 . A method for inhibiting hepcidin expression or activity in a mammalian subject exhibiting iron deficiency comprising administering to the subject an effective amount of a bone morphogenetic protein (BMP) antagonist, wherein the BMP antagonist comprises a protein that inhibits binding of a BMP with a BMP type II receptor. 
     
     
         104 . The method of  claim 103 , wherein the subject is suffering from a condition associated with iron deficiency. 
     
     
         105 . The method of  claim 104 , wherein the condition associated with iron deficiency is selected from the group consisting of anemia of chronic disease, iron deficiency anemia, functional iron deficiency, and microcytic anemia. 
     
     
         106 . The method of  claim 105 , wherein the condition associated with iron deficiency is anemia of chronic disease, and wherein said anemia of chronic disease is associated with chronic bacterial endocarditis, osteomyelitis, rheumatic fever, ulcerative colitis, a neoplastic disorder, infection, or inflammation. 
     
     
         107 . The method of  claim 106 , wherein the anemia of chronic disease is associated with infection, and wherein said infection is a pulmonary abscess, or tuberculosis. 
     
     
         108 . The method of  claim 106 , wherein the anemia of chronic disease is associated with inflammation, and wherein said inflammation is caused by rheumatoid arthritis, systemic lupus erythrematosus, Crohn's disease, hepatitis, or inflammatory bowel disease. 
     
     
         109 . The method of  claim 103 , wherein the mammal is a human. 
     
     
         110 . The method of  claim 103 , wherein the subject exhibits low hematocrit associated with iron deficiency. 
     
     
         111 . The method of  claim 103 , wherein the subject exhibits low serum hemoglobin associated with iron deficiency. 
     
     
         112 . The method of  claim 103 , wherein the BMP type II receptor is BMPRII, ActRIIA, or ActRIIB. 
     
     
         113 . The method of  claim 103 , wherein the BMP is BMP-2. 
     
     
         114 . The method of  claim 103 , wherein the BMP is BMP-4. 
     
     
         115 . The method of  claim 103 , wherein the protein is an antibody or a fragment thereof. 
     
     
         116 . The method of  claim 103 , wherein the protein specifically binds to the BMP type II receptor. 
     
     
         117 . The method of  claim 103 , wherein the protein specifically binds to the BMP. 
     
     
         118 . The method of  claim 117 , wherein the BMP is BMP-2. 
     
     
         119 . The method of  claim 117 , wherein the BMP is BMP-4. 
     
     
         120 . The method of  claim 115 , wherein the antibody or a fragment thereof specifically binds to BMP-2. 
     
     
         121 . The method of  claim 115 , wherein the antibody or a fragment thereof specifically binds to BMP-4.