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C. Camaschella et al.
Therapeutic implications
Hepcidin levels favor response (when low) or resistance (when high) to oral iron administration, explaining part of iron refractoriness.117 The dynamics of the increase in hep- cidin levels after oral iron therapy have suggested that alter- nate-day administration of iron salts is an alternative to daily refracted doses, with the former being a protocol that increases both efficacy and tolerability, at least in women with iron deficiency without or with mild anemia.116,118,119 The availability of more tolerated, iron-stable and effica- cious preparations has increased the use of intravenous iron, especially of the high-dose single-injection com- pounds.120 However, when used to correct iron deficiency in inflammation, intravenous iron may lead to macrophage iron accumulation whose long-term effects are unknown.
Manipulation of the hepcidin-ferroportin axis is the most logical experimental approach to iron disorders. The rationale is to use hepcidin agonists for iron overload dis- orders caused by inappropriate/low hepcidin and hep- cidin antagonists to release sequestered iron in IRIDA and in anemia of inflammation (Table 2).
Increasing hepcidin levels /decreasing ferroportin activity
Compounds Mechanism
IA. TO INCREASE HEPCIDIN OR REDUCE FERROPORTIN ACTIVITY122
age. Potentially useful in hemochromatosis, whose treat- ment is still based on phlebotomy,77 hepcidin agonists are of interest in disorders with ineffective erythropoiesis, such as β-thalassemia.107 Agonists include hepcidin ana- logues, minihepcidins, inhibitors of hepcidin repressors such as anti-TMPRSS6 molecules or compounds that block ferroportin activity. By inducing iron restriction hep- cidin agonists ameliorated anemia and iron overload in preclinical studies of thalassemia models;106,121 a few hep- cidin agonists are currently being investigated in phase I-II clinical trials (Table 2). Hepcidin mimics could also be use- ful to induce iron restriction in polycythemia.122 According to recent findings hepcidin might have a role as an antimi- crobial peptide in the treatment of Gram-negative sepsis102 and streptococcal necrotizing fasciitis.56
Other approaches
In non-transfusion-dependent β-thalassemia (Hbbth1/th1 and Hbbth3/+) mice transferrin infusions improve the pheno- type, increasing hepcidin and hemoglobin levels, improv- ing erythrocyte survival and limiting splenomegaly,123,124 effects similar to those observed when Tfr1 expression is decreased.125 Selective inactivation of bone marrow Tfr2 improves anemia in a non-transfusion-dependent Hbbth3/+ model, enhancing the sensitivity of erythroid cells to ery- thropoietin.126
Short interfering RNA against DMT1, administered in Table 2. Targeted therapeutic approaches for disorders with low and high hepcidin.
In preclinical studies, increasing hepcidin levels prevent- ed iron overload or redistributed iron to sites of safe stor-
Hepcidin analogues and minihepcidin121 BMPs
Anti-TMPRSS6 (ASO, siRNA)137
FPN inhibitor VIT-2763155
IB. OTHER APPROACHES
Transferrin injections123 Protoporphyrin IX138
Replacement therapy
Activating the hepcidin signaling pathway Counteracting hepcidin inhibition Blocking the hepcidin receptor
Decreasing transferrin receptor 1 Inhibiting heme oxygenase 1
Effect
Increased hepcidin
Reduced iron overload
Increased Hb in ineffective erythropoiesis
Reduction of iron uptake Reduction of iron recycling
Reduced hepcidin
Reduced macrophage iron sequestration Correction of hypoferremia
(Partial) correction of anemia
Correction of EPO defect
Correction of hypoferremia
IIA. TO DECREASE HEPCIDIN OR INCREASE FERROPORTIN ACTIVITY97
Anti cytokines (IL-6, IL-6R)103 Anti-BMP6 MoAb139
BMP receptor inhibitors140 Anti-hemojuvelin MoAb141 Heparins142
Anti-hepcidin MoAb143 Anti-hepcidin Spiegelmer144 Anti-hepcidin anticalin145 Anti-ferroportin MoAb139
GDP146
IIB. OTHER APPROACHES
Prolylhydroxylase inhibitors134
Reducing the hepcidin signaling pathway
Hepcidin binders
Interfering with hepcidin-ferroportin interaction Blocking iron export and decreasing Stat3 activation
Increasing EPO
Increasing iron absorption
I. Compounds potentially useful in hereditary hemochromatosis and β-thalassemia; II. Compounds potentially useful in anemia of inflammation. Compounds tested in clinical trials are indicated in bold. BMP: bone morphogenetic protein; ASO: antisense specific oligonucleotides; siRNA: short interfering RNA; FPN: ferroportin;VIT 2763: small molecule oral ferroportin inhibitor; Hb: hemoglobin; IL: interleukin; MoAb: monoclonal antibodies; GDP: guanosine 5'-diphosphate encapsulated in lipid vesicle; EPO: erythropoietin.
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