The effects of the anti-hepcidin Spiegelmer NOX-H94 on inflammation-induced anemia in cynomolgus monkeys.

Abstract

Anemia of chronic inflammation is the most prevalent form of anemia in hospitalized patients. A hallmark of this disease is the intracellular sequestration of iron. This is a consequence of hepcidin-induced internalization and subsequent degradation of ferroportin, the hepcidin receptor and only known iron-export protein. This study describes the characterization of novel anti-hepcidin compound NOX-H94, a structured L-oligoribonucleotide that binds human hepcidin with high affinity (Kd = 0.65 ± 0.06 nmol/L). In J774A.1 macrophages, NOX-H94 blocked hepcidin-induced ferroportin degradation and ferritin expression (half maximal inhibitory concentration = 19.8 ± 4.6 nmol/L). In an acute cynomolgus monkey model of interleukin 6 (IL-6)-induced hypoferremia, NOX-H94 inhibited serum iron reduction completely. In a subchronic model of IL-6-induced anemia, NOX-H94 inhibited the decrease in hemoglobin concentration. We conclude that NOX-H94 protects ferroportin from hepcidin-induced degradation. Therefore, this pharmacologic approach may represent an interesting treatment option for patients suffering from anemia of chronic inflammation.

• Authors: Frank Schwoebel, Lucas T van Eijk, Dirk Zboralski, Simone Sell, Klaus Buchner, Christian Maasch, Werner G Purschke, Martin Humphrey, Stefan Zöllner, Dirk Eulberg, Frank Morich, Peter Pickkers, Sven Klussmann
• Journal: Blood (Blood) Vol. 121 Issue 12 Pg. 2311-5 (Mar 21 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 23349391 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Antimicrobial Cationic Peptides
• HAMP protein, human
• Hamp protein, mouse
• Hemoglobins
• Hepcidins
• Interleukin-6
• Oligoribonucleotides
• NOX-H94
• Iron

Topics

• Anemia (drug therapy, etiology, pathology)
• Animals
• Anti-Inflammatory Agents (administration & dosage, pharmacology, therapeutic use)
• Antimicrobial Cationic Peptides (antagonists & inhibitors)
• Cells, Cultured
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Erythrocytes (drug effects, metabolism)
• Hemoglobins (analysis, drug effects)
• Hepcidins
• Inflammation (complications, drug therapy)
• Interleukin-6 (administration & dosage, adverse effects)
• Iron (blood, metabolism)
• Iron Metabolism Disorders (chemically induced)
• Macaca fascicularis
• Macrophages (drug effects, metabolism)
• Male
• Mice
• Oligoribonucleotides (administration & dosage, pharmacology, therapeutic use)