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

Schwoebel, Frank; Eijk, Lucas T. van; Zboralski, Dirk; Sell, Simone; Buchner, Klaus; Maasch, Christian; Purschke, Werner G.; Humphrey, M.F.; Zöllner, Stefan; Eulberg, Dirk; Morich, F.; Pickkers, Peter; Klussmann, Sven

doi:10.1182/blood-2012-09-456756

Cited by 137 publications

(93 citation statements)

References 26 publications

(23 reference statements)

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“…Concurrent administration of NOX-H94 blunted the development of anemia. 98 In the phase I trial in humans volunteers, NOX-H94 was safe and well tolerated, and after a single NOX-H94 dose, serum iron and transferrin saturation increased in a dosedependent manner. 99 In experimental human endotoxemia caused by an injection of LPS, treatment with NOX−H94 30 min after LPS greatly delayed the onset of hypoferremia.…”

Section: Class 2: Neutralizing Hepcidin Peptidementioning

confidence: 99%

Manipulation of the hepcidin pathway for therapeutic purposes

2013

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Section: Class 2: Neutralizing Hepcidin Peptidementioning

confidence: 99%

Manipulation of the hepcidin pathway for therapeutic purposes

2013

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“…A hepcidin antibody developed to block hepcidin binding to FPN1 increased hepcidin clearance in monkeys and lowered hepcidin levels (107). Spiegelmers (mirror image aptamers) directed to hepcidin decreased hepcidin-mediated downregulation of Fpn1 in a mouse macrophage cell line (108).…”

Section: Potential Therapeutic Targets For Hepcidin Regulationmentioning

confidence: 99%

Iron regulation by hepcidin

Zhao

Zhang²,

Enns³

2013

J. Clin. Invest.

192

158

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Discovery and function of hepcidin in iron homeostasisHepcidin is a key peptide hormone that regulates iron homeostasis in chordates. Hepcidin was initially characterized as an antimicrobial peptide in a mass spectrometry-based search for cysteine-rich defensin-like peptides in blood (1) and in urine (2). However, both groups showed that hepcidin displays only a weak antimicrobial activity. Further, unlike defensins, which vary in sequence among species, hepcidin is highly conserved from zebrafish to humans. Shortly after hepcidin was described, subtractive hybridization studies comparing the livers of normal and iron overloaded mice established a connection between iron loading and increased hepcidin mRNA (3, 4). The fundamental insight into hepcidin's role in iron homeostasis came in 2004 with the discovery that hepcidin acts to lower iron in the blood by binding to and downregulating the iron transporter, ferroportin (FPN1) (5). FPN1 is the only known transporter that is responsible for the efflux of iron from cells. Downregulation of FPN1 by hepcidin in splenic and hepatic macrophages decreases the ability of macrophages to export recycled iron from senescent rbcs, which constitute the primary source of iron in the plasma. In addition, a high concentration of hepcidin in the blood decreases the transport of iron out of intestinal epithelial cells, further limiting iron in the blood. Control of hepcidin expressionHepcidin is synthesized, processed to an active form, and secreted predominantly by hepatocytes (6, 7). The expression of hepcidin is mediated through the bone morphogenetic protein (BMP) and JAK2/STAT3 signaling pathways (Figure 1). Under nonpathological conditions, iron levels in the body upregulate hepcidin expression. Although the underlying mechanisms are poorly understood, recent studies have documented the essential roles of hemojuvelin (HJV), hereditary hemochromatosis protein (HFE), transferrin receptor 2 (TfR2), and matriptase-2 (MT2, encoded by the gene TMPRSS6) in the process of hepcidin regulation in humans and animal models as well as of BMP6, neogenin, and BMP receptors (ActRIIA/ALK2/ALK3) in animal models (8)(9)(10)(11)(12)(13)(14)(15)(16)(17).Intact BMP signaling is essential for hepcidin expression. The canonical BMP-signaling pathway is initiated upon BMP binding to a BMP receptor complex on the cell surface, which activates the receptor kinase to phosphorylate the cytoplasmic proteins SMAD1, SMAD5, and SMAD8. These phosphorylated, receptor-regulated SMADs then form transcription factor complexes with SMAD4, consisting of receptor-regulated SMADs and SMAD4, that translocate into the nucleus to induce the transcription of target genes such as hepcidin (18). In mice, liver-specific disruption of SMAD4 or the BMP receptors ALK2 or ALK3 markedly decreased hepcidin expression, resulting in iron overload (15,19).BMP6. At least 20 BMPs are expressed in mammals. In vitro studies reveal that BMP2, -4, -5, -6, -7, and -9 can robustly induce BMP signaling and markedly increase hepcidin expres...

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“…Recently, the effects of intravenous iron therapy for anemia and iron deficiency of HF patients have been studied (Anker et al 2009a, b). Other investigators have been developing anti-hepcidin drugs (Cooke et al 2013;Schwoebel et al 2013). Future studies are needed to classify anemia and FID of HF patients based on etiology and to establish proper therapies for anemia and FID of HF patients.…”

Section: Anemia Fid and Hepcidin Expression In Mct-treated Pah Ratsmentioning

confidence: 99%

Liver Congestion in Heart Failure Contributes to Inappropriately Increased Serum Hepcidin despite Anemia

Ohno¹,

Hanawa²,

Jiao³

et al. 2015

Tohoku J. Exp. Med.

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Hepcidin is a key regulator of mammalian iron metabolism and mainly produced by the liver. Hepcidin excess causes iron deficiency and anemia by inhibiting iron absorption from the intestine and iron release from macrophage stores. Anemia is frequently complicated with heart failure. In heart failure patients, the most frequent histologic appearance of liver is congestion. However, it remains unclear whether liver congestion associated with heart failure influences hepcidin production, thereby contributing to anemia and functional iron deficiency. In this study, we investigated this relationship in clinical and basic studies. In clinical studies of consecutive heart failure patients (n = 320), anemia was a common comorbidity (41%). In heart failure patients without active infection and ongoing cancer (n = 30), log-serum hepcidin concentration of patients with liver congestion was higher than those without liver congestion (p = 0.0316). Moreover, in heart failure patients with liver congestion (n = 19), the anemia was associated with the higher serum hepcidin concentrations, which is a type of anemia characterized by induction of hepcidin. Subsequently, we produced a rat model of heart failure with liver congestion by injecting monocrotaline that causes pulmonary hypertension. The monocrotaline-treated rats displayed liver congestion with increase of hepcidin expression at 4 weeks after monocrotaline injection, followed by anemia and functional iron deficiency observed at 5 weeks. We conclude that liver congestion induces hepcidin production, which may result in anemia and functional iron deficiency in some patients with heart failure.

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

Abstract: Key Points The hepcidin inhibitor NOX-H94, a structured mirror-image RNA oligonucleotide, and its in vitro and in vivo characterization are described. First published hepcidin inhibitor that entered clinical trials for the treatment of anemia due to functional iron deficiency.

Cited by 137 publications

References 26 publications

Manipulation of the hepcidin pathway for therapeutic purposes

Manipulation of the hepcidin pathway for therapeutic purposes

Iron regulation by hepcidin

Liver Congestion in Heart Failure Contributes to Inappropriately Increased Serum Hepcidin despite Anemia

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