New potential players in hepcidin regulation

Chappell, Matthew N.; Rivella, Stefano

doi:10.3324/haematol.2019.224311

Cited by 4 publications

(7 citation statements)

References 20 publications

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“…However, in β‐thalassaemia, hepcidin expression is suppressed contributing to uncontrolled absorption of dietary iron and insufficient iron retention by the reticuloendothelial system exacerbating ineffective erythropoiesis and anaemia 6 . Thus, the manipulation of hepcidin and related pathways have become the target for development of novel therapies for iron overload disorders 9–12 . Hepcidin is under negative control of the transmembrane serine protease 6 (TMPRSS6) via the inhibition of haemojuvelin (HJV) activity, a co‐receptor for the bone morphogenetic protein (BMP)‐mothers against decapentaplegic homologue (SMAD) signalling pathway, activated in a paracrine manner by BMP2 and BMP6 produced by liver sinusoidal endothelial cells 6,10,13 .…”

Section: Introductionmentioning

confidence: 99%

SLN124, a GalNac‐siRNA targeting transmembrane serine protease 6, in combination with deferiprone therapy reduces ineffective erythropoiesis and hepatic iron‐overload in a mouse model of β‐thalassaemia

Vadolas

Kysenius

et al. 2021

Br J Haematol

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Summary Beta‐thalassaemia is an inherited blood disorder characterised by ineffective erythropoiesis and anaemia. Consequently, hepcidin expression is reduced resulting in increased iron absorption and primary iron overload. Hepcidin is under the negative control of transmembrane serine protease 6 (TMPRSS6) via cleavage of haemojuvelin (HJV), a co‐receptor for the bone morphogenetic protein (BMP)‐mothers against decapentaplegic homologue (SMAD) signalling pathway. Considering the central role of the TMPRSS6/HJV/hepcidin axis in iron homeostasis, the inhibition of TMPRSS6 expression represents a promising therapeutic strategy to increase hepcidin production and ameliorate anaemia and iron overload in β‐thalassaemia. In the present study, we investigated a small interfering RNA (siRNA) conjugate optimised for hepatic targeting of Tmprss6 (SLN124) in β‐thalassaemia mice (Hbbth3/+). Two subcutaneous injections of SLN124 (3 mg/kg) were sufficient to normalise hepcidin expression and reduce anaemia. We also observed a significant improvement in erythroid maturation, which was associated with a significant reduction in splenomegaly. Treatment with the iron chelator, deferiprone (DFP), did not impact any of the erythroid parameters. However, the combination of SLN124 with DFP was more effective in reducing hepatic iron overload than either treatment alone. Collectively, we show that the combination therapy can ameliorate several disease symptoms associated with chronic anaemia and iron overload, and therefore represents a promising pharmacological modality for the treatment of β‐thalassaemia and related disorders.

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Section: Introductionmentioning

confidence: 99%

SLN124, a GalNac‐siRNA targeting transmembrane serine protease 6, in combination with deferiprone therapy reduces ineffective erythropoiesis and hepatic iron‐overload in a mouse model of β‐thalassaemia

Vadolas

Kysenius

et al. 2021

Br J Haematol

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“…Second, hepcidin increases the intracellular concentration of iron, which leads to the secretion of BMP6 from these cells [ 79 ]. As a consequence, BMP6 binds and activates receptors that trigger the phosphorylation of the SMAD complex and stimulate hepcidin expression in hepatic cells [ 80 ]. To date, most of the compounds that increased the expression of hepcidin show a very specific activity (that is hepcidin mimetics or FPN inhibitors) [ 81 , 82 ].…”

Section: Discussionmentioning

confidence: 99%

“…In general, these drugs belong to one of the four main categories: (i) hepcidin mimetics, (ii) hepcidin inducers, (iii) FPN inhibitors, and (iv) erythroferrone inhibitors. TMPRSS6 inhibitors can be defined as hepcidin inducers and/or BMP/SMAD pathway activators [ 80 ].…”

Section: Discussionmentioning

confidence: 99%

“…Obviously, a low production cost would also be desirable. Furthermore, the drug should have a clear mechanism of action, if possible [ 80 ].…”

Section: Discussionmentioning

confidence: 99%

“…In summary, the placenta-derived drugs Laennec and Porcine are very promising treatment options and can be used in patients affected by such disorders in which increased hepcidin expression is desirable and advantageous. If proven safe and effective, their use in clinical practice will steadily increase [ 80 ]. Similar to classical placenta drugs, Laennec and Porcine have also been used as “anti-aging” treatments and “skin care products.”…”

Section: Discussionmentioning

confidence: 99%

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A farewell to phlebotomy—use of placenta-derived drugs Laennec and Porcine for improving hereditary hemochromatosis without phlebotomy: a case report

Hamada¹,

Hirano

Sugimoto

et al. 2022

J Med Case Reports

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Background Human hepcidin, produced by hepatocytes, regulates intestinal iron absorption, iron recycling by macrophages, and iron release from hepatic storage. Recent studies indicate that hepcidin deficiency is the underlying cause of the most known form of hereditary hemochromatosis. Case presentation A 44-year-old Asian man who developed type 2 diabetes mellitus had elevated serum ferritin levels (10,191 ng/mL). Liver biopsy revealed remarkable iron deposition in the hepatocytes and relatively advanced fibrosis (F3). Chromosomal analysis confirmed the presence of transferrin receptor type 2 mutations (c.1100T>G, c.2008_9delAC, hereditary hemochromatosis type 3 analyzed by Kawabata). The patient received intravenous infusions of Laennec (672 mg/day, three times/week) or oral administration with Porcine (3.87 g/day) for 84 months as an alternative to repeated phlebotomy. At the end of the treatment period, serum ferritin level decreased to 428.4 ng/mL (below the baseline level of 536.8 ng/mL). Hemoglobin A1c levels also improved after treatment with the same or lower dose of insulin (8.8% before versus 6.8% after). Plural liver biopsies revealed remarkable improvements in the grade of iron deposition and fibrosis (F3 before versus F1 after) of the liver tissue. Conclusion The discovery of hepcidin and its role in iron metabolism could lead to novel therapies for hereditary hemochromatosis. Laennec (parenteral) and Porcine (oral), which act as hepcidin inducers, actually improved iron overload in this hereditary hemochromatosis patient, without utilizing sequential phlebotomy. This suggests the possibility of not only improving the prognosis of hereditary hemochromatosis (types 1, 2, and 3) but also ameliorating complications, such as type 2 diabetes, liver fibrosis, and hypogonadism. Laennec and Porcine can completely replace continuous venesection in patients with venesection and may improve other iron-overloading disorders caused by hepcidin deficiency.

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Characterization of acquired anemia in children by iron metabolism parameters

Ben-David

Koren

Colodner

et al. 2022

Sci Rep

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Inflammatory states are associated with anemia of chronic disease and acute infection. Hepcidin, a regulator of iron metabolism, is involved in iron pathophysiology during inflammation. We investigated biochemical characteristics in children with anemia from different causes. Four patient groups (n = 38; mean age: 12.44 ± 4.35 years) were studied: (1) inflammatory bowel disease (IBD, 10 patients); (2) iron deficiency anemia (IDA, 12); (3) celiac disease (CD, 8); (4) acute infection (AI, 8). Laboratory measurements were evaluated at diagnosis: blood count, serum iron, transferrin, ferritin, vitamin B12, folic acid, CRP, erythropoietin, hepcidin and soluble transferrin receptor (sTfR). IDA patients had the lowest Hgb (6.9 ± 1.7 g/dL), MCV (63.2 ± 7.2 fL), iron (16.8 ± 13.5 µg/dL), ferritin (4.5 ± 4.5 ng/mL) and hepcidin (3.1 ± 0.8 ng/mL) values, and the highest transferrin and sTfR values. AI patients had the highest ferritin (156.2 ± 124.5 ng/mL), CRP (144.6 ± 94 mg/L) and hepcidin (74.67 ± 12.3 ng/ml) values. Overall, hepcidin levels correlated with CRP and with ferritin (r = 0.83 and 0.85, respectively). Elucidating specific etiology-related biochemical profiles in pediatric patients with anemia from different causes using a combination of laboratory biomarkers, including hepcidin, can help physicians treat the anemia.

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New potential players in hepcidin regulation

Cited by 4 publications

References 20 publications

SLN124, a GalNac‐siRNA targeting transmembrane serine protease 6, in combination with deferiprone therapy reduces ineffective erythropoiesis and hepatic iron‐overload in a mouse model of β‐thalassaemia

SLN124, a GalNac‐siRNA targeting transmembrane serine protease 6, in combination with deferiprone therapy reduces ineffective erythropoiesis and hepatic iron‐overload in a mouse model of β‐thalassaemia

A farewell to phlebotomy—use of placenta-derived drugs Laennec and Porcine for improving hereditary hemochromatosis without phlebotomy: a case report

Characterization of acquired anemia in children by iron metabolism parameters

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