scholarly journals A Monoclonal Antibody Targeting ALK2 As a Potential Therapeutic Agent for Anemia of Inflammation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2007-2007
Author(s):  
Natalia Medeiros ◽  
Thomas A Backus ◽  
Christopher Materna ◽  
Ffolliott Fisher ◽  
Jenn Lachey ◽  
...  
Keyword(s):  
Mouse Model ◽  
Serum Iron ◽  
Publicly Traded ◽  
Hemoglobin Content ◽  
Once Daily ◽  
Hepcidin Expression ◽  
Inflammatory Conditions ◽  
Serum Hepcidin ◽  
Anemia Of Inflammation ◽  
Daily Oral Administration

Abstract Background: Iron homeostasis is primarily regulated by hepcidin, a hormone predominantly expressed in the liver. Hepcidin activates the degradation of the transmembrane iron exporter ferroportin, thereby downregulating the release of iron from cells. Hepcidin expression is, at least partly, regulated in response to signaling of the type I TGF-β receptor ALK2, via SMAD2/3 phosphorylation. IL-6, which is commonly elevated in chronic kidney disease (CKD) and other inflammatory conditions, upregulates hepcidin expression and reduces serum iron bioavailability. As a result, chronic inflammatory conditions are often accompanied by secondary anemia of inflammation (AI). We have previously demonstrated that ALK2 inhibition suppressed hepcidin expression in rodents, monkeys and healthy humans. We further described that administration of a selective small molecule ALK2 kinase inhibitor (KTI-2338) reversed changes in hepcidin and iron in a mouse model of CKD, supporting the potential benefit of ALK2 inhibition in AI. Another approach to targeting ALK2 signaling is use of a neutralizing antibody. KTI-018 is a neutralizing ALK2 antibody with high affinity and selectivity for ALK2. This biologic has been demonstrated to reduce serum hepcidin and increase serum iron in healthy non-human primates. Aims: To further elucidate the specific contribution of ALK2 signaling as a driver in AI, and to determine the therapeutic potential of the antibody in this type of anemia, we assessed the effect of KTI-018 in the CKD mouse model. Methods: The study was conducted with 6-week-old male C57Bl/6 mice. Mice in the CKD cohort (CKD) were treated with once daily oral administration of adenine, a compound that metabolizes to 2,8-dihydroxyadenine, forming crystals in the proximal tubular epithelia and causing inflammation and fibrosis in the kidneys. Mice in the control cohort (healthy) received once daily oral administration of vehicle. Upon confirmation of disease, the CKD cohort was subdivided into two groups. The treatment group received twice weekly intraperitoneal treatment with KTI-018 (CKD-KTI-018), and the control group received tris-buffered saline (CKD-TBS). Healthy mice received TBS only. All mice were maintained on their assigned daily adenine or vehicle regimen. At day 53, the study was terminated and hematologic parameters, serum hepcidin, iron, and IL-6 levels were assessed. Results: After 42 days of adenine or vehicle administration, serum hepcidin, serum iron, and hematologic parameters were assessed in representative cohorts of CKD-TBS and healthy mice. The CKD-TBS cohort experienced changes associated with anemia of inflammation as compared to the healthy mice, including increased hepcidin, decreased serum iron, and decreased hematologic parameters. The differences between the healthy and CKD-TBS groups were maintained through the duration of the study. At study termination, CKD-TBS mice had increased serum IL-6 levels (218%), elevated serum hepcidin (149%), and reduced serum iron (-30%) as compared to the healthy mice. Laboratory findings characteristic of anemia were present in the CKD-TBS group, including decreased red blood cells (-6.1%), hemoglobin (-13.2%), and reticulocyte hemoglobin content (-9.3%) as compared to healthy mice. In contrast, CKD-KTI-018 mice had decreased serum hepcidin (-25%) and increased serum iron (59%) as compared to CKD-TBS mice. This restoration of serum iron corresponded to improvements in red blood cells, hemoglobin, and reticulocyte hemoglobin content, which were increased by 7.6%, 9.6%, and 6.7%, respectively, in the CKD-KTI-018 mice as compared to the CKD-TBS mice. These results demonstrate that, by decreasing serum hepcidin, KTI-018 increased the bioavailability of iron, which led to the restoration of hematologic parameters and appeared to reverse AI in mice. Discussion: In this study, a neutralizing ALK2 antibody decreased serum hepcidin, increased serum iron and consequently reversed AI in a mouse model of CKD. These results support the role of ALK2 signaling in AI and suggest that inhibition of ALK2 may be a potential treatment approach for anemia resulting from CKD and other chronic inflammatory diseases. Future studies will explore if ALK2 inhibition may prevent or treat progression of CKD itself, and the role that ALK2 inhibition may play in other chronic inflammatory conditions associated with elevated hepcidin. Disclosures Medeiros: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Backus: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Materna: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Fisher: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Seehra: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Induced Disruption of the Iron-Regulatory Hormone Hepcidin Inhibits Acute Inflammatory Hypoferraemia

2016 ◽  
Vol 8 (5) ◽  
pp. 517-528 ◽  
Author(s):  
Andrew E. Armitage ◽  
Pei Jin Lim ◽  
Joe N. Frost ◽  
Sant-Rayn Pasricha ◽  
Elizabeth J. Soilleux ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mouse ◽  
Brucella Abortus ◽  
Serum Iron ◽  
Vibrio Vulnificus ◽  
Iron Status ◽  
Transgenic Mouse Model ◽  
Innate Immune ◽  
Serum Hepcidin

Withdrawal of iron from serum (hypoferraemia) is a conserved innate immune antimicrobial strategy that can withhold this critical nutrient from invading pathogens, impairing their growth. Hepcidin (Hamp1) is the master regulator of iron and its expression is induced by inflammation. Mice lacking Hamp1 from birth rapidly accumulate iron and are susceptible to infection by blood-dwelling siderophilic bacteria such as Vibrio vulnificus. In order to study the innate immune role of hepcidin against a background of normal iron status, we developed a transgenic mouse model of tamoxifen-sensitive conditional Hamp1 deletion (termed iHamp1-KO mice). These mice attain adulthood with an iron status indistinguishable from littermate controls. Hamp1 disruption and the consequent decline of serum hepcidin concentrations occurred within hours of a single tamoxifen dose. We found that the TLR ligands LPS and Pam3CSK4 and heat-killed Brucella abortus caused an equivalent induction of inflammation in control and iHamp1-KO mice. Pam3CSK4 and B. abortus only caused a drop in serum iron in control mice, while hypoferraemia due to LPS was evident but substantially blunted in iHamp1-KO mice. Our results characterise a powerful new model of rapidly inducible hepcidin disruption, and demonstrate the critical contribution of hepcidin to the hypoferraemia of inflammation.

Hepcidin inhibition improves iron homeostasis in ferrous sulfate and LPS treatment model in mice

Drug Research ◽  
2021 ◽  
Author(s):  
Vishal Patel ◽  
Amit Joharapurkar ◽  
Samadhan Kshirsagar ◽  
Maulik Patel ◽  
Hiren Patel ◽  
...  
Keyword(s):  
Ferrous Sulfate ◽  
Serum Iron ◽  
Iron Homeostasis ◽  
The Body ◽  
Rapid Screening ◽  
Iron Dextran ◽  
Liver Iron ◽  
Hepcidin Expression ◽  
Serum Hepcidin ◽  
Lps Treatment

Abstract Background Hepcidin, a liver-derived peptide, regulates the absorption, distribution, and circulation of iron in the body. Inflammation or iron overload stimulates hepcidin release, which causes the accumulation of iron in tissues. The inadequate levels of iron in circulation impair erythropoiesis. Inhibition of hepcidin may increase iron in circulation and improve efficient erythropoiesis. Activin-like kinase (ALK) inhibitors decrease hepcidin. Methods In this work, we have investigated an ALK inhibitor LDN193189 for its efficacy in iron homeostasis. The effect of LDN193189 treatment was assessed in C57BL6/J mice, in which hepcidin was induced by either ferrous sulfate or lipopolysaccharide (LPS) injection. Results After two hours of treatment, ferrous sulfate increased serum and liver iron, serum hepcidin, and liver hepcidin expression. On the other hand, LPS reduced serum iron in a dose-related manner after six hours of treatment. LDN193189 treatment increased serum iron, decreased spleen and liver iron, decreased serum hepcidin and liver hepcidin expression in ferrous sulfate-treated mice, and increased serum iron in LPS-induced hypoferremia. We observed that ferrous sulfate caused a significantly higher increase in liver iron, serum hepcidin, and liver hepcidin than turpentine oil or LPS in mice. Iron dextran (intraperitoneal or intravenous) increased serum iron, but LDN193189 did not show hyperferremia with iron dextran stimulus. Conclusion Ferrous sulfate-induced hyperferremia can be a valuable and rapid screening model for assessing the efficacy of hepcidin inhibitors.

scholarly journals PDE9 Inhibition By IMR-687 Improves Markers of Beta-Thalassemia in the Hbb th1/th1 Experimental Mouse Model

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 945-945
Author(s):  
Thiago Trovati Maciel ◽  
Caroline Carvalho ◽  
Rachel Rignault ◽  
Slimane Allali ◽  
Biree Andemariam ◽  
...  
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Research Funding ◽  
Weight Ratio ◽  
Total Body Weight ◽  
Beta Thalassemia ◽  
Flow Cytometry Analysis ◽  
Publicly Traded ◽  
Once Daily ◽  
Total Body

Abstract Introduction Hbb th1/th1 mice lack functional beta-globin, leading to decreased hemoglobin (Hb) production, decreased mature red blood cells (RBCs), and ineffective erythropoiesis. The model mimics several of the pathological changes seen in beta-thalassemia. IMR-687 (tovinontrine) is a highly selective phosphodiesterase-9 (PDE9) inhibitor which increases intracellular cGMP. The aim of this study was to assess the effect of IMR-687 on markers of beta-thalassemia in the Hbb th1/th1 mouse model. Methods Eighteen Hbb th1/th1 mice were divided into three groups of six animals each and dosed once daily, by gavage, for 30 days with IMR-687 at 30 or 60 mg/kg/day or vehicle control. On day 30, blood was collected for routine hematology including measurement of Hb, reticulocytes and RBCs, and spleen tissue was dissociated to assess erythrocyte differentiation using flow cytometry analysis of immature (Ery.B: Ter119 highCD71 highFSC low) and mature (Ery.C: Ter119 highCD71 lowFSC low) erythroblast populations. Animals were observed daily for mortality and measured for total body weight (Day 0 and Day 30) and spleen to body weight ratio at necropsy (Day 30). Results After 30 days of treatment, the groups of mice treated with IMR-687 at 30 or 60 mg/kg/day showed a mean increase in Hb of 1.0 g/dL (p<0.05) and 1.5 g/dL (p<0.01), respectively, relative to vehicle controls. RBCs showed a statistically significant increase (p<0.05) following treatment with IMR-687 at 30 or 60 mg/kg/day (6.9 and 7.2 x10 6 cells/ml, respectively) relative to vehicle (6.2 x10 6 cells/ml). The number of reticulocytes decreased after treatment with IMR-687 (only in the 30 mg/kg/day group, 1.8 x10 6 cells/ml, p<0.05) relative to vehicle (2.2 x10 6 cells/ml). Flow cytometry analysis of spleens showed that both doses of IMR-687 increased (p<0.05) the percentage of Ery.C cells (24.2% and 28.5% in 30 and 60 mg/kg/day, respectively) relative to vehicle (16.6%,) and decreased (p<0.05) the percentage of Ery.B cells (38.4% and 36.9% in 30 and 60 mg/kg/day, respectively) relative to vehicle (43.5%), resulting in a maturation ratio (Ery.B/Ery.C) that favored mature RBCs. There were no deaths nor any significant differences in total body weight or spleen to body weight ratio in animals treated with IMR-687 relative to vehicle controls. Conclusions Administration of IMR-687 at 30 or 60 mg/kg/day for 30 days improved markers of disease progression in a mouse model of beta-thalassemia, as shown by a statistically significant increase in Hb and RBCs and decrease in reticulocytes as well as improved differentiation of splenic erythroblasts. Both dose levels of IMR-687 were well tolerated with no treatment-related deaths or abnormal clinical signs. These results support a role for IMR-687 in beta-thalassemia by enabling RBC maturation and improving ineffective erythropoiesis, key components in ameliorating disease pathology. Clinical testing of IMR-687 (up to 400 mg) as a once daily, oral tablet is currently ongoing in a Phase 2 study of patients with beta-thalassemia (NCT04411082). Figure 1 Figure 1. Disclosures Maciel: Imara Inc.: Research Funding. Carvalho: Imara Inc.: Research Funding. Rignault: Imara Inc.: Research Funding. Allali: Imara Inc.: Research Funding. OCain: Imara Inc.: Current Employment, Current equity holder in publicly-traded company. Ballal: Imara Inc.: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Therapeutic efficacy of once-daily oral administration of a Kunitz-type protease inhibitor, bikunin, in a mouse model and in human cancer

Cancer ◽  
2004 ◽  
Vol 100 (4) ◽  
pp. 869-877 ◽  
Author(s):  
Hiroshi Kobayashi ◽  
Tatsuo Yagyu ◽  
Kiyokazu Inagaki ◽  
Toshiharu Kondo ◽  
Mika Suzuki ◽  
...  
Keyword(s):  
Mouse Model ◽  
Oral Administration ◽  
Protease Inhibitor ◽  
Therapeutic Efficacy ◽  
Human Cancer ◽  
Once Daily ◽  
Kunitz Type ◽  
Kunitz Type Protease Inhibitor ◽  
Daily Oral Administration

scholarly journals Role of Erythroferrone in the Pathophysiology of Common Anemias

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 213-213 ◽  
Author(s):  
Leon Kautz ◽  
Grace Jung ◽  
Elizabeta Nemeth ◽  
Tomas Ganz
Keyword(s):  
Bone Marrow ◽  
Mouse Model ◽  
Iron Overload ◽  
Wild Type ◽  
Hepcidin Expression ◽  
Iron Restriction ◽  
Equity Ownership ◽  
Deficient Mice ◽  
Anemia Of Inflammation

Abstract Introduction: We recently described the erythroid hormone erythroferrone (ERFE) as a critical regulator of hepcidin production during increased erythropoietic activity. Both anemia of inflammation (AI) and beta-thalassemia are associated with elevated levels of erythropoietin, the signal directing ERFE expression, suggesting that ERFE may play a role in the pathogenesis of these disorders. Indeed, Erfe mRNA expression was highly increased in the bone marrow and the spleen of a mouse model of β-thalassemia Hbbth3/+ (Th3/+). We therefore investigated the role of erythroferrone in hepcidin regulation in anemia of inflammation and β-thalassemia. We report that ERFE contributes to the recovery from anemia of inflammation and may be a hepcidin-suppressive factor responsible for iron accumulation in thalassemia. Methods: We explored the role of ERFE in anemia of inflammation using the heat-killed Brucellaabortus (BA) mouse model of AI. Hepcidin regulation and recovery from anemia was compared between wild-type and Erfe-deficient mice. To determine whether ERFE is the hepcidin-suppressive factor in thalassemia, we generated Erfe-/-/Th3/+ double mutant mice and compared them to their littermate WT, Erfe-/- and Th3/+ mice. Mice were compared at 3, 6 and 12 weeks of age. Results: Compared to wild-type mice, Erfe-deficient mice did not appropriately decrease hepcidin production during recovery from AI and exhibited greater severity of anemia (figure). These data suggest that compensatory hepcidin suppression during the recovery phase of AI is mediated by ERFE. However, in mice this defect was partly compensated by prolonged stimulation of erythropoiesis and higher reticulocytosis resulting in Erfe-deficient mice reaching wild-type hemoglobin levels by day 28 (figure). Figure 1 Figure 1. At the other end of the spectrum, we showed that thalassemic mice exhibited greatly increased expression of Erfe mRNA in the bone marrow and the spleen. Ablation of Erfe in Th3/+ mice restored normal hepcidin levels and significantly reduced serum iron concentration and hepatic iron overload at 6 weeks of age. Comparison of Erfe-/- / Th3/+ and Th3/+ mice at 3, 6 and 12 weeks of age did not show any difference in the severity of the anemia in absence of ERFE suggesting that ERFE regulates hepcidin expression but its absence did not cause iron restriction and did not ameliorate ineffective erythropoiesis. Conclusion: ERFE is a critical regulator of hepcidin expression during recovery from AI and ERFE agonists may alleviate iron restriction in AI. ERFE may also be the factor responsible for hepcidin suppression and secondary iron overload in β-thalassemia. Disclosures Ganz: Intrinsic LifeSciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Keryx Pharma: Consultancy; Merganser Biotech: Consultancy, Equity Ownership.

scholarly journals Administration of KER-047, a Novel ALK2 Inhibitor, Elicited Robust and Sustained Increases in Serum Iron in Healthy Participants

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-13
Author(s):  
Claudia Ordonez ◽  
Snyder Ben ◽  
Rachel Barger ◽  
Timna Serino ◽  
Claire C Tseng ◽  
...  
Keyword(s):  
Multiple Dose ◽  
Serum Iron ◽  
Phase 1 ◽  
Transferrin Saturation ◽  
Liquid Formulation ◽  
Publicly Traded ◽  
Hemoglobin Content ◽  
Phase 1 Study ◽  
The Past ◽  
Healthy Participants

Background: Hepcidin is the master regulator of iron homeostasis. Its expression is controlled, in part, by signaling through TGF-β receptors including activin receptor-like kinase-2 (ALK2). As part of a negative feedback loop, high hepcidin levels increase expression of matriptase-2, which cleaves the ALK2 co-receptor hemojuvelin from the cell surface and suppresses ALK2 signaling. Dysregulation of the negative feedback system results in high hepcidin, which mobilizes iron from storage tissues and leads to insufficient iron for red blood cell production in the bone marrow, resulting in anemia. KER-047 is a selective ALK2 inhibitor that has the potential to normalize ALK2 signaling and the downstream sequalae that results in anemia as a result of elevated hepcidin. Aims: The objective of this Phase 1 study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of single and multiple ascending dose levels of KER-047 in healthy participants. Methods: In Part 1, two formulations of KER-047 were evaluated in single ascending oral doses ranging from 1 mg to 300 mg of a capsule formulation, and 30 mg to 450 mg of a liquid formulation or placebo. In Part 2, the liquid formulation was evaluated in multiple ascending doses (50 mg, 100 mg, 200 mg and 350 mg) of KER-047 or placebo, administered daily for up to 7 days. Endpoints included adverse events (AEs) and pharmacokinetic and pharmacodynamic parameters. Informed consent was obtained from all participants prior to enrollment in the study. Results: Part 1 enrolled 80 participants; 60 received a single dose of KER-047 and 20 received placebo. Part 2 enrolled 41 participants; 32 received KER-047 and 9 received placebo daily for up to 7 days. There were no serious adverse events in either part of the study. In Part 1, 3 (9.4%) participants discontinued the study; none discontinued due to AEs. In Part 2, 3 (9.4%) participants administered KER-047 and 1 (11.1%) placebo discontinued the study; of these, 2 participants discontinued due to an AE (one in the 200 mg group and one on placebo). In Part 2, 1 of 8 (12.5%) administered 200 mg and 4 of 8 (50%) participants administered 350 mg discontinued study drug due to AEs. The majority of AEs observed in participants administered KER-047 were mild or moderate in severity; severe AEs were reported only at the 350 mg multiple dose in 1 of 8 (12.5%) participants. AEs reported in ≥2 of participants administered KER-047 and higher than placebo were: headache, nausea, vomiting, diarrhea, gastroenteritis, chills, pyrexia, myalgia, decreased appetite, lymphopenia, neutropenia, and liver enzyme increases. Decreases in lymphocyte and neutrophil counts were observed at 200 mg and 350 mg. Mean KER-047 AUC and Cmax increased linearly, with greater than dose-proportional increases observed across multiple doses from 50-200 mg. Half-life values ranged from approximately 10 to 15 hours. Administration of KER-047 elicited rapid, robust and sustained dose-related increases in serum iron and transferrin saturation. Increases in serum iron and transferrin saturation were observed beginning on Day 2 after single doses and were sustained after multiple doses. Decreases in ferritin were also observed. Decreases in serum hepcidin post-dose were also observed in all the multiple dose cohort in which changes were evaluated. Reticulocyte hemoglobin content increased starting on Day 3 post-dosing indicating increased iron availability in the bone marrow. Summary: In healthy participants, administration of KER-047 elicited rapid, robust and sustained dose-related increases in serum iron and transferrin saturation that were associated with decreases in ferritin and hepcidin. The observed decrease in ferritin and hepcidin coupled with increases in reticulocyte hemoglobin content are indicative of increased iron mobilization, resulting in increased iron incorporation into hemoglobin. The tolerability profile of KER-047 in healthy participants has been characterized in this Phase 1 study. KER-047's unique pharmacologic effect on hepcidin and iron mobilization has the potential to treat anemia that results from elevated hepcidin. Table Disclosures Ordonez: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company; Ackea Therapeutics: Ended employment in the past 24 months. Ben:Nucleus Network: Current Employment. Barger:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Serino:BioBridges: Ended employment in the past 24 months; Keros Therapeutics: Current Employment. Tseng:Mitobridge: Current equity holder in private company; Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Rovaldi:Keros Therapeutics: Consultancy. Lachey:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Seehra:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Selective Inhibition of ALK2 Signaling Suppresses Serum Hepcidin and Increases Serum Iron

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-14
Author(s):  
Thomas A Backus ◽  
Natalia Medeiros ◽  
Evan Lema ◽  
Ffolliott Fisher ◽  
Jasbir Seehra ◽  
...  
Keyword(s):  
Small Molecule ◽  
Serum Iron ◽  
Disease State ◽  
Deficiency Anemia ◽  
Publicly Traded ◽  
Multiple Modalities ◽  
Iron Mobilization ◽  
Bmp Receptors ◽  
Serum Hepcidin

Hepcidin is an endocrine regulator of iron metabolism that, when elevated, can decrease levels of iron available for erythropoiesis and, as a result, decrease red blood cell production. Signaling though activin-like kinase-2 (ALK2), a TGFβ type 1 receptor, has been implicated in regulation of hepcidin-mediated iron regulation and mobilization; however, to date, ALK2's specific degree of involvement has not been convincingly elucidated, mainly due to the redundant effects of the type 1 receptors ALK3 and ALK5. Activation of type 1 receptors including ALK2, ALK3, and ALK5 via ligand BMPs and co-receptor hemojuvelin (m-HJV), results in downstream SMAD phosphorylation, increased hepcidin, and decreased serum iron while suppression of the receptor signaling would have the opposite effects. In order to assess the specific effect of ALK2 inhibition on hepcidin and iron mobilization, we utilized multiple modalities of inhibition and tested inhibitors in both naive and diseased animals. KTI-2338, a small molecule ALK2 kinase inhibitor, has been characterized to inhibit ALK2 signaling potently and selectively in in-vitro assays. To further assess the specific contribution of ALK2 to hepcidin expression and iron mobilization, we evaluated the effect of the novel neutralizing antibody KTI-A2.0MAb. This fully human antibody is targeted against the extracellular domain of ALK2 with no affinity for the other type 1 receptors and provides a unique tool for understanding ALK2 involvement in this system. In wild-type animals, targeting ALK2 signaling with either a small molecule or biologic therapeutic leads to decreased serum hepcidin and increased serum iron. To assess the efficacy of ALK2 inhibition in a disease state, we utilized an siRNA-based model of Iron Refractory Iron Deficiency Anemia (IRIDA). In IRIDA, patients exhibit a loss of functional TMPRSS6, a gene that encodes the transmembrane type II serine protease Matriptase-2 (MT-2). MT-2 suppresses hepcidin secretion by cleaving m-HJV, interrupting ALK2 signaling and downstream SMAD activation. Failure to cleave m-HJV allows continued activation of BMPRs, increased hepcidin, and decreased serum iron. Phenocopying what is observed in IRIDA patients, intravenous dosing of TMPRSS6 targeted siRNA results in suppressed TMPRSS6 expression and functional MT-2, increases in serum hepcidin, and decreases in serum iron. Therapeutic dosing of either a small molecule or biologic ALK2 inhibitor in the siRNA based IRIDA model resulted in rescue of hemoglobin, hematocrit, serum hepcidin, and serum iron in the disease state. Following treatment, hemoglobin, hematocrit, and serum iron were increased and serum hepcidin was decreased in treated groups compared to control cohorts receiving vehicle. Herein, we have evaluated multiple modalities of ALK2 inhibition in both healthy and disease states. We have characterized that inhibition of ALK2 signaling via either modality in both naïve and anemic mice contributes to a decrease in serum hepcidin and increase in serum iron levels. Though the use of a selective ALK2 targeted biologic does not completely preclude involvement of other BMP receptors such as ALK3, these data support our assertion that ALK2 signaling is an integral part of hepcidin-mediated iron mobilization, and illustrate the potential therapeutic benefit of ALK2 inhibition (with a small molecule inhibitor or a neutralizing monoclonal antibody) in anemia of high hepcidin including IRIDA and anemia of inflammation. Disclosures Backus: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Medeiros:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lema:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Fisher:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Seehra:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lachey:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Serum Hepcidin: Its Correlation with Serum Ferritin, Serum Iron and Hemoglobin in Patients of Iron Deficiency Anemia

2015 ◽  
Vol 14 (2) ◽  
pp. 105-113
Author(s):  
Sajjad H. Naqvi ◽  
Syed Faizan-ul-Hassan Naqvi ◽  
Iftikhar H. Naqvi ◽  
Muhammad Farhan ◽  
Tanveer Abbas ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Serum Ferritin ◽  
Serum Iron ◽  
Deficiency Anemia ◽  
Serum Hepcidin

scholarly journals POS0567 HEPCIDIN IS POTENTIAL BIOMARKER TO DISTINGUISH BETWEEN IRON DEFICIENCY ANEMIA AND ANEMIA OF INFLAMMATION IN RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 518.2-518
Author(s):  
E. Galushko ◽  
A. Semashko ◽  
A. Gordeev ◽  
A. Lila
Keyword(s):  
Rheumatoid Arthritis ◽  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Complete Blood Count ◽  
Deficiency Anemia ◽  
Reactive Protein ◽  
Potential Biomarker ◽  
Serum Hepcidin ◽  
Proper Diagnosis ◽  
Anemia Of Inflammation

Background:Anemia of inflammation (AI) and iron deficiency anemia (IDA) are the two most prevalent forms of anemia in patients with rheumatoid arthritis (RA). Diagnosis becomes challenging if AI is associated with true ID (AI/ID), as there is still a lack of a gold standard for differentiation between AI and AI/ID. However, as therapies to overcome anemia differ, proper diagnosis and understanding of underlying pathophysiological regulations are necessary.Objectives:The aim of the study was to evaluate the clinical efficiency of hepcidin, a key regulator of iron metabolism, in the diagnosis of IDA, as well as the differential diagnosis of AI/ID and AI in patients with RA.Methods:The study was undertaken 96 patients with RA, 67 of them were diagnosed anemia according to WHO criteria (104,3±21,4 g/l). Anemic patients and anemia-free patients with RA (n=29) were comparable (p>0.05) in age (44.4±14.8 and 49.8±9.3 years), disease duration (73.5±65.4 and 59.8±48.3 months) and DAS28 (6.3±1.6 and 5.9±1.9). All cases were subjected to following tests: complete blood count with peripheral smear, serum C-reactive protein, serum interleukin-6, iron studies, serum soluble transferrin receptor (sTfR), and serum hepcidin. Patients with RA and anemia were divided two groups: 25 patients with IDA and 42 - with AI. The AI cases were subdivided into pure AI and AI with coexistent ID (n=15).Results:The mean serum hepcidin concentration was significantly increased in pure AI patients (123.85±25.8 ng/mL) as compared to those in IDA patients (63.9±22.8 ng/mL, P < 0.05) and anemia-free patients with RA (88.1±39.09 ng/mL). Also, compared to pure AI patients [normal sTfR levels (<3 µg/mL)], the serum hepcidin concentration was reduced significantly in AI patients with ID [high sTfR levels (≥3 µg/mL)] with a mean of 79.0±23.97 ng/mL.Conclusion:Hepcidin measurement can provide a useful tool for differentiating AI from IDA and also help to identify an iron deficiency in AI patients. This might aid in the appropriate selection of therapy for these patients.Disclosure of Interests:None declared

Anemia of Inflammation

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 276-280 ◽  
Author(s):  
Cindy N. Roy
Keyword(s):  
Inflammatory Diseases ◽  
Underlying Disease ◽  
Comorbid Condition ◽  
Regulatory Pathways ◽  
Hepcidin Expression ◽  
Disease States ◽  
Poor Outcomes ◽  
The Impact ◽  
Inflammatory Insult ◽  
Anemia Of Inflammation

Abstract Inflammation arising from various etiologies, including infection, autoimmune disorders, chronic diseases, and aging, can promote anemia. The anemia of inflammation (AI) is most often normocytic and normochromic and is usually mild. Characteristic changes in systemic iron handling, erythrocyte production, and erythrocyte life span all contribute to AI. The preferred treatment is directed at the underlying disease. However, when the inflammatory insult is intractable, or the cause has not been diagnosed, there are limited options for treatment of AI. Because anemia is a comorbid condition that is associated with poor outcomes in various chronic disease states, understanding its pathogenesis and developing new tools for its treatment should remain a priority. Hepcidin antimicrobial peptide has taken center stage in recent years as a potent modulator of iron availability. As the technology for quantitative hepcidin analysis improves, hepcidin's role in various disease states is also being revealed. Recent insights concerning the regulatory pathways that modify hepcidin expression have identified novel targets for drug development. As the field advances with such therapeutics, the analysis of the impact of normalized hemoglobin on disease outcomes will confirm whether anemia is a reversible independent contributor to the morbidity and mortality associated with inflammatory diseases.

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