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• W4385667545 abstract "Topic: 29. Iron metabolism, deficiency and overload Background: Beta-thalassemia is a genetic disorder arising from loss-of-function mutations in the beta-globin gene, leading to ineffective erythropoiesis, high red blood cell (RBC) turnover, and organ iron overload. The latter contributes to liver fibrosis, type 2 diabetes, cancer, and cardiac toxicities. Iron loading is caused by a suppression of bone morphogenetic protein 6 (BMP6)-hemojuvelin (HJV) signaling. BMP6-HJV signaling induces hepcidin expression via SMAD1/5 and SMAD4 activation. The transmembrane serine protease 6 (TMPRSS6) negatively regulates this pathway by proteolytically degrading HJV. Individuals with homozygous loss-of-function mutations in the TMPRSS6 gene have iron-restricted/iron-deficiency anemia and show high levels of circulating hepcidin. Thus, blocking TMPRSS6 may be a viable strategy to elevate hepcidin levels in beta-thalassemia to limit iron absorption and reduce organ iron overload. We generated a monoclonal antibody (REGN7999) that inhibits TMPRSS6 activity, to prevent HJV cleavage, that accentuate BMP6-HJV signaling, and consequently increases serum hepcidin. Aims: The aim of the study was to investigate the effect of TMPRSS6 blockade using REGN7999 in a mouse model of beta-thalassemia and in non-human primates (NHPs, cynomolgus monkey). Methods: For all mouse studies we used Hbbth3/+ mice and injected an isotype control antibody or REGN7999 or ACVR2B(L79D)-Fc (luspatercept) for up to 12 weeks (10 mg/kg, subcutaneously, weekly). RBC health in mice was determined using annexin V and reactive oxygen staining as well as determining the turnover via biotin-labeling of RBCs. Furthermore, we used forced exercise to determine functional RBC improvement. Studies in NHPs were limited to a single dose,with serum iron and antibody levels evaluated up to 8 weeks post dose (doses: 5 and 15 mg/kg). Results: Treatment with REGN7999 led to significant reduction in liver iron in Hbbth3/+ mice (~50% reduction compared to the isotype-treated group), and improved RBC health as determined by reduced annexin V staining and RBC turnover. This improvement of RBCs was reflected by a longer running distance and a reduction in serum lactate produced during forced running. Luspatercept increased hemoglobin levels, whereas REGN7999 restored red blood cell levels and reduced liver iron and improved RBC health. In NHPs, REGN7999 reduced serum iron levels up to 6 weeks after a single dose. Summary/Conclusion: Our data showed that targeting TMPRSS6 has significant advantages over current treatments such as luspatercept, or iron chelation. These therapeutics only target either RBC formation (luspatercept) or iron loading (iron chelators), but not both. Our results indicate that inhibition of TMPRSS6 may be a good addition to current therapeutic options for iron overload diseases such as beta-thalassemia, as it significantly reduces liver iron loading and significantly improves RBC health. Keywords: beta thalassemia, Red blood cell, Erythropoieisis, Iron overload" @default.
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• W4385667545 date "2023-08-01" @default.
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• W4385667545 title "S281: TMPRSS6 INHIBITION WITH A MONOCLONAL ANTIBODY IMPROVES RED BLOOD CELL HEALTH AND IRON OVERLOAD IN A MOUSE MODEL OF BETA-THALASSEMIA" @default.
• W4385667545 doi "https://doi.org/10.1097/01.hs9.0000968036.49896.27" @default.
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