Reducing TMPRSS6 ameliorates hemochromatosis and beta-thalassemia in mice

Brett Monia and Stefano Rivella discuss how reduction of TMPRSS6 expression with antisense oligonucleotides ameliorates iron metabolism disorders in mice. Highlights:

  • Iron metabolism is a complex and heavily regulated process that is required for basic physiological functions, including hematopoiesis and host immune responses.
  • Hemochromatosis and β-thalassemia are iron overload disorders caused by low levels of hepcidin, the hormone that regulates iron absorption.
  • Antisense oligonucleotides (ASOs) lowered Tmprss6 RNA and elevated hepcidin levels.
  • TMPRSS6 ASO treatment reversed anemia and iron overload in a mouse model of β-thalassemia.

Published March 25, 2013, by The JCI

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Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice
Shuling Guo, … , Brett P. Monia, Stefano Rivella
Shuling Guo, … , Brett P. Monia, Stefano Rivella
Published March 25, 2013
Citation Information: J Clin Invest. 2013;123(4):1531-1541. https://doi.org/10.1172/JCI66969.
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Research Article

Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice

Abstract

β-Thalassemia and HFE-related hemochromatosis are 2 of the most frequently inherited disorders worldwide. Both disorders are characterized by low levels of hepcidin (HAMP), the hormone that regulates iron absorption. As a consequence, patients affected by these disorders exhibit iron overload, which is the main cause of morbidity and mortality. HAMP expression is controlled by activation of the SMAD1,5,8/SMAD4 complex. TMPRSS6 is a serine protease that reduces SMAD activation and blocks HAMP expression. We identified second generation antisense oligonucleotides (ASOs) targeting mouse Tmprss6. ASO treatment in mice affected by hemochromatosis (Hfe–/–) significantly decreased serum iron, transferrin saturation and liver iron accumulation. Furthermore, ASO treatment of mice affected by β-thalassemia (HBBth3/+ mice, referred to hereafter as th3/+ mice) decreased the formation of insoluble membrane-bound globins, ROS, and apoptosis, and improved anemia. These animals also exhibited lower erythropoietin levels, a significant amelioration of ineffective erythropoiesis (IE) and splenomegaly, and an increase in total hemoglobin levels. These data suggest that ASOs targeting Tmprss6 could be beneficial in individuals with hemochromatosis, β-thalassemia, and related disorders.

Authors

Shuling Guo, Carla Casu, Sara Gardenghi, Sheri Booten, Mariam Aghajan, Raechel Peralta, Andy Watt, Sue Freier, Brett P. Monia, Stefano Rivella

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