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