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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Figure 5

Tmprss6-ASO treatment in th3/+ mice improved IE.

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Tmprss6-ASO treatment in th3/+ mice improved IE. (A) FACS analysis to...
(A) FACS analysis to discriminate different stages of erythroid differentiation in the spleen using the Ter119 and CD44 antibodies. This assay allows the separation of erythroid cells into distinct populations corresponding to proerythroblasts (fraction I), basophilic (II), polychromatic (III), orthochromatic cells, and reticulocytes (IV), and mature rbc (V). Absolute numbers of the different stages of erythroid cells are shown in the spleen in male (A) and female mice (B) and in the BM in male (C) and female mice (D). (E) TAU gel electrophoresis. (F) ROS analysis by FACS, showing a representative sample of the percentage of ROS-positive cells in fraction V. Results represent mean ± SD. n = 4 for male mice in each group; n = 4 and 5 for female mice in control and treatment groups, respectively. *P < 0.05; **P < 0.01 by Student’s t test when treatment group was compared with vehicle control group.