Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice

被引:190
作者
Guo, Shuling [1 ]
Casu, Carla [2 ]
Gardenghi, Sara [2 ]
Booten, Sheri [1 ]
Aghajan, Mariam [1 ]
Peralta, Raechel [1 ]
Watt, Andy [1 ]
Freier, Sue [1 ]
Monia, Brett P. [1 ]
Rivella, Stefano [2 ,3 ]
机构
[1] ISIS Pharmaceut, Carlsbad, CA 92010 USA
[2] Weill Cornell Med Coll, Dept Pediat, Div Hematol Oncol, New York, NY 10021 USA
[3] Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10021 USA
关键词
INEFFECTIVE ERYTHROPOIESIS; IRON OVERLOAD; HEPCIDIN EXPRESSION; MOUSE MODEL; ERYTHROID-CELLS; DOWN-REGULATION; ANEMIA; TRANSFERRIN; HEMOJUVELIN; DIFFERENTIATION;
D O I
10.1172/JCI66969
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
beta-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 beta-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, beta-thalassemia, and related disorders.
引用
收藏
页码:1531 / 1541
页数:11
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