Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice

• Published in: The Journal of clinical investigation Vol. 123; no. 4; pp. 1531 - 1541
• Main Authors: Guo, Shuling, Casu, Carla, Gardenghi, Sara, Booten, Sheri, Aghajan, Mariam, Peralta, Raechel, Watt, Andy, Freier, Sue, Monia, Brett P, Rivella, Stefano
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-04-2013
• Subjects: Animals; Antimicrobial Cationic Peptides - genetics; Antimicrobial Cationic Peptides - metabolism; Antisense drugs; beta-Thalassemia - blood; beta-Thalassemia - genetics; beta-Thalassemia - therapy; Care and treatment; Cells, Cultured; Female; Gene Knockdown Techniques; Genetic aspects; Health aspects; Hemochromatosis; Hemochromatosis - blood; Hemochromatosis - genetics; Hemochromatosis - therapy; Hemochromatosis Protein; Hepatocytes - metabolism; Hepcidins; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; Iron - blood; Iron - metabolism; Liver - metabolism; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotides, Antisense - genetics; Proteases; RNA, Messenger - genetics; RNA, Messenger - metabolism; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Spleen - metabolism; Spleen - pathology; Thalassemia; Transferrin - metabolism; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI66969

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 (HBB(th3/+) 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.