title: 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 (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.
authors.affiliation: Isis Pharmaceuticals, Carlsbad, California 92010, USA.
authors.forename: Shuling
authors.initials: S
authors.lastname: Guo
authors.forename: Carla
authors.initials: C
authors.lastname: Casu
authors.forename: Sara
authors.initials: S
authors.lastname: Gardenghi
authors.forename: Sheri
authors.initials: S
authors.lastname: Booten
authors.forename: Mariam
authors.initials: M
authors.lastname: Aghajan
authors.forename: Raechel
authors.initials: R
authors.lastname: Peralta
authors.forename: Andy
authors.initials: A
authors.lastname: Watt
authors.forename: Sue
authors.initials: S
authors.lastname: Freier
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: Stefano
authors.initials: S
authors.lastname: Rivella
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D055785:Gene Knockdown Techniques; D006432:Hemochromatosis / Q000097:blood / Q000235:genetics / Q000628:therapy*; D000071020:Hemochromatosis Protein; D022781:Hepatocytes / Q000378:metabolism; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D014168:Transferrin / Q000378:metabolism; D017086:beta-Thalassemia / Q000097:blood / Q000235:genetics / Q000628:therapy*
chemical_list: D023181:Antimicrobial Cationic Peptides; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014168:Transferrin; D007501:Iron; D012697:Serine Endopeptidases; C467801:matriptase 2