{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T10:15:42Z","timestamp":1791281742360,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T00:00:00Z","timestamp":1606435200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\u03b2\u2010thalassemias result from mutations in \u03b2\u2010globin, causing ineffective erythropoiesis and secondary iron overload due to inappropriately low levels of the iron regulatory hormone hepcidin. Mutations in transferrin receptor 2 (TFR2) lead to hereditary hemochromatosis (HH) as a result of inappropriately increased iron uptake from the diet, also due to improperly regulated hepcidin. TFR2 is also thought to be required for efficient erythropoiesis through its interaction with the erythropoietin receptor in erythroid progenitors. Transmembrane serine protease 6 (TMPRSS6)<jats:italic>,<\/jats:italic>a membrane serine protease expressed selectively in the liver, participates in regulating hepcidin production in response to iron stores by cleaving hemojuvelin (HJV). We have previously demonstrated that inhibiting<jats:italic>TMPRSS6<\/jats:italic>expression with a hepatocyte\u2010specific siRNA formulation, induces hepcidin, mitigates anemia, and reduces iron overload in murine models of \u03b2\u2010thalassemia intermedia and HH. Here, we demonstrate that<jats:italic>Tmprss6<\/jats:italic>siRNA treatment of double mutant<jats:italic>Tfr2<\/jats:italic><jats:sup>Y245X\/Y245X<\/jats:sup>HH<jats:italic>Hbb<\/jats:italic><jats:sup>th3\/+<\/jats:sup>thalassemic mice induces hepcidin and diminishes tissue and serum iron levels. Importantly, treated double mutant animals produce more mature red blood cells and have a nearly 50% increase in hemoglobin compared to untreated \u03b2\u2010thalassemic mice. Furthermore, we also show that treatment of<jats:italic>Tfr2<\/jats:italic><jats:sup>Y245X\/Y245X<\/jats:sup>HH mice leads to increased hepcidin expression and reduced total body iron burden. These data indicate that siRNA suppression of<jats:italic>Tmprss6<\/jats:italic>, in conjunction with the targeting of TFR2, may be superior to inhibiting<jats:italic>Tmprss6<\/jats:italic>alone in the treatment of the anemia and secondary iron loading in \u03b2\u2010thalassemia intermedia and may be useful as a method of suppressing the primary iron overload in TFR2\u2010related (type 3) hereditary hemochromatosis.<\/jats:p>","DOI":"10.1002\/ajh.26048","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T18:35:32Z","timestamp":1605206132000},"page":"251-257","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Global loss of Tfr2 with concomitant induced iron deficiency greatly ameliorates the phenotype of a murine thalassemia intermedia model"],"prefix":"10.1002","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6978-0656","authenticated-orcid":false,"given":"Paul J.","family":"Schmidt","sequence":"first","affiliation":[{"name":"Department of Pathology Boston Children's Hospital and Harvard Medical School Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Fitzgerald","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals, Inc. Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S.","family":"Butler","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals, Inc. Cambridge Massachusetts USA"},{"name":"Current: Intellia Therapeutics, Inc. 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