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Although these results were predominantly positive, not all the patients showed the expected increase in hemoglobin (Hb) levels or transfusion burden reduction. Additional studies indicated that administration of luspatercept in transfusion\u2010dependent BT was associated with increased erythropoietic markers, decreased hepcidin levels, and increased liver iron content. Altogether, these studies suggest that luspatercept may necessitate additional drugs for improved erythroid and iron management. As luspatercept does not appear to directly affect iron metabolism, we hypothesized that\n                    <jats:italic>TMPRSS6<\/jats:italic>\n                    \u2010ASO could improve iron parameters and iron overload when co\u2010administered with luspatercept. We used an agent analogous to murine luspatercept (RAP\u2010GRL) and another novel therapeutic, IONIS TMPRSS6\u2010LRx (\n                    <jats:italic>TMPRSS6\u2010<\/jats:italic>\n                    ASO), a hepcidin inducer, to treat non\u2010transfusion\u2010dependent BT\u2010intermedia mice. Our study shows that RAP\u2010GRL alone improved red blood cell (RBC) production, with no or limited effect on splenomegaly and iron parameters. In contrast,\n                    <jats:italic>TMPRSS6\u2010<\/jats:italic>\n                    ASO improved RBC measurements, ameliorated splenomegaly, and improved iron overload most effectively. Our results provide pre\u2010clinical support for combining\n                    <jats:italic>TMPRSS6\u2010<\/jats:italic>\n                    ASO and luspatercept in treating BT, as these drugs together show potential for simultaneously improving both erythroid and iron parameters in BT patients.\n                  <\/jats:p>","DOI":"10.1002\/ajh.27332","type":"journal-article","created":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T03:19:35Z","timestamp":1714015175000},"page":"1300-1312","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Combination of a\n                    <scp>TGF<\/scp>\n                    \u2010\u03b2 ligand trap (\n                    <scp>RAP\u2010GRL<\/scp>\n                    ) and\n                    <scp>\n                      <i>TMPRSS6<\/i>\n                      \u2010ASO\n                    <\/scp>\n                    is superior for correcting \u03b2\u2010thalassemia"],"prefix":"10.1002","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6602-1854","authenticated-orcid":false,"given":"Amaliris","family":"Guerra","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nolan","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Rivera","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perry","family":"Demsko","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"},{"name":"Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Cell and Molecular Biology Affinity Group (CAMB) University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuling","family":"Guo","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc.  Carlsbad California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Rivella","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Pediatrics The Children's Hospital of Philadelphia (CHOP)  Philadelphia Pennsylvania USA"},{"name":"Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Cell and Molecular Biology Affinity Group (CAMB) University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics\u2010CHOP  Philadelphia Pennsylvania USA"},{"name":"Penn Center for Musculoskeletal Disorders, CHOP  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,4,25]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(17)31822\u20106"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910182"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352\u20103026(22)00208\u20103"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.27102"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hoc.2017.11.009"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/HS9.0000000000000208"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102011\u201003\u2010283614"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0268\u2010960X(12)70005\u2010X"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102018\u201007\u2010815928"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2014.114827"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2023.283057"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2996"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24888"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102018\u201006\u2010857995"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022019195"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30247"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102012\u201001\u2010405563"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102006\u201009\u2010048868"},{"key":"e_1_2_9_20_1","volume-title":"Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT)","author":"Cappellini MD","year":"2014"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2015.133348"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.13820"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI66969"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102012\u201009\u2010453977"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.23934"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102012\u201001\u2010401885"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019004719"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12325\u2010022\u201002421\u2010w"},{"key":"e_1_2_9_29_1","unstructured":"Endpoints News.Ionis chops two PhII programs in acromegaly and beta thalassemia. 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