{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T10:38:46Z","timestamp":1792147126254,"version":"4.4.0"},"reference-count":26,"publisher":"SAGE Publications","issue":"9","license":[{"start":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T00:00:00Z","timestamp":1472688000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">MCT8<\/jats:italic>\n                      gene mutations produce thyroid hormone (TH) deficiency in the brain, causing severe neuropsychomotor abnormalities not correctable by treatment with TH. This proof-of-concept study examined whether transfer of human\n                      <jats:italic toggle=\"yes\">MCT8<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">hMCT8<\/jats:italic>\n                      ) cDNA using adeno-associated virus 9 (AAV9) could correct the brain defects of Mct8 knockout mice (\n                      <jats:italic toggle=\"yes\">Mct8KO<\/jats:italic>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      AAV9 vectors delivering long and\/or short hMCT8 protein isoforms or an empty vector were injected intravenously (IV) and\/or intracerebroventricularly (ICV) into postnatal day 1\n                      <jats:italic toggle=\"yes\">Mct8KO<\/jats:italic>\n                      and wild type (\n                      <jats:italic toggle=\"yes\">Wt<\/jats:italic>\n                      ) mice. Triiodothyronine (T3) was given daily for four days before postnatal day 28, at which time brains were collected after perfusion to assess increase in T3 content and effect on the T3-responsive transcription factor,\n                      <jats:italic toggle=\"yes\">Hairless<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Increased pup mortality was observed after IV injection of the\n                      <jats:italic toggle=\"yes\">AAV9-long<\/jats:italic>\n                      hMCT8 isoform, but not after injection of\n                      <jats:italic toggle=\"yes\">AAV9-short<\/jats:italic>\n                      hMCT8 isoform. Compared to IV, ICV delivery produced more\n                      <jats:italic toggle=\"yes\">hMCT8<\/jats:italic>\n                      mRNA and protein relative to the viral dose, which was present in various brain regions and localized to the cell membranes. Despite production of abundant\n                      <jats:italic toggle=\"yes\">hMCT8<\/jats:italic>\n                      mRNA and protein with ICV delivery, only IV delivered\n                      <jats:italic toggle=\"yes\">AAV9-hMCT8<\/jats:italic>\n                      targeted the choroid plexus and significantly increased brain T3 content and expression of\n                      <jats:italic toggle=\"yes\">Hairless<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>These results indicate that MCT8 delivery to brain barriers by IV but not ICV injection is crucial for its proper function. MCT8 has no constitutive activity but acts through an increase in T3 entering the brain tissue. Increasing MCT8 expression in brain cell membranes, including neurons, is insufficient to produce an effect without an increase in brain T3 content. The correct hMCT8 isoform along with an optimized delivery method are critical for an effective gene therapy to provide functional MCT8 in the brain of patients with MCT8 mutations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2016.0060","type":"journal-article","created":{"date-parts":[[2016,7,18]],"date-time":"2016-07-18T22:57:06Z","timestamp":1468882626000},"page":"1311-1319","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":42,"title":["Adeno Associated Virus 9\u2013Based Gene Therapy Delivers a Functional Monocarboxylate Transporter 8, Improving Thyroid Hormone Availability to the Brain of Mct8-Deficient Mice"],"prefix":"10.1177","volume":"26","author":[{"given":"Hideyuki","family":"Iwayama","sequence":"first","affiliation":[{"name":"The University of Chicago"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Hui","family":"Liao","sequence":"additional","affiliation":[{"name":"The University of Chicago"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyndsey","family":"Braun","sequence":"additional","affiliation":[{"name":"Research Institute at Nationwide Children's Hospital"},{"name":"The Ohio State University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soledad","family":"B\u00e1rez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Consejo Superior de Investigaciones Cient\u00edficas-Universidad Aut\u00f3noma de Madrid","place":["Spain"]},{"name":"Instituto de Salud Carlos III","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Kaspar","sequence":"additional","affiliation":[{"name":"Research Institute at Nationwide Children's Hospital"},{"name":"The Ohio State University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy E.","family":"Weiss","sequence":"additional","affiliation":[{"name":"University of Miami"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra M.","family":"Dumitrescu","sequence":"additional","affiliation":[{"name":"The University of Chicago"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Guada\u00f1o-Ferraz","sequence":"additional","affiliation":[{"name":"Consejo Superior de Investigaciones Cient\u00edficas-Universidad Aut\u00f3noma de Madrid","place":["Spain"]},{"name":"Instituto de Salud Carlos III","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Refetoff","sequence":"additional","affiliation":[{"name":"The University of Chicago"},{"name":"The University of Chicago"},{"name":"The University of Chicago"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2016,9,1]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300909200"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/380999"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)17226-7"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.2009.03471.x"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1177\/0883073814555189"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-2162"},{"key":"e_1_3_3_8_2","first-page":"325","article-title":"Some examples of the inheritance of mental deficiency: apparently sex-linked idiocy and microcephaly","volume":"48","author":"Allan W","year":"1944","unstructured":"Allan W, , Herndon CN, , Dudley FC. 1944. 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