{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T05:52:51Z","timestamp":1775886771851,"version":"3.50.1"},"reference-count":44,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Myotonic dystrophy type 1 (DM1) is a highly variable, multisystemic genetic disorder caused by a CTG repeat expansion in the 3\u2032 untranslated region of\n                      <jats:italic>DMPK.<\/jats:italic>\n                      Toxicity is exerted by repeat\u2010containing\n                      <jats:italic>DMPK<\/jats:italic>\n                      transcripts that sequester muscleblind\u2010like (MBNL) proteins and lead to deleterious yet predictable changes in alternative splicing. To contend with high phenotypic and molecular variability that complicate application of viral\u2010based therapies, we develop and test a DM1\u2010responsive genetic element to control viral\u2010based therapeutic output.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used MBNL\u2010dependent cassette exons to generate adeno\u2010associated virus (AAV)\u2010compatible control elements (DMX\n                      <jats:sup>on<\/jats:sup>\n                      ). Minigenes were tested in vitro using a Dox\u2010inducible MBNL1 cell model and induced pluripotent stem cell (iPSC)\u2010derived DM1 myotubes and in vivo using DM1 model mice following intramuscular and systemic AAV injection. DMX\n                      <jats:sup>on<\/jats:sup>\n                      splicing, correction of endogenous splicing or skeletal muscle myotonia, and prevention of cardiac toxicity associated with therapeutic MBNL1 overexpression were assessed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      DMX\n                      <jats:sup>on<\/jats:sup>\n                      cassettes respond to MBNL1 dose or expression of CUG repeat RNA. DMX\n                      <jats:sup>on<\/jats:sup>\n                      controlled expression of therapeutic MBNL1 protein can improve skeletal muscle myotonia or prevent cardiac toxicity due to MBNL1 overexpression in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      DMX\n                      <jats:sup>on<\/jats:sup>\n                      control elements can increase the therapeutic window of viral\u2010based therapeutics in DM1, and activity is dependent upon delivered cargo and model severity. ANN NEUROL 2026;99:211\u2013222\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78024","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T11:11:42Z","timestamp":1756465902000},"page":"211-222","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Co\u2010Opting\n                    <scp>MBNL<\/scp>\n                    \u2010Dependent Alternative Splicing Cassette Exons to Control Gene Therapy in Myotonic Dystrophy"],"prefix":"10.1002","volume":"99","author":[{"given":"Samuel T.","family":"Carrell","sequence":"first","affiliation":[{"name":"Department of Neurology University of Pennsylvania  Philadelphia PA"},{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics The Children's Hospital of Philadelphia  Philadelphia PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellie M.","family":"Carrell","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics The Children's Hospital of Philadelphia  Philadelphia PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Giovenco","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics The Children's Hospital of Philadelphia  Philadelphia PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3715-6290","authenticated-orcid":false,"given":"Beverly L.","family":"Davidson","sequence":"additional","affiliation":[{"name":"Raymond G. Perelman Center for Cellular and Molecular Therapeutics The Children's Hospital of Philadelphia  Philadelphia PA"},{"name":"Department of Pathology and Laboratory Medicine University of Pennsylvania  Philadelphia PA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1706198"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26755"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-022-00683-z"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000213604"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.08.028"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-60497-8"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-60000-3"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adr2531"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03770-2"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab233"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-022-01224-2"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2022.10.023"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1212\/CON.0000000000001184"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.06.041"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.08.027"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00336.2006"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00563-4"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23992"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI185426"},{"key":"e_1_2_9_21_1","volume-title":"Myotonic dystrophy","author":"Harper PS","year":"2001"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0604970103"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI186416"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz065"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds306"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.123.066860"},{"issue":"4","key":"e_1_2_9_27_1","first-page":"18","article-title":"Development of dual AAV\u2010mediated RNAi and protein expression therapy for myotonic dystrophy [Abstract 35]","volume":"30","author":"Karolak M","year":"2022","journal-title":"Mol Ther"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab022"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.09.003"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1808303116"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006316"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl132"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy432"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5485.1769"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-021-00838-2"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddac254"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2016.97"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpsc.64"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/7651_2014_134"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00313-7"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00827-3"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33523-2"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz753"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1192128"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11362"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78024","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ana.78024","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T05:27:31Z","timestamp":1775885251000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.78024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,29]]},"references-count":44,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/ana.78024"],"URL":"https:\/\/doi.org\/10.1002\/ana.78024","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.01.23.634565","asserted-by":"object"}]},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,29]]},"assertion":[{"value":"2025-05-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}