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Utrophin (\n                    <jats:italic>UTRN<\/jats:italic>\n                    ), the genetic and functional paralogue of\n                    <jats:italic>DMD<\/jats:italic>\n                    , is upregulated in some DMD patients\n                    <jats:sup>3\u20135<\/jats:sup>\n                    . To further investigate this\n                    <jats:italic>UTRN<\/jats:italic>\n                    upregulation, we first developed an inducible messenger RNA (mRNA) degradation system for\n                    <jats:italic>DMD<\/jats:italic>\n                    by introducing a premature termination codon (PTC) in one of its alternatively spliced exons. Inclusion of the PTC-containing exon triggers\n                    <jats:italic>DMD<\/jats:italic>\n                    mutant mRNA decay and\n                    <jats:italic>UTRN<\/jats:italic>\n                    upregulation. Notably, blocking nonsense-mediated mRNA decay results in the reversal of\n                    <jats:italic>UTRN<\/jats:italic>\n                    upregulation, whereas overexpressing\n                    <jats:italic>DMD<\/jats:italic>\n                    does not. Furthermore, overexpressing\n                    <jats:italic>DMD<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>PTC<\/jats:italic>\n                    <\/jats:sup>\n                    minigenes in wild-type cells causes\n                    <jats:italic>UTRN<\/jats:italic>\n                    upregulation, as does a wild-type\n                    <jats:italic>DMD<\/jats:italic>\n                    minigene containing a self-cleaving ribozyme. To place these findings in a therapeutic context, we used splice-switching antisense oligonucleotides (ASOs) to induce the skipping of out-of-frame exons of\n                    <jats:italic>DMD<\/jats:italic>\n                    , aiming to introduce PTCs. We found that these ASOs cause\n                    <jats:italic>UTRN<\/jats:italic>\n                    upregulation. In addition, when using an ASO to restore the\n                    <jats:italic>DMD<\/jats:italic>\n                    reading frame in myotubes derived from a\n                    <jats:italic>DMD<\/jats:italic>\n                    <jats:sup\/>\n                    patient, an actual DMD treatment,\n                    <jats:italic>UTRN<\/jats:italic>\n                    upregulation was reduced. Altogether, these results indicate that an mRNA decay-based mechanism called transcriptional adaptation\n                    <jats:sup>6\u20138<\/jats:sup>\n                    plays a key role in\n                    <jats:italic>UTRN<\/jats:italic>\n                    upregulation in\n                    <jats:italic>DMD<\/jats:italic>\n                    <jats:sup\/>\n                    patients, and they highlight an unexplored therapeutic application of ASOs, as well as ribozymes, in inducing genetic compensation via\u00a0transcriptional adaptation.\u00a0\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-08539-x","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T11:03:28Z","timestamp":1739358208000},"page":"493-502","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Transcriptional adaptation upregulates utrophin in Duchenne muscular dystrophy"],"prefix":"10.1038","volume":"639","author":[{"given":"Lara","family":"Falcucci","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Dooley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5062-2586","authenticated-orcid":false,"given":"Douglas","family":"Adamoski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9654-3717","authenticated-orcid":false,"given":"Thomas","family":"Juan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4454-3168","authenticated-orcid":false,"given":"Justin","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3215-427X","authenticated-orcid":false,"given":"Angelina M.","family":"Georgieva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamel","family":"Mamchaoui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cansu","family":"Cirzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0382-0026","authenticated-orcid":false,"given":"Didier Y. 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