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Reactivating paternal\n                    <jats:italic>UBE3A<\/jats:italic>\n                    holds promise for treating AS. We previously showed topoisomerase inhibitors can reactivate paternal\n                    <jats:italic>UBE3A<\/jats:italic>\n                    , but their therapeutic challenges prompted our search for small molecule unsilencers with a different mechanism of action. Here, we found that (\n                    <jats:italic>S<\/jats:italic>\n                    )-PHA533533 acts through a novel mechanism to significantly increase paternal\n                    <jats:italic>Ube3a<\/jats:italic>\n                    mRNA and UBE3A protein levels while downregulating\n                    <jats:italic>Ube3a-ATS<\/jats:italic>\n                    in primary neurons derived from AS model mice. Furthermore, peripheral delivery of (\n                    <jats:italic>S<\/jats:italic>\n                    )-PHA533533 in AS model mice induces widespread neuronal UBE3A expression. Finally, we show that (\n                    <jats:italic>S<\/jats:italic>\n                    )-PHA533533 unsilences paternal\n                    <jats:italic>UBE3A<\/jats:italic>\n                    in AS patient-derived neurons, highlighting its translational potential. Our findings provide a lead for developing a small molecule treatment for AS that could be safe, non-invasively delivered, and capable of brain-wide unsilencing of paternal\n                    <jats:italic>UBE3A<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-49788-8","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T06:04:03Z","timestamp":1720418643000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Ube3a unsilencer for the potential treatment of Angelman syndrome"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6128-636X","authenticated-orcid":false,"given":"Hanna","family":"Vihma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5629-8589","authenticated-orcid":false,"given":"Anna","family":"Welton-Arndt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5982-463X","authenticated-orcid":false,"given":"Audrey L.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3668-569X","authenticated-orcid":false,"given":"Kiran R.","family":"Bettadapur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7435-263X","authenticated-orcid":false,"given":"Rachel B.","family":"Gilmore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8230-2157","authenticated-orcid":false,"given":"Justin L.","family":"Cotney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsueh-Cheng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8086-1802","authenticated-orcid":false,"given":"Jon L.","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stormy J.","family":"Chamberlain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9381-3611","authenticated-orcid":false,"given":"Hyeong-Min","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Aub\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2746-9143","authenticated-orcid":false,"given":"Benjamin D.","family":"Philpot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,8]]},"reference":[{"key":"49788_CR1","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1002\/ajmg.1320600317","volume":"60","author":"MB Petersen","year":"1995","unstructured":"Petersen, M. 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No other parts of the project were supported by Pfizer. Pfizer reviewed and approved the manuscript submission, but did not contribute to the conceptualization, design, data collection, data analysis, or preparation of the manuscript. The authors do not have any other competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5558"}}