{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T21:57:01Z","timestamp":1793051821116,"version":"4.5.0"},"reference-count":77,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"688","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,3,22]]},"abstract":"<jats:p>\n                    Angelman syndrome is a devastating neurogenetic disorder for which there is currently no effective treatment. It is caused by mutations or epimutations affecting the expression or function of the maternally inherited allele of the ubiquitin-protein ligase E3A (\n                    <jats:italic>UBE3A<\/jats:italic>\n                    ) gene. The paternal\n                    <jats:italic>UBE3A<\/jats:italic>\n                    allele is imprinted in neurons of the central nervous system (CNS) by the\n                    <jats:italic>UBE3A<\/jats:italic>\n                    antisense (\n                    <jats:italic>UBE3A-AS<\/jats:italic>\n                    ) transcript, which represents the distal end of the small nucleolar host gene 14 (\n                    <jats:italic>SNHG14<\/jats:italic>\n                    ) transcription unit. Reactivating the expression of the paternal\n                    <jats:italic>UBE3A<\/jats:italic>\n                    allele in the CNS has long been pursued as a therapeutic option for Angelman syndrome. Here, we described the development of an antisense oligonucleotide (ASO) therapy for Angelman syndrome that targets an evolutionarily conserved region demarcating the start of the\n                    <jats:italic>UBE3A-AS<\/jats:italic>\n                    transcript. We designed and chemically optimized gapmer ASOs targeting specific sequences at the start of the human\n                    <jats:italic>UBE3A-AS<\/jats:italic>\n                    transcript. We showed that ASOs targeting this region precisely and efficiently repress the transcription of\n                    <jats:italic>UBE3A-AS<\/jats:italic>\n                    , reactivating the expression of the paternal\n                    <jats:italic>UBE3A<\/jats:italic>\n                    allele in neurotypical and Angelman syndrome induced pluripotent stem cell\u2013derived neurons. We further showed that human-targeted ASOs administered to the CNS of cynomolgus macaques by lumbar intrathecal injection repress\n                    <jats:italic>UBE3A-AS<\/jats:italic>\n                    and reactivate the expression of the paternal\n                    <jats:italic>UBE3A<\/jats:italic>\n                    allele throughout the CNS. These findings support the advancement of this investigational molecular therapy for Angelman syndrome into clinical development (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/ClinicalTrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                    , NCT04259281).\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.abf4077","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T13:58:36Z","timestamp":1679493516000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":93,"title":["An ASO therapy for Angelman syndrome that targets an evolutionarily conserved region at the start of the\n                    <i>UBE3A-AS<\/i>\n                    transcript"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9146-3339","authenticated-orcid":true,"given":"Scott V.","family":"Dindot","sequence":"first","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"Department of Molecular and Cellular Medicine, College of Medicine, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"GeneTx Biotherapeutics LLC, Sarasota, FL 34233, USA."},{"name":"Research Department, Ultragenyx Pharmaceutical, Novato, CA 94949, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4919-4531","authenticated-orcid":true,"given":"Sarah","family":"Christian","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&amp;M University, College Station, TX 77843, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3699-0723","authenticated-orcid":true,"given":"William J.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&amp;M University, College Station, TX 77843, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allyson","family":"Berent","sequence":"additional","affiliation":[{"name":"GeneTx Biotherapeutics LLC, Sarasota, FL 34233, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5292-5836","authenticated-orcid":true,"given":"Jennifer","family":"Panagoulias","sequence":"additional","affiliation":[{"name":"GeneTx Biotherapeutics LLC, Sarasota, FL 34233, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6555-8270","authenticated-orcid":true,"given":"Annalise","family":"Schlafer","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&amp;M University, College Station, TX 77843, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6973-6003","authenticated-orcid":true,"given":"Johnathan","family":"Ballard","sequence":"additional","affiliation":[{"name":"Texas A&amp;M Institute for Genomic Medicine (TIGM), Texas A&amp;M University, College Station, TX 77843, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8770-8834","authenticated-orcid":true,"given":"Kamelia","family":"Radeva","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8554-0994","authenticated-orcid":true,"given":"Luke","family":"Myers","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0097-8968","authenticated-orcid":true,"given":"Thomas","family":"Jepp","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&amp;M University, College Station, TX 77843, USA."},{"name":"School of Biosciences and Medicine, University of Surrey, Guildford GU2 7XH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3890-7727","authenticated-orcid":true,"given":"Hillary","family":"Shaheen","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&amp;M University, College Station, TX 77843, 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C.\u00a0A.\u00a0Williams \"Angelman syndrome \" in GeneReviews R.\u00a0A.\u00a0Pagon M.\u00a0P.\u00a0Adam T.\u00a0D.\u00a0Bird C.\u00a0R.\u00a0Dolan C.\u00a0T.\u00a0Fong R.\u00a0J.\u00a0H. Smith K.\u00a0Stephens Eds. 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T.\u00a0Crooke,Inhibition of splicing of wild-type and mutated luciferase-adenovirus pre-mRNAs by antisense oligonucleotides. Mol. Pharmacol.48,905\u2013918 (1995).","journal-title":"Mol. 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Med. Wieku Rozw.13,114\u2013122 (2009).","journal-title":"Med. 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