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Antisense oligonucleotides (ASOs) influence protein expression by sequence-specific binding of RNA, resulting in targeted degradation or alternative splicing, and thereby provide a promising avenue for clinical therapeutics. Angelman Syndrome (AS), caused by loss-of-function of maternal\n                    <jats:italic>UBE3A<\/jats:italic>\n                    , has emerged as a monogenic neurodevelopmental disorder for which ASO therapy might be particularly amenable due to genomic imprinting. In an AS mouse model,\n                    <jats:italic>Ube3a<\/jats:italic>\n                    reactivation of the paternal allele using ASOs has been previously shown to rescue disease-relevant phenotypes. However, the poor sequence homology between murine and human\n                    <jats:italic>UBE3A-ATS<\/jats:italic>\n                    requires a human model system for screening of ASOs with clinical therapeutic potential. Here we evaluate an ASO targeting\n                    <jats:italic>UBE3A-ATS<\/jats:italic>\n                    using human induced pluripotent stem cell (hiPSC)-derived AS neurons in vitro and in vivo\n                    <jats:italic>.<\/jats:italic>\n                    We assessed the effect of ASO-treatment on cultured AS patient hiPSC-derived neurons through protein and RNA expression analysis. To increase clinical translatability, we designed a platform to evaluate this ASO in vivo by xenotransplantation of hiPSC-derived AS neurons into the brains of neonatal mice, with intracerebroventricular administration of the\n                    <jats:italic>UBE3A-ATS<\/jats:italic>\n                    ASO three weeks later. One week after ASO treatment, we observed in vivo reinstatement of\n                    <jats:italic>UBE3A<\/jats:italic>\n                    expression in xenotransplanted human neurons. These results highlight the potential for a versatile platform to evaluate efficacy of human-specific ASOs, for which AS provides an instructive proof-of-concept for therapeutic reactivation of UBE3A.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-41197-9","type":"journal-article","created":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T14:48:49Z","timestamp":1772290129000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A xenotransplantation model for reactivation of paternal UBE3A using human-specific antisense oligonucleotides"],"prefix":"10.1038","volume":"16","author":[{"given":"Hilde","family":"Smeenk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bas","family":"Lendemeijer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirle G.","family":"Buurma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michell A.","family":"Forgione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise E.","family":"Slump","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roos A.","family":"Monshouwer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilse","family":"Wallaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin J.","family":"Mientjes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Witte J. 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In addition, all mouse experiments were conducted in accordance with ARRIVE guidelines and the European Commission Council Directive 2010\/63\/EU. We obtained national and local approval under CCD license AVD1010020173544 and AVD10100202215931 (Centrale Commissie Dierproeven, the Hague, the Netherlands).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"11443"}}