{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T11:54:18Z","timestamp":1792756458219,"version":"4.5.0"},"reference-count":59,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2025,8,30]],"date-time":"2025-08-30T00:00:00Z","timestamp":1756512000000},"content-version":"vor","delay-in-days":3,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004337","name":"F. Hoffmann-La Roche Ltd","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004337","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of neuronal ubiquitin E3 ligase UBE3A, with no available treatment. Restoring UBE3A by downregulating the paternally cis-acting long noncoding antisense transcript (UBE3A-ATS) is a potentially disease modifying strategy. However, developing molecules targeting human UBE3A-ATS is challenging due to its selective expression in mature neurons and lack of sequence conservation across species. To overcome this, we screened a library of locked\u00a0nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) in AS patient-derived neurons. This let to the identification of rugonersen (RO7248824), which selectively and potently reduces UBE3A-ATS and upregulates UBE3A messenger RNA (mRNA) and protein in neurons derived from neurotypical humans, AS patients, and cynomolgus monkeys. In vivo studies with rugonersen or tool molecules in wild-type and AS mice, and cynomolgus monkeys revealed a steep relationship between Ube3a-ats knock-down and UBE3A mRNA\/protein upregulation, requiring \u223c90% knock-down for 50% upregulation. Two studies of up to three lumbar intrathecal (IT)\u00a0rugonersen doses in monkeys showed no adverse effects and produced long-lasting paternal UBE3A mRNA\/protein reactivation in key brain regions. In summary, we identified rugonersen, an ASO targeting UBE3A-ATS with excellent drug-like properties. Its sustained efficacy supports infrequent, IT dosing, and underlies its ongoing clinical development for AS.<\/jats:p>","DOI":"10.1093\/nar\/gkaf851","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T11:57:36Z","timestamp":1755172656000},"source":"Crossref","is-referenced-by-count":12,"title":["Angelman syndrome patient-derived neuron screen leads to clinical ASO rugonersen targeting\n                    <i>UBE3A<\/i>\n                    -ATS with long-lasting effect in monkeys"],"prefix":"10.1093","volume":"53","author":[{"given":"Ravi","family":"Jagasia","sequence":"first","affiliation":[{"name":"Roche Pharma Research and Early Development, Neuroscience and Rare Disease discovery and translational area, Roche Innovation Center Basel , Basel 4070 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Bon","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early 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