biostudies-literatureUnknown53(16)Jagasia RF. Hoffmann-La Roche LtdAngelman 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 nucleic 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 ∼90% knock-down for 50% upregulation. Two studies of up to three lumbar intrathecal (IT) rugonersen 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.Nucleic acids researchgkaf851https://www.ebi.ac.uk/biostudies/studies/S-EPMC12397906biostudies-literatureAngelman syndrome patient-derived neuron screen leads to clinical ASO rugonersen targeting UBE3A-ATS with long-lasting effect in monkeys.PMC12397906Muller LWang CPrasad MBadillo SChamberlain SJoenson LHipp JFBon CPatsch CKremer TMiller MTBuchy DPedersen LJagasia RRasmussen SVTerrigno MKoller EBraendli-Baiocco ABerrera MPandya NJHoener MCTehler DErichsen KDBonni ACosta VfalseAngelman syndrome patient-derived neuron screen leads to clinical ASO rugonersen targeting UBE3A-ATS with long-lasting effect in monkeys.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 nucleic 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 ∼90% knock-down for 50% upregulation. Two studies of up to three lumbar intrathecal (IT) rugonersen 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.2025-01-01T00:00:00Z2025 Aug2026-05-29T22:08:41.073Z2026-04-08T06:13:18.037ZS-EPMC123979064088439710.1093/nar/gkaf851