{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["53(16)"],"submitter":["Jagasia R"],"funding":["F. Hoffmann-La Roche Ltd"],"pubmed_abstract":["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."],"journal":["Nucleic acids research"],"pagination":["gkaf851"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12397906"],"repository":["biostudies-literature"],"pubmed_title":["Angelman syndrome patient-derived neuron screen leads to clinical ASO rugonersen targeting UBE3A-ATS with long-lasting effect in monkeys."],"pmcid":["PMC12397906"],"pubmed_authors":["Muller L","Wang C","Prasad M","Badillo S","Chamberlain S","Joenson L","Hipp JF","Bon C","Patsch C","Kremer T","Miller MT","Buchy D","Pedersen L","Jagasia R","Rasmussen SV","Terrigno M","Koller E","Braendli-Baiocco A","Berrera M","Pandya NJ","Hoener MC","Tehler D","Erichsen KD","Bonni A","Costa V"],"additional_accession":[]},"is_claimable":false,"name":"Angelman syndrome patient-derived neuron screen leads to clinical ASO rugonersen targeting UBE3A-ATS with long-lasting effect in monkeys.","description":"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.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Aug","modification":"2026-05-29T22:08:41.073Z","creation":"2026-04-08T06:13:18.037Z"},"accession":"S-EPMC12397906","cross_references":{"pubmed":["40884397"],"doi":["10.1093/nar/gkaf851"]}}