Angelman syndrome patient-derived neuron screen leads to clinical ASO rugonersen targeting UBE3A-ATS with long-lasting effect in monkeys.

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 fr

SUBMITTER: Jagasia R 

PROVIDER: S-EPMC12397906 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature