Comparative evaluation of UBE3A-ATS targeting ASOs in a novel humanized mouse and human patient-derived models of Angelman syndrome [bulk_rnaseq_invivo]

ABSTRACT: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of maternal UBE3A. The paternal allele is normally silenced in neurons by the UBE3A antisense transcript (UBE3A-ATS). A promising therapeutic approach for AS is the use of antisense oligonucleotides (ASOs) targeting UBE3A-ATS. Standard cell and animal models are often unsuitable for testing human-specific ASO sequences, making it difficult to select the molecule that will provide the greatest therapeutic benefit to patients. To address this translational gap, we employed a multi-model pipeline, including patient-derived neurons, brain organoids, and a novel humanized mouse model to compare three ASOs directed at the same genetic target. Although all ASOs significantly downregulate UBE3A-ATS, we observed differences in efficacy and durability in restoring UBE3A mRNA and protein. Results from the precisely engineered mouse model were strikingly consistent with data from published non-human primate (NHP) studies. Collectively our findings establish a platform for the assessment of AS therapeutics, potentially reducing reliance on NHPs for some aspects of therapeutic development.

ORGANISM(S): Mus musculus

PROVIDER: GSE350739 | GEO | 2026/10/18

REPOSITORIES: GEO