Stormy Chamberlain Submitted:

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 in restoring UBE3A mRNA and protein. Strikingly, results from the humanized mouse model were consistent with data from non-human primate (NHP) studies. Collectively our findings establish a platform for the assessment of AS therapeutics and suggest that precisely engineered mouse models may be highly predictive of ASO performance, potentially reducing reliance on more complex NHP models.