Predicting ASO Neurotoxicity and Efficacy in CNS-3D Brain Organoids

November 5, 2026 | 8:00 AM PT / 11:00 AM ET / 5:00 PM CET‍

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Developing successful antisense oligonucleotide (ASO) therapies requires identifying sequences that combine strong target knockdown with low neurotoxicity. Unfortunately, preclinical models often fall short, as species-specific RNA sequences can limit assessment of human target activity in animal models, while conventional in vitro assays may miss acute neurotoxic liabilities.

In this webinar, we’ll show how 28bio CNS-3D Brain Organoids enable integrated evaluation of ASO neurotoxicity and target knockdown in a single human model. High-throughput calcium imaging detects ASO-induced changes in network activity, identifying neurotoxicity risk with greater accuracy than sequence-based and 2D methods. Together with qPCR-based assessment of target knockdown, this approach helps researchers prioritize candidates based on both functional tolerability and target activity.‍

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Key Takeaways‍

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•  ASO neurotoxicity prediction outperforms sequence-based and 2D methods: 92% sensitivity and 92% specificity across 24 ASOs, enabling confident identification of neurotoxic liabilities while minimizing false positives.
• Clinical ASO assessment: Nusinersen and tofersen show low predicted acute neurotoxicity alongside measurable target knockdown.
• Integrated safety and target activity assessment: Evaluate ASO-mediated target knockdown alongside neurotoxicity in the same human organoid model.

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Speaker‍

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Nicholas Coungeris, Research Scientist II at 28bio

Nick Coungeris has over 10 years of experience developing human iPSC-based neural models. His work focuses on advancing 28bio CNS-3D Technology for neurotoxicity prediction, disease modeling, and efficacy testing, including the recent development of brain organoids containing microglia for studying neuroinflammation and anti-inflammatory efficacy.‍

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