Authors
Hien T Zhao, Jill O'Moore, Daniel A Sprague, Juliana E Gentile, Sagar Damle, Briana Noble, Taylor L Corridon, Simone Lord, Jason Le, Samantha Graffam, Michael Howard, Kendrick DeSouza-Lenz, Hongda Li, John Matson, Susan Li, Stephanie Klein, Tyler Caron, Alissa A Coffey, Sonia M Vallabh, Holly B Kordasiewicz, Andrea Grindeland Panter, Eric Vallabh Minikel
Published in
Nucleic acid therapeutics. Pages 21593337261494829. Oct 10, 2026. Epub Oct 10, 2026.
Abstract
Some, but not all, gapmer antisense oligonucleotides (ASOs) delivered into cerebrospinal fluid exhibit fatal subacute toxicity in late-stage prion-infected mice but not in uninfected mice. Here, we performed a battery of in vivo studies demonstrating that the toxicity is compound- and disease- stage-dependent, and not predicted by behavioral or molecular measurements in uninfected animals. A panel of toxic ASOs all elicited a consistent transcriptomic response signature in prion-infected mice, which emerged over the course of 7 days post dose. This signature, driven chiefly by decreased expression of a specific set of astrocyte-expressed genes, was absent in uninfected mice receiving the same ASOs, was absent, less intense, and/or more transient in infected mice receiving tolerated ASOs, and was distinct from the transcriptomic effect of prion disease itself. Our data argue that the toxicity is an interaction between ASO and prion disease at high doses for specific compounds, and does not represent an exacerbation of ASO toxicity nor of prion disease.
PMID:
42856037
Bibliographic data and abstract were imported from PubMed on 10 Oct 2026.
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