Antisense Oligonucleotides that Are Toxic to Prion-Infected Mice Share an Emergent Mechanism

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.