Unraveling and controlling late-onset neurotoxicity of antisense oligonucleotides through strategic chemical modifications.

ABSTRACT: Antisense oligonucleotides (ASOs) represent an attractive therapeutic approach for CNS disorders. However, ASO-induced neurotoxicity, especially late-onset adverse events, remains a crucial issue, leading to failures in clinical applications. This study aims to determine the neurological features and molecular mechanisms of the late-onset neurotoxicity and provide strategies to overcome this toxicity. We initially established neurobehavioral assays of rodent neurotoxicity with intracerebroventricular and intrathecal injections of various gapmer-type ASOs and a neuronal cytotoxicity analysis. Through both in vitro and in vivo assessments, we identified a site-specific chemical modification, 5'-cyclopropylene (5'-CP), that significantly reduced late-onset neurotoxicity without

SUBMITTER: Kuroda T 

PROVIDER: S-EPMC12744863 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature