Quantifying and mitigating motor phenotypes induced by antisense oligonucleotides in the central nervous system.

ABSTRACT: Antisense oligonucleotides (ASOs) are emerging as a promising class of therapeutics for neurological diseases. When injected directly into cerebrospinal fluid, ASOs distribute broadly across brain regions and exert long-lasting therapeutic effects. However, many phosphorothioate (PS)-modified gapmer ASOs show transient motor phenotypes when injected into the cerebrospinal fluid, ranging from reduced motor activity to ataxia or acute seizure-like phenotypes. Using a behavioral scoring assay customized to reflect the timing and nature of these effects, we show that both sugar and phosphate modifications influence acute motor phenotypes. Among sugar analogs, DNA induces the strongest motor phenotypes while 2'-substituted RNA modifications improve the tolerability of PS ASOs. Reducing the PS c

SUBMITTER: Moazami MP 

PROVIDER: S-EPMC11638874 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature