Splice-modulating antisense oligonucleotides targeting a pathogenic intronic variant in adult polyglucosan body disease correct mis-splicing and restore enzyme activity in patient cells.

ABSTRACT: Adult polyglucosan body disease (APBD) is a rare, adult-onset neurodegenerative disorder caused by loss-of-function variants in the glycogen branching enzyme (GBE1) gene, essential for glycogen biosynthesis. The second most common pathogenic mutation in APBD (c.2053-3358_2053-3350delinsTGTTTTTTACATGACAGGT) is a deep intronic deletion insertion (indel) variant creating an ectopic splice acceptor site, resulting in a mutant transcript with a pseudoexon encoding an unstable truncated protein. Such mutations can be effectively targeted with splice-modulating antisense oligonucleotides (ASOs) to restore normal splicing. Here, we characterized the indel in-depth using long-read sequencing techniques and discovered several new features of the mutant transcript. The indel sequence varies from the

SUBMITTER: Thomas R 

PROVIDER: S-EPMC12266137 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature