Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide.

ABSTRACT: Expansions of a G₄C₂ repeat in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating adult-onset neurodegenerative disorders. Using C9-ALS/FTD patient-derived cells and C9ORF72 BAC transgenic mice, we generated and optimized antisense oligonucleotides (ASOs) that selectively blunt expression of G₄C₂ repeat-containing transcripts and effectively suppress tissue levels of poly(GP) dipeptides. ASOs with reduced phosphorothioate content showed improved tolerability without sacrificing efficacy. In a single patient harboring mutant C9ORF72 with the G₄C₂ repeat expansion, repeated dosing by intrathecal delivery of the optimal ASO was well tolera

SUBMITTER: Tran H 

PROVIDER: S-EPMC8861976 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature