Cammack, Alexander J; Balendra, Rubika; Isaacs, Adrian M; (2024) Failure of C9orf72 sense repeat-targeting antisense oligonucleotides: lessons learned and the path forward. Brain , 147 (8) pp. 2607-2609. 10.1093/brain/awae168.

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Abstract

A G4C2 repeat expansion in the first intron of the C9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion is bidirectionally transcribed, producing both sense (G4C2) and antisense (G2C4) repeat RNAs, which are translated in every reading frame into five distinct dipeptide repeat proteins (DPRs).1 In addition, the presence of the repeat expansion causes reduced C9orf72 RNA and protein levels.1 Considerable evidence implicates gain-of-function mechanisms through toxicity of repetitive RNAs or DPRs as important drivers of disease. Therefore, the recent failure of two independent clinical trials targeting sense repeat-containing RNAs with antisense oligonucleotides (ASOs) was a great disappointment for the field. Here we discuss the data from these trials, possible reasons for the failures, and the future of C9orf72 therapeutic targeting moving forward.

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