Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration

The most frequent genetic cause of ALS and frontotemporal degeneration is a hexanucleotide expansion in a noncoding region of the C9orf72 gene. Similar to other repeat expansion diseases, we characterize the hallmark feature of repeat expansion RNA-mediated toxicity: nuclear RNA foci. Remarkably, two distinct sets of foci are found, one containing RNAs transcribed in the sense direction and the other containing antisense RNAs. Antisense oligonucleotides (ASOs) are developed that selectively target sense strand repeat-containing RNAs and reduce sense-oriented foci without affecting overall C9orf72 expression. Importantly, reducing C9orf72 expression does not cause behavioral or pathological changes in mice and induces only a few genome-wide mRNA alterations. These findings establish ASO-mediated degradation of repeat-containing RNAs as a significant therapeutic approach.