Figure 7. Sustained reduction in RNA foci and DPR proteins from a single dose of ASOs targeting C9ORF72 repeat-containing RNAs.

(A) Schematic of injected ASOs targeting the sense strand C9ORF72 transcripts for degradation in 3 month old C9^450B mice. (B) Schematic of the C9ORF72 gene showing the GGGGCC repeats within the first intron, the two transcription initiation sites (arrows), the positions of five ASOs, and primers for detection (by qRT-PCR) of various C9ORF72 RNAs. (C–E) Expression of (C) repeating-containing, (D) total and (E) exon 1b-containing C9ORF72 RNAs determined by qRT-PCR in mice treated either with ASO1 targeting only the repeat-containing RNAs, ASO2 targeting all C9orf72 variants, or a control ASO. (F) Number of sense and antisense foci (per 100 nuclei) determined by FISH and (G) quantification of sense foci per nucleus in hippocampal dentate gyrus. (H–I) Levels of (H) poly(GP) or (I) poly(GA) in the cortex and spinal cord of C9^450B mice treated with ASO1, ASO2 or a control ASO, as measured by immunoassay. Error bars represent s.e.m in n=5–6 biological replicates. * p<0.05, ** p<0.01, n.s. not significant using one-way ANOVA.

(See also Figure S8).