Figure 1: Chronic ASO treatment reduces somatic instability in mutant Htt’s CAG repeat and reduces Htt transcriptional rate in the livers of Htt^Q111/+ mice.

A) Overview of peripheral ASO administration mouse cohorts. B) Chronic ASO treatment reduces levels of both wildtype (63% reduction; p = 0.001) and mutant HTT (54% reduction; p = 0.086) in the liver, as assayed with MSD at 14 months of age following 12 months of ASO treatment (N = 7–8 per arm). C) Total Htt mRNA, as assayed by qRT-PCR, is also reduced by chronic ASO treatment (94% reduction; p<0.0001). D) Exemplar traces of the size distribution of PCR products from a CAG-spanning PCR reaction. The top panel arises from a mouse treated with saline, while the bottom one is treated with Htt-targeted ASO. E) Somatic instability is reduced by chronic peripheral dosing of HTT ASO, regardless of length of treatment (39%, 35%, 51% reductions at 7.5, 10 and 14 months, respectively; p = 0.0002, p < 0.0001, p < 0.0001). F) Chronic ASO treatment reduces the levels of Htt pre-mRNA, as quantified by qRT-PCR with primer pairs that span the indicated exon-intron boundaries, with reduction increasing downstream of the ASO binding site (exon 2-intron 2: 44% reduction, p = 0.035; exon 37-intron 38: 66%, p = 0.009; exon 66-intron 66: 69%, p = 0.002). G) Overview of locations of the ASO target and exon/intron primer pairs. For box and whisker plots, each data point is shown, and the horizontal lines indicate the 25th, 50th and 75th percentiles of the data, with vertical lines indicating the range, with outliers detached from the vertical lines.