Figure 3.

2S-dT has a positional effect on allele selectivity. (A) Dose-dependent reduction of muHTT and wtHTT mRNA in human GM04022 fibroblasts using ASOs A15 and A16. (B) Human RNase H1 cleavage patterns for A16 with 2S-dT at position 6 and A15 with 2S-dT at position 5. (C) Pictorial representation of human RNase H cleavage patterns for A16 and A15. 2S-dT at position 5 blocks cleavage sites (d and c), whereas 2S-dT at position 6 blocks cleavage sites (b and c) on the matched and mismatched duplexes. The GT base pair ablates cleavage sites (a and b) on the mismatched duplex for ASOs A15 and A16. Underlined nucleotide indicates position across from the SNP site. (D) Summary of potency and selectivity profile of A15 and A16. Error bars are in ±SD.