Fig. 6: SNP6-11 selectively silences mutant HTT in an HD mouse model.

a BAC97 HD mice have a high copy number of transgenic mutant human huntingtin (Htt) with a polyQ expansion of 97 repeats, and two normal copies of wild-type (WT) mouse Htt. Both the human BAC97 huntingtin and the WT mouse Htt have homology at the SNP6-11 target site, except for a heterozygosity at SNP site rs362273, mimicking the WT/mutant Htt SNP heterozygosity in patients. b for in vivo delivery, the SNP 6–11 compound was synthesized in a di-valent configuration as depicted. c When treated with 225 µg (10nmols) of siRNA (SNP6-11) in a divalent scaffold, allele-specific silencing of mutant HTT protein in mouse brain is achieved one month after bilateral injection into the lateral ventricles (ICV injection). d Across brain regions, WT mouse HTT is preserved with no significant silencing detected (except in striatum), while transgenic mutant HTT is lowered significantly, averaging 70% silencing across brain regions (p-value <0.00001). Protein levels were measured via WES Protein Simple. A two-way ANOVA with multiple comparisons was performed for all protein analysis, comparing treatment groups to the PBS control for each brain region; n = 5–6 animals per group. Error bars extend to minimum and maximum value. The lower bound of the box is the 25th percentile and the upper is the 75th, with a line at the median. Source data are provided as a source data file.