Figure 6: ZFP treatment reduces HTT’s transcriptional rate and blocks CAG SI, while delta-KRAB lowers SI but spares transcription.

A) Schematic of ZFP constructs: the DNA-binding domain (DBD) binds CAG repeats, while the KRAB domain induces repressive chromatin. B) Schematic of treatment paradigm - each subject mouse is treated with two viruses - one in each hemisphere. C) Htt transcript levels as measured by bDNA assay decrease after ZFP treatment (full ZFP vs KRAB-only, 20% reduction, p = 0.0002) but are unaffected by DBD-only treatment (NS). NB, this is a non-allele selective assay, and so likely underestimates the amount of allele-selective lowering of mHtt. D) Treatment with the complete ZFP constructs leads to a marked reduction in exon-1 only mHtt (Htt1a) levels as measured by bDNA assay (50% reduction, p < 0.0001), but are unaffected by DBD-only treatment (NS). E) Somatic instability of mHtt’s CAG tracts is reduced (70%, p < 0.0001) by the full ZFP construct, with the DBD-only construct resulting in an intermediate reduction (42%, p < 0.0001). F) Exemplar traces from each treatment group.