Suppression of Huntington’s disease somatic instability by transcriptional repression and direct CAG repeat binding

Huntington’s disease arises from a CAG expansion in the huntingtin gene beyond a critical threshold. Current therapeutics primarily aim to reduce toxicity by lowering levels of mutant HTT mRNA and protein. Genetic data support a role for somatic instability in HTT’s CAG repeat as a driver of age of motor dysfunction onset, but currently, the relationship between instability and HTT lowering remains unexplored. Here, we investigate various HTT-lowering modalities to establish the relationship between HTT lowering and instability in Huntington’s disease knock-in mice. We find that repressing transcription of mutant Htt reduces instability, using genetic and pharmacological approaches. Remarkably, zinc finger proteins that target CAG repeats, but lack a repressive domain, protect from somatic instability despite not reducing HTT mRNA or protein levels. These results suggest that DNA-targeted HTT-lowering treatments may have advantages compared to other HTT-lowering approaches, and that steric blockage of CAG repeats may reduce instability while sparing HTT expression.

Methods
All data was either collected directly by the Carroll lab at Western Washington University and University of Washington, or sent to us by collaborating labs where data was collected: Evotec SE, Hamburg, Germany; RNA Therapeutics Institute, University of Massachusetts Chan Medical School; Ionis Pharmaceuticals; CHDI Management, Inc.; Center for Genomic Medicine, Massachusetts General Hospital. 

The data is in its raw form, with the exception of somatic instability data, which has been processed through an R script (available on Zenodo) to generate expansion indices for each mouse.