Abstract We have developed a novel inducible Huntington’s disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant Huntingtin (m Htt ) expression. We asked whether moderate global lowering of m Htt (∼50%) was sufficient for long-term amelioration of HD-related deficits and, if so, whether early m Htt lowering (before measurable deficits) was required. Both early and late m Htt lowering delayed behavioral dysfunction and mHTT protein aggregation, as measured biochemically. However, long-term follow up revealed that the benefits, in all m Htt lowering groups, attenuated by 12 months of age. While early m Htt lowering attenuated cortical and striatal transcriptional dysregulation evaluated at 6 months of age, the benefits diminished by 12- months of age and late m Htt lowering was unable to ameliorate striatal transcriptional dysregulation at 12 months of age. Only early m Htt lowering delayed the elevation in cerebrospinal fluid neurofilament light chain that we observed in our model starting at 9 months of age. As small-molecule HTT -lowering therapeutics progress to the clinic, our findings suggest that moderate m Htt lowering allows disease progression to continue, albeit at a slower rate, and could be relevant to the degree of m HTT lowering required to sustain long-term benefit in humans.

Benefits of global mutant huntingtin lowering diminish over time in a Huntington’s disease mouse model