Abstract
We have developed a novel inducible Huntington’s disease (HD) mouse model that allows temporal control of whole-body allele-specific mutant Huntingtin (mHtt) expression. We asked whether moderate global lowering of mHtt (∼50%) was sufficient for long-term amelioration of HD-related deficits and, if so, whether early mHtt lowering (before measurable deficits) was required. Both early and late mHtt lowering delayed behavioral dysfunction and mHTT protein aggregation, as measured biochemically. However, long-term follow up revealed that the benefits, in all mHtt lowering groups, attenuated by 12 months of age. While early mHtt lowering attenuated cortical and striatal transcriptional dysregulation evaluated at 6 months of age, the benefits diminished by 12- months of age and late mHtt lowering was unable to ameliorate striatal transcriptional dysregulation at 12 months of age. Only early mHtt 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 mHtt lowering allows disease progression to continue, albeit at a slower rate, and could be relevant to the degree of mHTT lowering required to sustain long-term benefit in humans.
Competing Interest Statement
This work was supported by the non-profit CHDI Foundation, Inc. DMM, VK, BL, JR, JA, MA, ES, IMS and DH are employed by CHDI Management, Inc. as advisors to CHDI Foundation, Inc., and declare no conflict of interest. CHDI Foundation is a nonprofit biomedical research organization exclusively dedicated to collaboratively developing therapeutics that substantially improve the lives of those affected by Huntington's disease. CHDI Foundation conducts research in a number of different ways; for the purposes of this manuscript, all research was conceptualized, planned, and directed by all authors and conducted at the contract research organizations Psychogenics, Evotec SE, Charles River and Rancho Biosciences.
Footnotes
Competing Interests: This work was supported by the non-profit CHDI Foundation, Inc. DMM, VK, BL, JR, JA, MA, ES, IMS and DH are employed by CHDI Management, Inc. as advisors to CHDI Foundation, Inc., and declare no conflict of interest. CHDI Foundation is a nonprofit biomedical research organization exclusively dedicated to collaboratively developing therapeutics that substantially improve the lives of those affected by Huntington’s disease. CHDI Foundation conducts research in a number of different ways; for the purposes of this manuscript, all research was conceptualized, planned, and directed by all authors and conducted at the contract research organizations Psychogenics, Evotec SE, Charles River and Rancho Biosciences.