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JCI Insight. 2017 Dec 7;2(23). pii: 95665. doi: 10.1172/jci.insight.95665.

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice.

Author information

1
Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore (A*STAR), Singapore.
2
Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel.
3
Immuneering Corporation, Cambridge, Massachusetts, USA.
4
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
5
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Abstract

Pridopidine is currently under clinical development for Huntington disease (HD), with on-going studies to better characterize its therapeutic benefit and mode of action. Pridopidine was administered either prior to the appearance of disease phenotypes or in advanced stages of disease in the YAC128 mouse model of HD. In the early treatment cohort, animals received 0, 10, or 30 mg/kg pridopidine for a period of 10.5 months. In the late treatment cohort, animals were treated for 8 weeks with 0 mg/kg or an escalating dose of pridopidine (10 to 30 mg/kg over 3 weeks). Early treatment improved motor coordination and reduced anxiety- and depressive-like phenotypes in YAC128 mice, but it did not rescue striatal and corpus callosum atrophy. Late treatment, conversely, only improved depressive-like symptoms. RNA-seq analysis revealed that early pridopidine treatment reversed striatal transcriptional deficits, upregulating disease-specific genes that are known to be downregulated during HD, a finding that is experimentally confirmed herein. This suggests that pridopidine exerts beneficial effects at the transcriptional level. Taken together, our findings support continued clinical development of pridopidine for HD, particularly in the early stages of disease, and provide valuable insight into the potential therapeutic mode of action of pridopidine.

KEYWORDS:

Mouse models; Movement disorders; Neurodegeneration; Neuroscience; Therapeutics

PMID:
29212949
PMCID:
PMC5752291
DOI:
10.1172/jci.insight.95665
[Indexed for MEDLINE]
Free PMC Article

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