A Novel Huntington's Disease Assessment Platform to Support Future Drug Discovery and Development

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Huntington's disease (HD) is a fatal neurodegenerative disorder lacking effective treatments.
• Translating preclinical findings to clinical applications is hindered by gaps in understanding disease mechanisms, target identification, model characterization, and biomarker development.

Purpose of the Study:

• To characterize a novel mouse model (zQ175^Δneo) for Huntington's disease.
• To comprehensively analyze behavioral, neuropathological, and immunohistological changes over time.
• To compile a dataset of small-molecule modulators for HD drug discovery.

Main Methods:

• Generation of the zQ175^Δneo mouse line by excising the neomycin resistance cassette from zQ175 mice.
• Longitudinal assessment of behavioral, neuropathological, and immunohistological parameters from 15 to 57 weeks of age.
• Compilation and analysis of a multitarget dataset (HD_MDS) of small-molecule Huntington's disease modulators.

Main Results:

• zQ175^Δneo mice displayed early astrogliosis (15 weeks), growth retardation, weight loss, and anxiety (29 weeks).
• Motor deficits and reduced muscle strength were observed from 36 weeks, with mild microgliosis by 57 weeks.
• The HD_MDS dataset identified 358 unique compounds targeting over 80 pharmacological targets and pathways relevant to HD.

Conclusions:

• The zQ175^Δneo mouse model accurately recapitulates key Huntington's disease phenotypes, offering a valuable preclinical tool.
• The identified small-molecule modulators and targets provide a foundation for developing novel therapeutic strategies for HD.
• This study establishes a comprehensive resource for advancing drug discovery and development for Huntington's disease.