Brain Alterations in Aged OVT73 Sheep Model of Huntington's Disease: An MRI Based Approach

Area of Science:

• Neuroscience
• Genetics
• Animal Models

Background:

• Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder with no effective treatments.
• Large animal models offer realistic preclinical testing due to similar brain anatomy and physiology.
• Developing effective therapeutics requires robust preclinical models for biodistribution, efficacy, and toxicity studies.

Purpose of the Study:

• To characterize neurological and neuroimaging alterations in aged Huntington's disease (HD) sheep.
• To evaluate the utility of OVT73 HD sheep as a preclinical model for HD therapeutics.
• To assess the correlation between specific biomarkers and clinical decline in HD sheep.

Main Methods:

• Non-invasive characterization of white matter microstructure and neurochemistry in aged OVT73 HD sheep.
• Measurement of mutant Huntingtin protein (mHTT) levels in cerebrospinal fluid (CSF).
• Longitudinal analysis of neurological status, gait, and clinical rating scores.

Main Results:

• CSF mHTT levels effectively differentiate HD sheep from normal controls.
• Aged female HD sheep show more severe neurological decline and brain alterations.
• White matter changes in the corpus callosum and occipital cortex correlate with impaired gait and clinical scores.
• Striatal energy metabolism markers correlate with reduced clinical rating and eye coordination.

Conclusions:

• OVT73 HD sheep serve as a viable pre-manifest large animal model for Huntington's disease.
• This model facilitates preclinical testing of HD therapeutics.
• The model allows for non-invasive tracking of therapeutic efficacy in HD research.