Grant: DRA : Canada Graduate Research Scholarship - Doctoral Program (CGRS D)

Huntington's disease (HD) is a fatal neurodegenerative disorder affecting 1 in 7000 Canadians. HD leads to worsening psychiatric, motor, and cognitive issues. Despite lacking a cure, ongoing clinical trials explore gene therapies such as antisense oligonucleotides (ASOs) that aim to reduce the huntingtin (HTT) protein that is known to cause HD. However, there are two forms of huntingtin proteins, mutant (mHTT) and wild-type (wtHTT), and it is unclear what the role of wtHTT is in the adult brain. My research seeks to determine the impact of selective (only reduce mHTT) and non selective ASOs (reduce both mHTT and wtHTT) on the brain in a mouse model of HD. We hypothesize that selective ASOs will be more efficient than non-selective treatments in improving neuroanatomical and cognitive deficits. 3D magnetic resonance imaging (MRI) is currently used in humans to study HD; and yet, this method has yet to be explored with ASO treatment in mice. Humanized HD mice, reproducing HD genetics and the symptoms observed in human HD, will be used in this study. Three treatment groups will be examined: non-selective ASO, selective ASO, and a saline control group. Behavioral assessments will examine motor function, cognitive abilities, anxiety, and depressive-like behavior. Following behavioral assessments, 3D high-resolution MRI will be used to assess volume differences in the brain. The goal of this research is to use 3D MRI to provide insight into how ASOs influence brain structure in the HD mouse model (e.g., which ASO treatment reverses the decrease in volume of the striatum). Findings can be translated to humans due to the clinically relevant MRI technology. By engaging knowledge users, such as the Huntington Society of Canada, sharing and discussion of results will ideally enhance and improve patient care.