Grant: Master's Award: Canada Graduate Scholarships

Huntington's disease (HD) is a fatal neurodegenerative disorder affecting 1 in 7000 Canadians. Despite lacking a cure, ongoing clinical trials explore RNA-targeting therapies, like antisense oligonucleotides (ASOs) that aim to reduce the mutant huntingtin protein (mHTT). Many trials use non-selective ASOs and have led to worsening outcomes. We propose that non-selective therapies may adversely affect the non-pathogenic wild-type huntingtin protein (wtHTT). The role of decreased wtHTT in the adult brain is unclear, although it is crucial for early development. Selective ASOs have been designed to target mHTT and avoid lowering total HTT. This project seeks to determine the impact of selective and non-selective ASOs on neuroanatomy and cognitive function in a humanized mouse model of HD. We hypothesize that selective ASOs will be more effective than non-selective treatments in improving neuroanatomical and cognitive deficits. To test this hypothesis, we will use behavioral testing and 3D whole brain magnetic resonance imaging (MRI) in three groups: 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 analyze brain structures. The goal of this work is to provide insight into how ASOs impact brain structure in the HD mouse model and to compare the abilities of non-selective and selective ASOs to prevent brain pathology. Findings can be translated to humans due to the clinically relevant MRI technology. Engaging knowledge users, such as the Huntington Society of Canada, will allow us to share our results and enhance their impact on patient care.