Huntington disease (HD) is an inherited disorder that causes brain cells to die and impacts approximately 1 in 7000 Canadians. A person with HD experiences worsening psychiatric, motor, and memory impairments. While there is still no cure for HD, gene therapies have shown promise and entered clinical trials with the goal of lowering the huntingtin protein responsible for the symptoms of HD. In 2021, a phase III clinical trial was stopped early because of poor drug performance, a devastating setback for the HD community. The goal of this project is to use a mouse model that reproduces the clinical features of HD and advanced magnetic resonance imaging technologies to understand the impact of gene therapy on whole brain anatomy and hopefully shed light on why the clinical trial failed. In addition, we will explore another strategy for therapy, selectively lowering only the pathogenic huntingtin protein while keeping the non-pathogenic huntingtin protein. We will also determine whether the timing of the therapy affects the disease progression and if females and males respond differently to treatment.
In collaboration with world-renowned experts in gene therapy for HD, this study has the potential to transform our understanding of the mechanisms of the disease and for testing therapies. Because the imaging technology used in this project is the same as what is used clinically to diagnose HD, our findings in mice can be rapidly translated to use in humans and will inform future clinical trials. Determination of the best strategy to prevent or reverse HD-associated brain pathology will lead to improved therapies for HD patients.