Grant: Canada Postdoctoral Research Award (CPRA) program

Huntington's disease (HD) is a rare, inherited brain disorder that causes progressive problems with movement, thinking, and mood. It is caused by a mutation in the huntingtin (HTT) gene, where an unusually long DNA repeat sequence leads to the production of a toxic mutant protein. This mutant protein damages specific brain cells, particularly neurons in a region called the striatum, which is especially important for voluntary movement (for example, walking). HD patients with longer repeat sequences develop symptoms earlier and experience faster disease progression. There are currently no treatments that slow or stop HD, only medications that help manage symptoms, but researchers are developing new treatments that target the root cause of the disease. One promising approach uses a category of therapeutics called antisense oligonucleotides (ASOs), which can shut down activity of target genes in a highly specific way. Two important ASO targets for HD are mutant HTT and MSH3, a gene that can influence the length of the HD DNA repeat sequence. Lowering either of these may slow disease progression, but it's still unclear which approach works better, or if targeting both together is more effective. In this project, I will use a mouse model of HD to test ASOs that lower HTT, MSH3, or both. I will measure how well each therapy slows disease progression, and identify biological "markers" in blood and spinal fluid that could help track treatment success. By answering these questions, this study will provide critical insights for improving upcoming clinical trials and may bring us closer to effective, gene-based therapies for HD.