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

Spinal bulbar muscular atrophy (SBMA) is a rare genetic disease that mostly affects men. It causes gradual muscle weakness, loss of nerve cells, and difficulties with speaking and swallowing. My recent research showed that Indigenous communities in Western Canada have the highest rates of SBMA anywhere in the world. Yet today, there are still no treatments that can slow or stop this disease, which leaves families without options and deepening existing health inequities. This project will develop and test two promising new genetic therapies for SBMA in close partnership with the affected Indigenous communities. The first approach uses small pieces of DNA-like molecules, called antisense oligonucleotides (ASOs), which can "switch off" production of the harmful protein that causes the disease. To improve their ability to reach the right place, the ASOs will be packaged in lipid nanoparticles (LNPs), tiny protective parcels that deliver the treatment directly into muscle cells where it is needed most. The second approach uses a gene-editing tool called CRISPR activation (CRISPRa) to "switch on" a protective version of the gene, which can counteract the effects of the harmful protein. These strategies will be tested in mouse models to determine which therapies are most effective at protecting muscle and nerve function, while carefully monitoring safety. Throughout the study, a Community Guiding Circle will ensure the work is guided by Indigenous knowledge, priorities, and values. This project focuses on advancing SBMA therapies for clinical translation, with the ultimate goal of improving the health and quality of life of people living with SBMA, including Indigenous communities disproportionately affected. It will also reduce health inequities and contribute to the development of genetic therapies for other rare diseases, while modelling effective community-guided research in Canada.