Project 456004

Brain disease is a leading cause of death and disability in the Canadian population representing an immense economic and societal burden. Most brain diseases have no cure, progressively decrease quality of life, and become more common with increasing age. This is of particular importance for our rapidly aging population, making the development of new treatments for brain diseases a priority for Canadian science, medicine, and industry. In this proposal we will use a newly developed nanotechnology delivery system to get gene-based drugs (called nucleic acid therapeutics) into the brain to correct defective disease-causing genes. Initial work will focus on optimizing the system to deliver a kind of gene therapy that will modify a reporter signal in brain cells. This reporter signal can be visualized in brain cells and will allow us to understand the distribution of our delivery system within the brain following various types of injections. Subsequently, the reporter signal will be replaced by a gene-editing construct that can correct mutations in disease causing genes. Specifically the gene-editing construct is an enzyme that cuts DNA called Cas9, co administered with a guide RNA (gRNA) that directs the Cas9 to a specific target gene, and a repair template that directs correction of the mutation. Our brain disease model is a mouse expressing a human gene called progranulin with a specific genetic mutation that causes frontotemporal dementia (FTD) in humans. We will use our gene-editing construct (carried in the nanotechnology delivery system) to correct the FTD-causing mutation in progranulin in the brain of mice. In this proposal we use FTD as a model for human brain disease, but the optimized nanotechnology delivery system that we have developed for genetic therapy in the brain is a platform technology that can be adapted to any brain disease with a genetic basis or for which gene therapy can be applied.