My laboratory develops new treatments for neurodegenerative diseases such as Huntington’s disease. We do this by first developing transgenic mouse models of specific human diseases, and then by testing new disease treatments in these mouse models. The YAC128 mouse model of Huntington’s disease accurately replicates the changes seen in humans with this disease, and is a critical tool that permits my laboratory to evaluate new treatment strategies in mice prior to undertaking large-scale clinical trials in human patients. Currently, my work is primarily focused on transgenic mouse models of Huntington’s disease, but in the future will expand to utilize the same standardized approach to investigate new therapeutics in mouse models of other devastating neurodegenerative disorders, such as ALS, prion disease, Parkinson's, and Alzheimer's disease.
I’ve recently established The Laboratory for Experimental Therapeutics in Animal Models of Human Disease at the Centre for Molecular Medicine and Therapeutics (CMMT), dedicated to developing new treatments for hereditary brain diseases, such as Huntington’s disease, Fragile X, and Lou Gehrig’s disease. Molecular genetic tools are used to generate transgenic animal models of these diseases. New approaches to treatment are then tested in these models, with the goal of accelerating the progress of new treatments from the bench to the clinic. This facility’s resources and expertise provide the basis for collaborative projects with scientists worldwide.
My laboratory includes a mouse behavioural testing unit allowing phenotypic characterization of large numbers of transgenic mice using a standardized behavioural protocol, as well as a dedicated small animal surgical suite allowing a variety of surgical procedures including administration of stem cells, compounds or gene therapy vectors directly into the CNS. I’ve established a dedicated image analysis suite, stereology system, and automated neuropathology unit for high-throughput quantitative analysis of neurodegeneration in transgenic mouse brains. We currently have an established level II biohazard protocol, and are performing gene therapy experiments using adenoviral and adeno-associated viral vectors. I also have several ongoing projects investigating the role of wild-type huntingtin in neuronal apoptosis and a possible role for loss of huntingtin function in neurodegenerative disease.
The primary mouse model used in my laboratory is a Yeast Artificial chromosome (YAC) transgenic mouse model of Huntington’s Disease (HD) originally developed in Michael Hayden's laboratory at the CMMT. This mouse model faithfully replicates key features of the human disease; specifically these mice develop age-related motor dysfunction, behavioural abnormalities, and selective neurodegeneration of medium spiny neurons of the striatum. YAC transgenic mice have now been generated with the full-length human HD gene containing normal (YAC18) and expanded (YAC46, 72, and 128) CAG repeats. Different lines of transgenic mice have varying copy numbers of the human transgene and express varying amounts of transgenic huntingtin protein. The progressive motor and neurodegenerative phenotype of the YAC128 mouse model of HD makes in vivo screening of novel therapeutic approaches viable.
Several trials of potential therapeutic agents have now been initiated in our YAC transgenic mouse model. Novel therapeutic approaches effective in our HD model will likely have utility in a broad range of neurodegenerative disorders, and in the future we’ll utilize the same approach to investigate new therapeutics in other neurodegenerative disorders, such as ALS, Parkinson’s disease, and Alzheimer’s disease.
In addition, I’m a neurologist with an ongoing clinical practice and clinical research program in neurogenetics, with a focus on hereditary movement disorders, specifically various forms of ataxia and chorea. I’m involved in post-mortem studies of HD patients as well as clinical research directed at identifying novel forms of CAG repeat disorders. I’m involved in clinical trials of new therapeutics in Huntington’s disease and other hereditary neurologic disorders such as the spinocerebellar ataxias and Friedrich’s Ataxia. I’m also the Director of the Canadian Genetic Disease Network Transgenic Core Facility at the CMMT, which generates transgenic and gene-targeted mice as models of human disease for investigators from across North America.Honours & Awards
Young Investigator Award, Brain Research Centre, University of British Columbia, 1999
Award for Outstanding Achievement by a Postdoctoral Fellow, BC Research Institute for Children’s & Women’s Health, 2001
Michael Smith Foundation for Health Research Career Investigator Award, 2007Research Group Members
Hilal Al Shekaili, PhD Candidate
Laura Chan, Medical Genetics Graduate Program Rotation Student
Angela Gurney, Research Coordinator
Ben Life, Doctoral Student
Kayla Shayne, Manager Transgenic Facility
Sarah Thomson, Graduate Student
Jasmine (Ming) Yang, Research Assistant