My Laboratory at the Centre for Molecular Medicine and Therapeutics is dedicated to developing new treatments for hereditary brain diseases, such as Huntington’s disease, Frontotemporal Dementia, and Lou Gehrig’s disease.
The tools of modern molecular genetics are used to generate transgenic animal models of these diseases. New approaches to treatment are then tested in these animal models, with the express goal of accelerating the progress of new treatments for neurodegenerative disorders from the bench to the clinic. The resources and expertise of my laboratory provide the experimental basis for collaborative projects with many scientists world-wide.
My laboratory includes a mouse behavioral testing unit allowing phenotypic characterization of large numbers of transgenic mice using a standardized behavioral 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 have 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 research projects that are 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 that is used in my laboratory is a Yeast Artificial Chromosome (YAC) transgenic mouse model of Huntington 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, behavioral 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 a viable option.
Several trials of potential therapeutic agents have now been initiated in our YAC transgenic mouse model of HD. Novel therapeutic approaches that are effective in our HD animal model will likely have utility in a broad range of neurodegenerative disorders, and in the future we will utilize the same approach to investigate new therapeutics in models of other neurodegenerative disorders, such as A.L.S., Fronto Temporal Dementia, and Alzheimer’s disease.
I am also the Director of the CMMT Transgenic Facility, which generates transgenic and gene-targeted mice as models of human disease for investigators from across Canada and North America.
In addition to my basic research interests, I am 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 am involved in post-mortem studies of HD patients as well as clinical research directed at identifying novel forms of CAG repeat disorders. I am involved in clinical trials of new therapeutics in Huntington disease and other hereditary neurologic disorders such as the spinocerebellar ataxias and Friedrich’s Ataxia.
Tabrizi SJ, Scahill RI, Durr A, Roos RA, Leavitt BR, Jones R, Landwehrmeyer GB, Fox NC, Johnson H, Hicks SL, Kennard C, Craufurd D, Frost C, Langbehn DR, Reilmann R, Stout JC, . Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol 10(1):31-42. (2011)
Bechtel N, Scahill RI, Rosas HD, Acharya T, van den Bogaard SJ, Jauffret C, Say MJ, Sturrock A, Johnson H, Onorato CE, Salat DH, Durr A, Leavitt BR, Roos RA, Landwehrmeyer GB, Langbehn DR, Stout JC, Tabrizi SJ, Reilmann R. Tapping linked to function and structure in premanifest and symptomatic Huntington disease.(2010)
Sturrock A, Laule C, Decolongon J, Dar Santos R, Coleman AJ, Creighton S, Bechtel N, Reilmann R, Hayden MR, Tabrizi SJ, Mackay AL, Leavitt BR. Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease.Neurology 75(19):1702-10. (2010)
Metzler M, Gan L, Mazarei G, Graham RK, Liu L, Bissada N, Lu G, Leavitt BR, Hayden MR. Phosphorylation of huntingtin at Ser421 in YAC128 neurons is associated with protection of YAC128 neurons from NMDA-mediated excitotoxicity and is modulated by PP1 and PP2A. J. Neurosci. 30(43):14318-29. (2010)
Lahiri N, Tabrizi SJ, Kennard C, Durr A, Leavitt BR, Fox N, Roos RA. POMD07 Quantitative assessment of biological and clinical manifestations of Huntington's disease before and after diagnosis--the TRACK-HD study. J. Neurol. Neurosurg. Psychiatr. 81(11):e59. (2010)
Petkau TL, Neal SJ, Orban PC, MacDonald JL, Hill AM, Lu G, Feldman HH, Mackenzie IR, Leavitt BR. Progranulin expression in the developing and adult murine brain. J. Comp. Neurol. 518(19):3931-47. (2010)
Pouladi MA, Xie Y, Skotte NH, Ehrnhoefer DE, Graham RK, Kim JE, Bissada N, Yang XW, Paganetti P, Friedlander RM, Leavitt BR, Hayden MR. Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression.Hum. Mol. Genet. 19(8):1528-38. (2010)
Becanovic K, Pouladi MA, Lim RS, Kuhn A, Pavlidis P, Luthi-Carter R, Hayden MR, Leavitt BR. Transcriptional changes in Huntington disease identified using genome-wide expression profiling and cross-platform analysis. Hum. Mol. Genet.19(8):1438-52. (2010)
Mazarei G, Neal SJ, Becanovic K, Luthi-Carter R, Simpson EM, Leavitt BR.Expression analysis of novel striatal-enriched genes in Huntington disease. Hum. Mol. Genet. (2009)
Tabrizi SJ, Langbehn DR, Leavitt BR, Roos RA, Durr A, Craufurd D, Kennard C, Hicks SL, Fox NC, Scahill RI, Borowsky B, Tobin AJ, Rosas HD, Johnson H, Reilmann R, Landwehrmeyer B, Stout JC, . Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. 8(9):791-801. (2009)
Michael Smith Foundation for Health Research Career Investigator Award – 2007
Young Investigator Award, Brain Research Centre, The University of British Columbia – 1999