• Leavitt, Blair R.

    Titles
    Investigator, BC Children's Hospital

    Acting Director and Senior Scientist, Centre for Molecular Medicine and Therapeutics
    Professor, Department of Medical Genetics, University of British Columbia

    Degrees / Designations
    MD
    Primary Area of Research
    Brain, Behaviour & Development
    Secondary Area(s) of Research
    Phone
    604-875-3801
    Fax
    604-875-3840
    Lab Phone
    604-875-2345 ext. 7570
    Assistant
    Angela Gurney
    Assistant Phone
    604-875-3828
    Mailing Address

    BC Children's Hospital Research Institute
    950 West 28th Avenue, Room 2020
    Vancouver, BC V5Z 4H4

    Research Areas
    • Neurogenetics
    • Huntington's disease
    • Experimental therapeutics
    • Stem cells
    • Neurodegeneration
    • Transgenic mice
    • Gene therapy
    • Amyotrophic Lateral Sclerosis (ALS)
    Summary

    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.

    Current Projects

    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.

    Selected Publications

    Callaghan J, Stopford C, Arran N, Boisse MF, Coleman A, Santos RD, Dumas EM, Hart EP, Justo D, Owen G, et al (Leavitt BR). 2015. Reliability and factor structure of the short problem behaviors assessment for huntington's disease (PBA-s) in the TRACK-HD and REGISTRY studies. J Neuropsychiatry Clin Neurosci 27(1):59-64. DOI: 10.1176/appi.neuropsych.13070169. PMID: 25716488

    Sturrock A, Laule C, Wyper K, Milner RA, Decolongon J, Santos RD, Coleman AJ, Carter K, Creighton S, Bechtel N, et al (Leavitt BR). 2015. A longitudinal study of magnetic resonance spectroscopy huntington's disease biomarkers. Mov Disord 30(3):393-401. DOI: 10.1002/mds.26118. PMID: 25690257

    De Souza RA and Leavitt BR. 2014. Neurobiology of huntington's disease. Curr Top Behav Neurosci.  DOI: 10.1007/7854_2014_353. PMID: 25205327

    Muller M and Leavitt BR. 2014. Iron dysregulation in huntington's disease. J Neurochem 130(3):328-50.  DOI: 10.1111/jnc.12739. PMID: 24717009

    Petkau TL and Leavitt BR. 2014. Progranulin in neurodegenerative disease. Trends Neurosci 37(7):388-98.  DOI: 10.1016/j.tins.2014.04.003. PMID: 24800652

    Ross CA, Aylward EH, Wild EJ, Langbehn DR, Long JD, Warner JH, Scahill RI, Leavitt BR, Stout JC, Paulsen JS, et al. 2014. Huntington disease: Natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol 10(4):204-16. DOI: 10.1038/nrneurol.2014.24. PMID: 24614516

    Saft C, Leavitt BR, Epplen JT. 2014. Clinical utility gene card for: Huntington's disease. Eur J Hum Genet 22(5):10.1038/ejhg.2013.206. Epub 2013 Oct 9. PMCID: PMC3992568. DOI: 10.1038/ejhg.2013.206. PMID: 24105375

    Wang SP, Wu JW, Bourdages H, Lefebvre JF, Casavant S, Leavitt BR, Labuda D, Trasler J, Smith CE, Hermo L, et al. 2014. The catalytic function of hormone-sensitive lipase is essential for fertility in male mice. Endocrinology 155(8):3047-53. DOI: 10.1210/en.2014-1031. PMID: 24797631

    Jones R, Stout JC, Labuschagne I, Say M, Justo D, Coleman A, Dumas EM, Hart E, Owen G, Durr A,Leavitt BR, Roos R, O'Regan A, Langbehn D, Tabrizi SJ, Frost C (2014) The potential of composite cognitive scores for tracking progression in Huntington's disease. Journal of Huntington’s Disease 3(2):197-207. SG PMID: 25062862

    Plecash AR, Leavitt BR (2014) Aquatherapy for neurodegenerative disorders. Journal of Huntington’s Disease 3(1):5-11 SA PMID: 25062761

    Kostro D, Abdulkadir A, Durr A, Roos R, Leavitt BR, Johnson H, Cash D, Tabrizi SJ, Scahill RI, Ronneberger O, Klöppel S; Track-HD Investigators (2014) Correction of inter-scanner and within-subject variance in structural MRI based automated diagnosing. Neuroimage. 2014 Sep;98:405-15 SG. PMID: 24791746

    Reilmann R, Leavitt BR, Ross C (2014) Huntington's disease: A field on the move. Movement Disorders. 2014 Sep 15;29(11):1333-4. SG PMID: 25164859

    Reilmann R, Leavitt BR, Ross CA (2014) Diagnostic criteria for Huntington's disease based on natural history. Movement Disorders.  2014 Sep 15;29(11):1335-41 SG. PMID: 25164527

    Huntington Study Group Reach2HD Investigators (2015) Safety, tolerability, and efficacy of PBT2 in Huntington's disease: a phase 2, randomised, double-blind, placebo-controlled trial.. The Lancet Neurology, 2015 Jan;14(1):39-47 SG. PMID: 25467848

    Postnatal muscle modification by myogenic factors modulates neuropathology and survival in an ALS mouse model. Park KH, Franciosi S, Leavitt BR. Nat Commun. 2013 Dec 18;4:2906. doi: 10.1038/ncomms3906. PMID 24346342

    Fang Q, Strand A, Law W, Faca VM, Fitzgibon MP, Hamel N, Houle B, Liu X, May DH, Poschmann G, Roy L, Stühler K, Ying W, Zhang J, Zheng Z, Bergeron JJ, Hanash S, He F, Leavitt BR, Meyer HE, Qian X, McIntosh MW. Brain-specific proteins decline in the cerebrospinal fluid of humans with Huntington's disease. Mol. Cell Proteomics (2008) PMID 18984577

    Semaka A, Warby S, Leavitt BR, Hayden MR. Re: Autopsy-proven Huntington's disease with 29 trinucleotide repeats. Mov. Disord. 23(12):1794-5; author reply 1793. (2008) PMID 18548612

    Björkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, Raibon E, Lee RV, Benn CL, Soulet D, Magnusson A, Woodman B, Landles C, Pouladi MA, Hayden MR, Khalili-Shirazi A, Lowdell MW, Brundin P, Bates GP, Leavitt BR, Möller T, Tabrizi SJ. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease. J. Exp. Med. 205(8):1869-77. (2008) PMID 18625748

    Park KH, Vincent I. Presymptomatic biochemical changes in hindlimb muscle of G93A human Cu/Zn superoxide dismutase 1 transgenic mouse model of amyotrophic lateral sclerosis. Biochim. Biophys. Acta 1782(7-8):462-8. (2008) PMID 18485920

    Björkqvist M, Leavitt BR, Nielsen JE, Landwehrmeyer B, Ecker D, Mulder H, Brundin P, Petersén A. Cocaine- and amphetamine-regulated transcript is increased in Huntington disease. Mov. Disord. 22(13):1952-4. (2007) PMID 17722045

    Kuhn A, Goldstein DR, Hodges A, Strand AD, Sengstag T, Kooperberg C, Becanovic K, Pouladi MA, Sathasivam K, Cha JH, Hannan AJ, Hayden MR, Leavitt BR, Dunnett SB, Ferrante RJ, Albin R, Shelbourne P, Delorenzi M, Augood SJ, Faull RL, Olson JM, Bates GP, Jones L, Luthi-Carter R. Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage. Hum. Mol. Genet. 16(15):1845-61. (2007) PMID 17519223

    Dalrymple A, Wild EJ, Joubert R, Sathasivam K, Björkqvist M, Petersén A, Jackson GS, Isaacs JD, Kristiansen M, Bates GP, Leavitt BR, Keir G, Ward M, Tabrizi SJ. Proteomic profiling of plasma in Huntington's disease reveals neuroinflammatory activation and biomarker candidates. J. Proteome Res. 6(7):2833-40. (2007) PMID 17552550

    Van Raamsdonk JM, Murphy Z, Selva DM, Hamidizadeh R, Pearson J, Petersén A, Björkqvist M, Muir C, Mackenzie IR, Hammond GL, Vogl AW, Hayden MR, Leavitt BR. Testicular degeneration in Huntington disease. Neurobiol. Dis. 26(3):512-20. (2007) PMID 17433700

    Wong D, Dwinnel M, Schulzer M, Nimmo M, Leavitt BR, Spacey SD. Ataxia and the role of antigliadin antibodies. 34(2):193-6. (2007) PMID 17598597

    Van Raamsdonk JM, Pearson J, Rogers D, Bissada N, Vogl AW, Hayden MR, and Leavitt BR. Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease. Human Molecular Genetics. 2005; 14(10)1379–92. PMID 15829505

    Grants
    Honours & Awards

    Michael Smith Foundation for Health Research Career Investigator Award, 2007

    Award for Outstanding Achievement by a Postdoctoral Fellow, BC Research Institute for Children’s & Women’s Health, 2001

    Young Investigator Award, Brain Research Centre, University of British Columbia, 1999

    Research Group Members

    Angela Gurney, Research Coordinator 
    Austin Hill, Lab Manager 
    Ge Lu, Research Assistant 
    Gelareh Mazarei, MSc Student 
    Kevin Park, Research Associate 
    Terri Sosa, Research Assistant 
    Jenny Thiele, MSc Student 
    Terri Petkau Postdoctoral Research Fellow
    Pam Wager, Research Technician
    Jasmine Wang, Research Technician
    Colum Connolly, PhD student
    Rebecca De Souza, PhD student