• Hayden, Michael

    Titles

    Senior Clinician Scientist, CFRI
    Senior Scientist, Centre for Molecular Medicine and Therapeutics at CFRI
    Canada Research Chair in Human Genetics and Molecular Medicine
    University Killam Professor, Department of Medical Genetics, University of British Columbia

    Degrees / Designations
    MB.ChB, PhD, FRCPC, FRSC, OBC, CM
    Primary Area of Research
    Centre for Molecular Medicine & Therapeutics
    Secondary Area(s) of Research
    Phone
    604-875-3535
    Fax
    604-875-3819
    Lab Phone
    604-875-3809
    Assistant
    Dawn Ng
    Assistant Phone
    604-875-3535
    Mailing Address
    Room 3026, 950 West 28th Avenue
    Vancouver, BC V5Z 4H4
    Affiliate Websites
    Research Areas
    • Genetics
    • Huntington Disease
    • Lipids
    • Atherosclerosis
    • Pharmacogenomics of adverse drug reactions
    • Drug safety
    • Genetic Testing
    • Tangier Disease
    • Predictive Testing
    • Lipoprotein Lipase Deficiency
    • Personalized and Stratified Medicine
    Summary

    Dr. Hayden’s work focuses on understanding the genetic roots of illness and using that understanding to develop better approaches to treatment for patients. He researches diabetes, coronary artery disease, and is part of a large collaboration to determine the genetic basis for adverse drug reactions. Much of his career has also been dedicated to understanding the development of Huntington disease and finding a way to cure it.

    Current Projects
    Exploration of the Pathogenesis of Huntington's Disease and Evaluation of Novel Therapeutic Strategies

    We have developed a YAC model for Huntington disease (HD) (YAC128) which displays age and CAG-dependent phenotypes that recapitulate many features of the human disease. Specifically, enhanced susceptibility to excitotoxic stress, protein cleavage and nuclear localization of (huntingtin) htt occurs early and precedes the cognitive dysfunction, motor deficits and selective striatal degeneration of HD.

    We have recently provided compelling in vivo evidence that caspase-6 cleavage of mutant htt (mhtt) at amino acid (aa) 586 is a crucial, rate limiting event in the pathogenesis of HD. Mice expressing mhtt resistant to cleavage at the 586aa caspase-6 site (C6R) maintain normal neuronal function and do not develop cognitive or neurological abnormalities or any evidence of neurodegeneration. This represents the first intervention in any animal model for HD to prevent motor, cognitive and neuropathological features of HD. This finding supports further experiments to address critical questions including mechanisms for toxicity of the 586aa fragment, determination of initiating events leading to caspase-6 activation and whether decreasing levels of caspase-6 is associated with amelioration of HD.

    The sequence of events between excitotoxicity and cleavage of htt is unknown. Alterations of the kynurenine pathway and NMDAR activity are early events in the pathogenesis of HD. Delineation of the natural history and the relationship between these features of excitotoxicity and cleavage of htt is crucial as it will provide data for designing effective therapeutic strategies for this disease. We will evaluate compounds known to modulate these two pathways, using reagents and approaches well established in our laboratory, in primary neuronal cultures and in the YAC128 model of HD to determine if these are viable therapeutic approaches for HD. If an excitotoxic insult is the upstream event that initiates cleavage of mhtt at the caspase-6 site, drugs that inhibit excitotoxicity would be expected to be associated with less cleavage as this site.

    There is considerable evidence that post translational modification of htt by phosphorylation and palmitoylation play a role in the pathogenesis of HD. The mutation for HD disturbs the interaction of htt with the htt interacting protein 14 (Hip14), now known to be a palmitoyl-transferease leading to less palmitoylation of mhtt and enhanced neuronal toxicity. These findings directly link alterations in palmitoylation of htt with neurodegeneration in HD.

    Silencing the gene that causes Huntington disease - The mutant huntingtin protein, the cause of Huntington disease (HD), accumulates within cells and engages in a variety of aberrant interactions. Preventing generation of this toxic protein by gene silencing, the process of switching off a gene, should prevent all subsequent pathology and prevent or delay the onset of HD. Everyone has two copies of the huntingtin gene. In HD, one of these copies carries the mutation while the other copy is normal. The normal huntingtin protein is important for maintaining neuronal health, and long-term reduction of this protein may not be well-tolerated. We are developing a strategy of silencing only the mutant copy of a patient’s huntingtin gene using antisense oligonucleotides targeted to HD mutation-associated single nucleotide polymorphisms as a treatment for HD.

    The overall goal of this work is to delineate important steps in the pathogenesis of HD and to assess novel approaches to treating this disease.



    The Role of ABCA1 on Cellular Cholesterol Homeostasis and Beta-Cell Function
    Type 2 diabetes is caused by the inability of endocrine cells in the pancreas to meet the increasing metabolic demands and insulin resistance brought on by obesity and ageing. Impaired ß-cell function is an early step in the pathogenesis of type 2 diabetes; however, the reasons for the development of ß-cell dysfunction in diabetes are not completely understood. One emerging theme is that the build-up of toxic lipids such as cholesterol leads to ß-cell destruction. ABCA1 regulates the removal of excess cellular cholesterol to an apolipoprotein receptor. We discovered that mice lacking ABCA1 have impaired glucose tolerance and that ABCA1 is highly expressed in islet cells of the pancreas. Using conditional gene targeting in mice to specifically inactivate Abca1 in ß-cells, we found that the lack of ABCA1 in these cells markedly impaired insulin secretion due to a cholesterol-dependent reduction in insulin granule exocytosis. We found that cholesterol efflux via ABCA1 is the primary contributor to maintenance of beta cell cholesterol homeostasis and that carriers of loss-of-function mutations in ABCA1 show impaired insulin secretion without any change in insulin sensitivity. We have recently shown that microRNA-33a (miR-33a) is expressed in pancreatic islets and in vitro modulation of its expression impacts ABCA1 protein levels in islets, thereby affecting intracellular cholesterol levels and insulin secretion. Our findings establish a novel role for ABCA1 in ß-cell cholesterol homeostasis and insulin secretion, and suggest that cholesterol accumulation may contribute to ß-cell dysfunction in type 2 diabetes, and point to ß-cell ABCA1 as a novel therapeutic target for this disease.

    ABCA1 – Biology and Relation to HDL Cholesterol and Cardiovascular Disease
    Cardiovascular disease (CVD) is a leading cause of mortality among Canadians, and a leading cause of disability and mortality throughout the world. One risk factor for the development of CVD is alterations in cholesterol levels. Cholesterol is transported throughout the body by either low density lipoprotein (LDL) cholesterol (“bad cholesterol”) which increases the risk for CVD, or high density lipoprotein (HDL) cholesterol (“good cholesterol”) which protects against the development of CVD. The majority of our current therapies aimed at preventing CVD target LDL cholesterol levels (statins). However, low levels of HDL cholesterol are a common abnormality amongst patients with CVD and currently, no viable therapeutic strategy exists to safely raise HDL. In 1999, our laboratory identified a gene called ATP-binding cassette A1 (ABCA1), which we and others have since found to be crucial for HDL production. In the past decade, our group has worked to understand how ABCA1 is regulated, the role of ABCA1 in HDL generation, and the function of ABCA1 in different tissues. Using conditional gene targeting techniques; we were able to turn off ABCA1 expression in individual tissues to study its role in specific organs. Using this approach we determined that the liver and intestine are the major sites of initializing HDL production in the body. This information has become crucial for the design of novel therapies to protect against CVD by raising ABCA1 expression in these specific tissues. We also found ABCA1 to be highly expressed in the brain, where it may play a role in protecting neurons from injury and delaying the onset of Alzheimer’s disease. ABCA1 expression in the pancreas is crucial for maintaining proper levels of sugar in the blood, and may play a role in the protection from type II diabetes. This work has generated important new knowledge about the role of ABCA1 in different tissues and cell types, and we are currently investigating novel ways to regulate ABCA1 expression in these different tissues. By understanding how ABCA1 functions in different parts of the body, we are close to designing novel therapeutic strategies for the prevention and treatment of CVD, a leading cause of death in Canadians.

    Pharmacogenomics
    The debilitating and lethal consequences of adverse drug reactions (ADRs) are ranked as the 4th leading cause of death in the USA. In Canada, there are an estimated 200,000 severe ADRs, claiming 10,000-22,000 lives, and costing $13.7-17.7 billion each year. The goal of Canadian Pharmacogenomics Network of Drug Safety (CPNDS) is to prevent ADRs in childhood by identifying predictive genomic markers for specific ADRs. Within five years, CPNDS intends to incorporate these markers into diagnostic tools that will be used to predict and prevent ADRs in children through specific dosing recommendations for commonly used drugs based on an individual's genetic make-up. The long-term goal for this project is to develop a user-friendly, and effective ADR monitoring tool and national database, to proactively prevent adverse drug reactions in susceptible children.

    Specific projects seek to identify the key causal genetic factors of serious ADRs in children, including severe hearing loss caused by cisplatin chemotherapy; a lethal reaction to codeine in newborns and young children, anthracycline-induced heart failure, vincristine-induced peripheral neurotoxicity and drug-induced severe rash.

    In 2011, the CPNDS research group identified novel genetic variants that cause deafness in pediatric patients who receive cisplatin chemotherapy and in response to the work of the CPNDS, the FDA changed the cisplatin drug label to include this new pharmacogenetic risk information. The CPNDS team also expanded upon previous research on codeine and discovered novel genetic factors that cause codeine-induced infant CNS depression/respiratory arrest, and in some cases death. In addition, the CPNDS team identified genetic variants associated with anthracycline-induced cardiotoxicity. Research is underway to identify genetic variants for additional severe adverse drug reactions. Importantly, the CPNDS team are working to translate the findings of this research into the clinic for the benefit of patients.

    Selected Publications

    Kaur A, Patankar JV, de Haan W, Ruddle P, Wijesekara N, Groen AK, Verchere CB, Singaraja RR,  Hayden MR. Loss of Cyp8b1 improves glucose homeostasis by increasing GLP-1. Diabetes. 2015 64(4):1168-79 PMID:25338812.

    Southwell AL, Franciosi S, Villanueva EB, Xie Y, Winter LA, Veeraraghavan J, Jonason A, Felczak B, Zhang W, Kovalik V, Waltl S, Hall G, Pouladi MA, Smith ES, Bowers WJ, Zauderer M, Hayden MR. Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. Neurobiol Dis 2015 76:46-56. PMID: 25662335.

    Martin DDO, Ladha S, Ehrnhoefer DE, Hayden MR. Autophagy in Huntington disease and huntingtin in autophagy. Trends Neurosci. 2015 38(1):26-35. Review. PMID: 25282404. Figure featured on journal cover.

    Southwell AL, Skotte NH, Kordasiewicz H, Østergaard ME, Watt AT, Carroll JB, Doty CN, Villanueva EB, Petoukhov E, Vaid K, Xie Y, Freier SM, Swayze EE, Seth PP, Bennett CF, Hayden MR. In vivo evaluation  of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotide drugs. Mol Ther. 2014 22(12):2093-106. PMID: 25101598. Figure featured on journal cover.

    de Haan W, Karasinska J, Ruddle P, Hayden M. Hepatic ABCA1 expression improves Β-cell function and glucose tolerance. Diabetes. 2014 63(12):4076-82. PMID: 25028523.

    Butland SL, Sanders SS, Schmidt ME, Riechers SP, Lin DTS, Martin DDO, Vaid K, Graham RK, Singaraja RR, Wanker EE, Conibear E, Hayden MR. The Palmitoyl acyltransferase HIP14 Shares a High Proportion of Interactors with Huntingtin: Implications for a Role in the Pathogenesis of Huntington Disease. Hum Mol Genet. 2014. 23(15):4142-60. PMID: 24705354. Figure featured on journal cover.

    Sanders SS, Mui KKN, Sutton LM, Hayden MR. Identification of a binding site in Huntingtin for the Huntingtin interacting proteins HIP14 and HIP14L. PLoS ONE. 2014 28;9(2):e90669. PMID: 24651384.

     

    Ehrnhoefer DE, Skotte NH, Ladha S, Nguyen YT, Qiu X, Deng Y, Huynh KT, Engemann S, Nielsen SMB, Becanovic K, Leavitt BR, Hasholt L, Hayden MR. p53 increases caspase-6 expression and activation in muscle tissue expressing mutant huntingtin. Hum Mol Genet. 2014. 1;23(3):717-29. PMID: 24070868.

    Aminkeng F, Ross CJD, Rassekh SR, Brunham LR, Sistonen J, Dube MP, Ibrahim M, Nyambo TB,  Omar SA, Froment A, Bodo JM, Tishkoff S, Carleton BC, Hayden MR, and The Canadian Pharmacogenomics Network for Drug Safety Consortium. Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent. The Pharmacogenomics Journal 2014. 14(2):160-70. PMID: 23588107.

    Pouladi MA, Morton J, Hayden MR. Choosing an animal model for the study of Huntington's disease. Nat Rev Neurosci. 2013. (14) 708-721. PMID: 24052178.

    Hawkins Virani A, Creighton S, Hayden MR Developing a Comprehensive, Effective Patient Friendly Website to Enhance Decision-Making in Predictive Testing for Huntington Disease.Genet Med. 2013 15(6):466-72. PMID: 23222664.

    Kang MH#, Zhang L#, Wijesekara N, Butland S, Bhattacharjee A, Hayden MR. Regulation of ABCA1 Protein Expression and Efflux Function in Hepatic and Pancreatic Islet Cells by miR-145. Arterioscler  Thromb Vasc Biol (# These authors contributed equally to this work) 2013. 33(12):2724-32. PMID: 24135019.

    Kastelein JJP, Ross CJD, Hayden MR. From Mutation Identification to Therapy: Discovery and Origins of the First Approved Gene Therapy in the Western World. Hum Gene Ther. 2013 24(5):472-8. PMID: 23578007. Top 10 cited in the Hum Gene Ther from 2012-2014. 

    Karasinska JM, de Haan W, Franciosi S, Ruddle P, Fan J, Kruit JK, Stukas S, Lutjohann D, Gutmann DH, Wellington CL, Hayden MR. ABCA1 influences neuroinflammation and neuronal death. Neurobiol Dis 2013 54:445-55. PMID: 23376685.

    Southwell AL, Warby SC, Carroll JB, Doty CN, Skotte NH, Zhang W, Villanueva EB, Kovalik V, Xie Y, Pouladi MA, Collins JA, Yang XW, Franciosi SF, Hayden MR. A fully humanized transgenic mouse model of Huntington disease. Hum Mol Genet. 2013 1;22(1):18-34. PMID: 23001568. In Brief:  Genetics: Fully humanized mouse model of Huntington disease. Nature Rev Neurol 8, 594 (2012)/qwe456.

    For a full list of publications, click here.

    Grants

    Team grant: Drug Safety and Effectiveness Network Collaborating Centre for Prospective Studies (DSEN PREVENT) (CIHR)

    Implementation of a Pharmacogenetic ADR Prevention Program in B.C. (Genome BC)

    Regulation of Function and Activity of ABCA1 (CIHR)

    Palm HD (CIHR)

    Function and regulation of cell-type specific ABCA1 in HD (Alzheimer Society)

    Canadian Pharmacogenomics Network of Drug Safety (CIHR)

    Honours & Awards

    Selected Awards (since 2007)

    Honorary Doctorate, University of Gottingen, Germany, 2014

    Aubrey J. Tingle Prize, Michael Smith Foundation for Health Research, 2011

    Killam Prize, Canada Council of the Arts, 2011

    Margolese National Prize, University of British Columbia, 2011

    Canada Gairdner Wightman, Gairdner Foundation, 2011

    Genome BC Award for Scientific Excellence, LifeSciences British Columbia, 2011

    Order of Canada, 2010

    Jacob Biely Faculty Research Prize, University of British Columbia (UBC’s premier research award), 2010

    The Distinguished Technopreneur Prize, Country of Singapore, 2010

    Order of British Columbia, 2009

    Honorary Professor, Division of Human Genetics, University of Cape Town, 2009

    Honorary Doctor of Science, University of Alberta, 2009

    Canada’s Health Researcher of the Year, CIHR Michael Smith Prize in Health Research, 2008

    Nation Builder competition, (one of five finalists) Globe and Mail, 2008

    Distinguished Alumnus Award, University Cape Town, 2008

    Prix Galien, Research Category, 2007

    Distinguished Achievement Award, UBC, 2007

    Research Group Members

    Folefac Aminkeng, Postdoctoral Fellow
    Mahsa Amirabbasi, Lab Operations Manager
    Jennifer A. Collins, Research Assistant
    Crystal Doty, Research Assistant
    Dagmar Ehrnhoefer, Postdoctoral Research Fellow
    Michelle Higginson, Research Assistant

    Chris Kay, PhD Student
    Safia Ladha, PhD Student
    Nasim Massah, Research Assistant
    Dale Martin, Postdoctoral Research Fellow
    Fudan Miao, Research Assistant
    Betty Nguyen, Research Assistant
    Xiaofan Qiu, Research Assistant
    Piers Ruddle, Research Assistant
    Shaun Sanders, Postdoctoral fellow
    Niels Skotte, Postdoctoral Research Fellow
    Amber Southwell, Postdoctoral Research Fellow
    Erika Villanueva, Research Assistant
    Huijun Mark Wang, Research Assistant
    Qingwen Xia, Research Assistant
    Robert Xie, Research Assistant
    Yu-Zhou Yang, Research Associate
    Yun Ko, Research Assistant
    Bobby Felczak, Research Assistant
    Nick Caron Postdoctoral Fellow
    Emily Ye, Research Assistant
    Nikola Lazic, Research Assistant
    Ramy Selma, Co-op student
    Lisa Anderson, Research Assistant
    Daphne Cheung, Research Assistant
    Galen Wright Postdoctoral Fellow