• Genetics
• Huntington Disease
• Lipids
• Atherosclerosis
• Pharmacogenomics of adverse drug reactions
• Drug safety
• Genetic Testing
• Tangier Disease
• Predictive Testing
• Lipoprotein Lipase Deficiency

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.

We have provided compelling in vivo evidence that caspase-6 cleavage of mutant HTT (mHTT) at amino acid 586 is a crucial, rate limiting event in the pathogenesis of HD. Mice expressing mHTT which is resistant to cleavage at the caspase-6 site maintain normal neuronal function, are resistant to excitotoxic stress 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. Since cleavage of mHTT at the caspase-6 site is critical in the pathogenesis of HD, a potential therapeutic approach is to inhibit caspase-6. Since no specific inhibitors of this enzyme are currently available, we have developed methods suitable for high-throughput screening that are sensitive and specific and allow us to test inhibitor compounds in vitro as well as in cell culture.

To evaluate the effect of caspase-6 inhibition on HD pathogenesis in vivo, we have generated constitutive caspase-6 knockout mice (C6-/-) for crossing to the YAC128 model. We demonstrate that C6-/- neurons are protected against excitotoxicity, nerve growth factor deprivation and myelin-induced axonal degeneration. Furthermore, caspase-6-deficient mice show an age-dependent increase in cortical and striatal volume. In addition, these mice show a hypoactive phenotype and display learning deficits. The age-dependent behavioral and region-specific neuroanatomical changes observed in the C6-/- mice suggest that caspase-6 deficiency has a more pronounced effect in brain regions that are involved in neurodegenerative diseases, such as the striatum in HD.

The sequence of events between excitotoxicity and cleavage of HTT is unknown. Alterations of the kynurenine pathway and NMDA receptor 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. In addition, there is considerable evidence that post translational modification of HTT by phosphorylation and palmitoylation play a role in the pathogenesis of HD. The mutation in HD disturbs the interaction of HTT with Huntingtin Interacting Protein 14 (HIP14) leading to less palmitoylation of mHTT and enhanced neuronal toxicity. Of the 23 known enzymes that mediate palmitoylation, HIP14 and HIP14-Like are the two that contribute the most to palmitoylation of HTT. Mice lacking HIP14 show many features of HD, including striatal volume loss, motor deficits, and decreased palmitoylation of neuronal proteins. These findings directly link alterations in palmitoylation of HTT with neurodegeneration in HD.

We are developing a strategy of allele-specifically silencing mutant Htt as a treatment for HD. Our lab has identified SNPs that are tightly linked to CAG expansion. Population genetics analysis indicates that developing silencing reagents targeting as few as 3 or 4 of these HD-associated SNPs could provide a therapeutic option for 80-90% of the HD population. We have generated a large number of antisense oligonucleotides (ASOs) targeting these HD-SNPs as well as a mouse model of HD that recapitulates HD-SNPs and develops HD-like symptoms. We have used these HD mice in short-term studies to identify ASOs that can selectively silence the mutant Htt gene in the living brain without overt adverse effects. We have seen up to 85% reduction of mutant HTT protein with negligible reduction of wildtype HTT protein demonstrating the feasibility of ASO-mediated selective mutant Htt gene silencing. Next we will perform a pre-clinical trial to determine if selective mutant Htt gene silencing can delay or prevent the onset of HD-like symptoms. If successful in mice, this therapy can be rapidly translated to human applications.

The overall goal of this work is to delineate important steps in the pathogenesis of HD and to generate knowledge that will lead to 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.

Wijesekara N; Zhang L-H; Kang M; Bhattacharjee A; Verchere C; Hayden MR. miR-33a modulates ABCA1 expression, cholesterol accumulation and insulin secretion in pancreatic islets. Diabetes. 2012 61(3):653-8. PMID:22315319

Hawkins AK, Hayden MR. A Grand Challenge: Providing Benefits of Clinical Genetics to Those in Need. Genetics in Medicine. 2011 Mar; 13(3):197-200. PMID: 21283011

Young FB; Butland SL; Sanders SS; Sutton LM; Hayden MR. Putting proteins in their place: Palmitoylation in Huntington disease and other neuropsychiatric diseases. Prog Neurobiol. 2011 Dec 7. [Epub ahead of print] PMID:22155432

Visscher H; Ross CJD; Rassekh SR; Barhdadi A; Dubé MP; Al-Saloos H; Sandor GS; Caron HN; van Dalen EC; Kremer LC; van der Pal HJ; Brown AMK; Rogers PC; Phillips MS; Rieder MJ; Carleton BC; Hayden MR; CPNDS consortium. Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children. J Clin Oncol. 2011 Sep 6. [Epub ahead of print] PMID:21900104

Okamoto S-I*, Pouladi MA*, Talantova M, Yao D, Xia P, Ehrnhoefer D.E, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, Chen HS, Tong G, Hayden MR § & Lipton SA §. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingin. Nat Med. 2009; 15(12):1407-13. *Co- first authors. § Co- Senior authors PMID:19915593

Editorial: La Spada AR. Memantine strikes the perfect balance. Nat Med. 2009; 15 (12):1355-6. PMID:19966768

Editorial: Senior K. Neurodegenerative disease: Synaptic activity could hold the key to therapy for Huntington disease. Nat Rev Neurol. 2009; 6 (1):1.

Editorial: Friedman, R. Memantine Improves Symptoms and Pathology in Huntington Mice. Neur Today. 10 (2):37-38.

Ross CJD, Katzov-Eckert H, Dubé MP, Brook B, Rassekh SR, Barhdadi A, Feroz-Zadac Y, Visscher H, Brown AMK, Rogers PC, Phillips MS, Carleton B, Hayden MR. TPMT and COMT genetic variants are predictive for severe hearing loss in children receiving cisplatin chemotherapy. Nat Genet. 2009; 41(12):1345-9. PMID:19898482

Bombard Y, Veenstra G, Friedman JM, Creighton S, Currie L, Paulsen JS, Bottorff JL, Hayden MR. Perceptions of genetic discrimination among persons at-risk for huntington disease: Cross-Sectional Survey. BMJ. 2009; 338:b2175. PMID:19509425

Editorial: Tibben A. Genetic discrimination in Huntington's disease.BMJ. 2009; 338:b1281. PMID:19509423

Editorial: Pulst SM. Neurodegenerative disease. Genetic discrimination in Huntington disease. Nat Rev Neurol. 2009; 5(10):525-6. PMID:19794509

Editorial: Dispelling the stigma of Huntington's disease. Lancet Neurol. 2009; 9(8):751.

Brunham LR, Kruit JK, Verchere CB, Hayden MR. Cholesterol in Islet Dysfunction and Type 2 Diabetes. J.Clin Invest. 2008, 118 (2):403-8. Review. PMID:18246189

Brunham LR, Kruit JK, Pape TD, Timmins JM, Reuwer AQ, Marsh BJ, Parks JS, Verchere, Hayden MR. The role of β-cell ABCA1 influences insulin secretion, glucose houmeostatis and response to thiazolidinedione treatment. Nat Med. 2007; 13:340-7. PMID:17322896. Cited 34 times.

Editorial: Chakravarthy MV, Semenkovich CF. The ABCs of β-cell dysfunction in type 2 diabetes. Nat Med. 2007; 13(3):241-2. PMID:17342111

Singaraja RR, van Eck M, Bissada N, Zimetti F, Collins HL, Hildebrand RB, Brunham LR, Kang MH, Fruchart J-C, van Berkel T, Parks J, Staels B, Rothblat GH, Fievet C, Hayden MR. Both hepatic and extrahepatic ABCA1 have discrete and essential functions in the maintenance of plasma HDL-C levels in vivo. Circulation. 2006; 114:1301-9. PMID:16940190

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)

Selected Awards (since 2007)

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