Research Pillar: Clinical
New indications for old drugs: Do statins, angiotensin converting enzyme inhibitors or proton pump inhibitors impact long-term disease progression in multiple sclerosis?
The most widely prescribed drugs for multiple sclerosis (beta interferons) have been shown to be only partially effective while carrying high costs and adverse side-effects. However, statins, angiotensin converting enzyme (ACE) inhibitors, and proton pump inhibitors (PPIs), which are effective against lipids, blood pressure, and acid, respectively, are safe, relatively inexpensive, and also have anti-inflammatory and immunomodulating properties that may be beneficial in the treatment of MS. There is a shortage of clinical data supporting the beneficial effects of these drugs in MS treatment.
This project will study the real-world therapeutic potential of statins, ACE inhibitors, and PPIs in the treatment of multiple sclerosis.
Dr. de Jong will examine the impact of statins, ACE inhibitors, and PPIs on multiple sclerosis disease progression, alone or in combination with beta interferon therapy, in a large cohort of patients with relapsing-onset MS from British Columbia. She will also describe the safety and tolerability of these drugs in patients with MS treated with and without a beta interferon. In both studies, a time-dependent Cox proportional hazards model will be used. Results will be expressed as hazard rates with 95 percent confidence intervals.
This research has the potential to improve the treatment of multiple sclerosis by establishing the efficacy, safety, and tolerability of alternative drugs for the treatment of MS.
Mechanisms of cardiovascular disease in children with mental health conditions
Prescriptions of second-generation antipsychotic (SGA) medication for children in British Columbia increased 22-fold from 1996 to 2010. These medications treat the underlying mental health issues (e.g. psychosis, depression, attention deficit/hyperactivity disorder) but often come with side-effects, including metabolic syndrome.
Metabolic syndrome is a cluster of clinical features that includes excess weight around the middle, high blood pressure, and high blood sugar or triglyceride concentrations. Given that metabolic syndrome is a risk factor for cardiovascular disease, there are serious implications for the long-term health of these children. Development of a secondary chronic disease such as CVD, on top of an existing mental health condition, further marginalizes the life-long health of these children.
Accordingly, there is a need to develop a means by which to distinguish children at risk for developing metabolic syndrome from those who are not. The goal of this research is to identify genetic markers that will indicate which children will develop risk factors for heart disease and stroke when treated with SGAs so that appropriate prevention strategies may be implemented in these children.
Examining executive functions as mediators of a mental and social enrichment intervention for older adults with chronic stroke
Significant proportions of stroke survivors suffer long-term physical disability and are predisposed to sedentary lifestyles. This limits their performance of activities necessary for independent living in the community and contributes to increased risk for recurrent stroke and heart disease. Dr. John Best recognizes that intervention strategies are needed to motivate stroke survivors to engage in routine physical activity and to optimize their physical and motor functions.
Best’s research will examine executive functions (EFs) as mediators of a mental and social enrichment intervention for older adults with chronic stroke. Broadly speaking, EFs refer to the cognitive processes that allow for adaptive behavior and self-control.
One promising strategy targets EFs by engaging stroke survivors in complex mental and social activities. Best’s research will evaluate the importance of improving EFs within the context of a mental and social enrichment intervention in order to have a meaningful impact on physical and motor functions, the ability to perform daily activities, and routine engagement in physical activity.
The information garnered from Best’s research will be crucial for improving stroke rehabilitation for older Canadians who suffer chronic disability from stroke.
Characterizing the impact of silent lesions on stroke recovery using multimodal neuroimaging
Half of individuals recovering from a stroke have some form of impaired cognition, which hampers their independence. One possible contributor to impaired cognition after stroke is the presence of small “silent” lesions, which are detected in up to 28 percent of individuals with stroke.
Currently, there is little data describing the impact of silent lesions on stroke recovery. This study will determine if impaired cognition after stroke is associated with the presence and quantity of silent lesions.
Multimodal neuroimaging will identify how silent lesions affect brain function after stroke and determine if the number and/or type of silent lesion differently impacts cognition or brain function. The impact of silent lesions on brain function will be assessed by measuring cerebral vascular reactivity and examining neural network activity during a cognitive task.
Together with a battery of cognitive assessments, these measures will help explain how silent lesions alter cognition after a stroke. This knowledge will lead to the development of new interventions that account for silent lesions, resulting in improved quality of life for Canadians with stroke.
Psycho-social predictors of physical activity in community-dwelling and vulnerable seniors: Linking daily life processes with long-term health outcomes
Canada is an aging society, and the proportion of Canadians older than 65 is estimated to double within the next 10 years. It is well known that aging is associated with declining health, but there is also tremendous variability in aging outcomes. While physical activity can reduce the risk of many age-related diseases, such as cardiovascular disease and diabetes, Canadian seniors have low rates of physical activity.
Dr. Christiane Hoppmann’s research takes an innovative approach to examining key psychological factors, such as goals and planning, that may explain why some seniors are successful at implementing physical activity into their daily lives while others remain physically inactive. There is also recognition that the translation of physical activity goals into action demands cognitive and emotional resources that become increasingly limited with aging. For example, seniors with memory failures and fear of falling may encounter more difficulties engaging in physical activity. Hoppmann’s team will conduct an in-depth investigation of the psychological determinants of daily physical activity using a design called time-sampling. This method, which involves seniors completing a diary of their physical activities, memory, and emotions several times a day, will allow an examination of daily fluctuations across domains of functioning. Physical activity will also be assessed using portable electronic devices worn on the hip called accelerometers. Hoppmann’s team will also conduct one- and two-year follow-up assessments to link daily physical activity with long-term physical and mental health.
This research constitutes an important step to better understanding the psychological determinants of physical activity in seniors and their impact on physical and mental health. Findings will inform novel interventions (e.g. targeting goals and emotion-regulation) to promote healthy aging in community-dwelling and particularly vulnerable seniors in Canada.
Manipulating the trajectory of the human fetal, newborn & infant immune system
Millions of newborns and infants die each year from infectious diseases. Many of these deaths are preventable, and analysis of the immune development of children can help define paths for medical intervention that may save lives.
Dr. Tobias Kollmann’s research team is conducting the first global comparison of immune development in cohorts of children from different countries. This project will compare the immune development of children born in Vancouver to those born in South Africa, Mozambique, Ecuador and Belgium. Preliminary research has found striking qualitative and quantitative differences in children’s immune development that appear to be directly related to their genetic make-up as well as the particular environment to which they are exposed. Kollmann’s team is dissecting the cause-effect relationship for the role of host genetics and studying the environmental factors that direct the developmental path of the innate and adaptive immune responses. Analysis of these genetic and environmental factors will potentially reveal pathways that direct future efforts to treat and prevent infectious diseases.
Kollmann’s team is already developing a platform that will help deliver targeted vaccinations to protect newborns. Using genetically altered strains of Listeria monocytogenes, the vaccine will induce a desired immune response only in specific cells and then disappear without harming the child. Preliminary data suggest this goal is within reach, and Kollmann’s team is working in partnership with industry to design and test a Listeria-based vaccination for newborns. Through this work, safe yet effective methods will be identified to prevent millions of newborn and infant deaths due to infectious diseases.
Training parents as friendship coaches for children with Attention-Deficit/Hyperactivity Disorder
Attention-Deficit/Hyperactivity Disorder (ADHD) is a syndrome marked by inattention and/or hyperactivity/impulsivity that affects 5-8 percent of Canadian youth. It makes up the most frequent referral for children’s mental health services and is associated with considerable psychosocial morbidity. A significant aspect of the impairment in ADHD is the difficulty these children face in getting along with peers. More than half of children with this condition are severely disliked by their peers or do not have a single friend. Peer problems result in loneliness and sadness for children with ADHD, and heighten the risk for future school failure, drug abuse, and delinquency. Treatments for the core symptoms of ADHD are ineffective at changing peers’ liking of children with ADHD, and if existing treatments do not also improve peer relationship problems, children with ADHD remain likely to experience poor health outcomes. These findings underscore the importance of developing adjunctive treatments capable of addressing the peer problems faced by children with ADHD.
Dr. Amori Mikami’s research focuses on the development, efficacy testing, and knowledge translation of novel psychosocial interventions for peer problems in children with ADHD. She proposes to expand upon an innovative intervention: training parents to improve the peer relationships of their children with ADHD. This is known as parental friendship coaching (PFC). Supported by the National Institute of Mental Health, Mikami created the PFC intervention and demonstrated in a randomized trial of 62 children with ADHD that PFC appeared effective relative to a no-treatment control group.
Mikami is following up on these promising preliminary results with a more definitive test of PFC and a better study of the mechanisms behind treatment efficacy. She will compare PFC against an active attention control intervention (to ensure the incremental value of the PFC techniques beyond social support and therapist time), involve 150 children from two diverse areas in Canada, follow up with participants eight months post-intervention, and use a thorough battery to measure outcomes, mediators, and moderators. Future studies will focus on disseminating new knowledge about PFC and peer problems to practitioners.
Understanding tumor microenvironment interactions in lymphoid cancers: Translation into improved treatment outcome prediction and development of personalized therapies
Malignant lymphomas are the fifth most frequent cancer in humans, affecting patients of all ages. Despite generally effective treatments, a significant number of patients still die from the progressive disease. Interactions of the malignant cells with cells of the tumor microenvironment are increasingly recognized to play a pivotal role in the development of many lymphoma subtypes. However, the clinical potential of an improved understanding of microenvironment-related biology remains largely untapped.
Dr. Christian Steidl’s research focuses on B-cell lymphomas; in particular on the two related subtypes — Hodgkin lymphoma and primary mediastinal B-cell lymphoma — that often affect adolescents and young adults. This study will investigate tumor microenvironment interactions as therapeutic targets in B-cell lymphomas. Steidl’s team will seek to elucidate the underlying pathobiology of the tumor microenvironment, and macrophage interactions in particular, to identify novel drug targets and pave the way for the design of innovative clinical trials.
The study will also identify outcome predictors and resistance mechanisms of childhood and adult Hodgkin lymphoma. Molecular treatment outcome predictors will be developed using genomics approaches. Better outcome prediction using biological markers will identify patients at high risk and allow for personalized treatment approaches for children and adults suffering from relapsed Hodgkin lymphoma. Specifically, the recent emergence of novel targeted therapies holds the promise to overcome this high risk using these therapies to augment or replace existing therapies.
Finally, this research will define the mutational landscape of Hodgkin lymphoma and primary mediastinal B-cell lymphoma. This will involve the complete characterization of mutations by next-generation sequencing approaches. Preliminary data indicate that somatic mutations in both diseases are critically deregulating molecular pathways that might be targetable by novel therapeutic approaches. These studies will aim to transform novel findings into meaningful advances in clinical hematology.
Translation of next-generation sequencing to HIV treatment and prevention in British Columbia
Next-generation sequencing (NGS) is the automation of high-throughput DNA sequencing on a massive scale that is rapidly transforming biology and medicine. It can enable laboratories to detect small, but clinically significant, numbers of drug-resistant viruses in blood samples from infected individuals.
The lack of computational tools to process and interpret NGS data collected from rapidly-evolving populations such as HIV remains a major obstacle in the application of NGS to HIV treatment and prevention. Dr. Poon’s research will bridge this divide by developing computational methods for NGS analysis designed to address key issues in HIV prevention and treatment. He will share his software as a free resource to the basic and clinical research communities.
He will take advantage of resources available to him through the BC Centre for Excellence in HIV/AIDS (BC-CfE): an extensive archive of HIV plasma specimens; one of the world’s few NGS cores dedicated to HIV research; and his own expertise in molecular evolution and bioinformatic sequence analysis.
As part of his research, he is developing and validating a new method to reconstruct the time of HIV infection from NGS data. Using specimens from the BC-CfE, he will estimate times of HIV infection and reconstruct the historical trend of HIV incidence (the rate of new HIV infections) in BC. This will help assess the long-term impact of expanding access to HIV therapy in BC and identify other correlates of HIV incidence.
He will also use “phylogenetic” methods, which can infer the ancestral tree that relates observed genetic sequences, to reconstruct the history of HIV transmissions in BC. This will allow him to evaluate the impact of expanding access to HIV therapy in BC on the rate of transmitting drug-resistant HIV, and to characterize the variation in rates of HIV transmission over the course of the epidemic.
Finally, he will develop a new class of methods for analyzing NGS data to characterize the adaptation of HIV to the host-specific immune response, and to reconstruct the genetic sequence of the transmitted HIV strain. The results from these methods can provide key information for the development of HIV vaccine candidates – a core aim of HIV prevention research.