Shots: 

• Multiple Sclerosis affects over 2.8M people globally. Despite several tech infusions in MS research, the exact cause of the condition remains unknown 

• Recently, Metabolon, known for providing metabolomics solutions joined hands with the Division of Psychological Medicine and Clinical Neuroscience (DPMCN) at Cardiff University to discover new biomarkers to expedite the understanding and treatment of MS 

• Today, at PharmaShots, we engaged in an illuminating dialogue with Kari Wong from Metabolon and Dr. Emma Tallantyre from Cardiff University 

Saurabh: Congratulations on your alliance with Cardiff University’s Division of Psychological Medicine and Clinical Neuroscience. To start with can you provide us with the insights behind the collaboration with Cardiff University’s Division of Psychological Medicine and Clinical Neuroscience? What led to this collaboration and how do the goals of Metabolon and Cardiff University align with one another?   

Kari: We are very excited to be working together to take a systems approach to better understand the pathology of multiple sclerosis (MS). As a multi-factorial disease, understanding the interplay between genetic predisposition and environmental influences is crucial for unraveling the complexities of MS.  Notably, limited treatment options are available for progressive forms of MS, particularly primary progressive MS (PPMS) and secondary progressive MS (SPMS), both of which are included in this cohort study. Overall, this partnership holds promise for advancing our understanding of MS, improving diagnostics and treatments, and ultimately developing personalized approaches to treatment. 

Saurabh: Currently, around 2.5 million people are living with Multiple Sclerosis worldwide with very limited approved therapies for the disease. Could you please share with us the roadmap of your future plan?   

Kari: In order to develop personalized medicine approaches, research must begin with well-powered and well characterized cohorts to truly investigate patient stratification.  Cardiff University’s Division of Psychological Medicine and Clinical Neuroscience has compiled samples from a large longitudinal cohort focused on multiple sclerosis. This research will reveal the dynamic patterns of metabolic signatures as they relate to disease progression, activity, and disease type.  The goals will be two-fold: identify metabotypes based on the clinical data that will allow for increased patient stratification, and 2) integrate genomic signals with the metabolite profiles to identify biomarkers and potentially novel therapeutic targets.  Important to this foundational work is the ability to translate research findings into clinical applications, such as developing predictive models for disease prognosis or response to therapies, identifying novel drug targets, and eventually guiding personalized treatment strategies for MS patients. 

Saurabh: What is the pathology of Multiple sclerosis? Can you please share with us the insights from your current research that hint at the environmental factors that influence Multiple Sclerosis?  

Dr. Tallantyre: Multiple sclerosis is characterized by focal inflammatory demyelination within the brain and spinal cord. Genetic risk of developing MS is heavily weighted towards variations in genes of the immune system. However, the genes only explain part of the risk of developing MS. Epidemiological studies suggest that vitamin D, timing of Epstein Barr virus infection, smoking, body habitus and other environmental factors could all play a part in either the risk of getting MS or the risk of developing more rapid disability worsening once MS is established. Likewise, certain body processes such as cholesterol metabolism, anti-oxidation, or the relationship between the gut and brain have all been implicated in MS pathology. By studying the genome and metabolome, we aim to try to unpick some of the relationships between risk of MS and risk of disability. 

Saurabh: Could you shed some light on the importance of profiling plasma and CSF and how it enhances the ability to define the temporal evolution of pathologies at an individual level?   

Kari: As a neurological disease, CSF is the most proximal sample type to study disease pathology.  The metabolomic profile of the CSF may be integral in understanding pathways dysregulated in diseased patients, which in turn, may reveal new therapeutic targets. There are a number of publications demonstrating metabolic profile differences in CSF from MS patients and controls; however, because collecting CSF is quite invasive, we hope to take advantage of the paired collection of CSF and plasma, where applicable, to identify corresponding signals in the circulation.  Collecting CSF in a longitudinal manner is not clinically practical, but by surveying both matrices for analogous signals, we hope to develop methods and signatures that enable longitudinal assessment of MS patients in a minimally invasive manner. 

Saurabh: How does Metabolon intend to integrate Multiomic data to provide a holistic understanding of the Molecular underpinning of Multiple sclerosis?  

Kari: A current focus in modern research revolves around integrating multiomic data streams, a challenging task due to the vast amount of data involved. Researchers across disciplines are grappling with reducing this data into manageable and actionable pieces. Statistical methods such as metabolite-gene association (mGWAS) and Mendelian Randomization (MR) are being employed to merge genomic, metabolomic, and clinical data. mGWAS analyzes genetic data alongside metabolite profiles to pinpoint genetic variations linked to metabolite level disparities, shedding light on how genetic differences impact metabolite production and metabolism in the context of disease. Mendelian randomization delves into the causal connections between genetic variants affecting metabolite levels and health outcomes. Together, these methodologies facilitate the integration of diverse omics datasets, providing clinically relevant results. 

Saurabh: Since there are very few therapies approved for Multiple Sclerosis, how do you expect the proposed research to inform how Multiple sclerosis patients approach treatment options?   

Dr. Tallantyre: Current treatments for MS mainly target different aspects of the immune system, aiming to switch off focal inflammatory demyelination occurring in the brain and spinal cord. There is currently a large research focus around potential treatments aimed at neuroprotection, remyelination or repair. Currently, treatment decisions are guided by some baseline characteristics about the person with MS such as their disability or attack frequency, but are not personalized in the truest sense. We recognize considerable variation in the disability trajectory and treatment response of people with MS. We believe that combined study of genomics and metabolomics will shed more light on pathways that are important in driving MS disability, and may also help to explain variations we observe in individual treatment response. 

Image Source: Canva 

About the Author: 

Kari Wong  

Dr. Kari Wong is a Scientific Strategy Director and has been at Metabolon for almost eight years.  She currently develops partnerships and scientific strategies that support sustained company growth by working with collaborators to understand how metabolomics can be integrated into research and development pipelines.  Previously, she headed the Population Health group, working with large cohorts from around the world.  Dr. Wong has also collaborated with industry stakeholders to understand the application of metabolomics in their drug discovery and development strategies.  
 
Prior to Metabolon, Dr. Wong served as a research scientist and postdoctoral fellow at the Duke Molecular Physiology Institute where she began working with metabolomics datasets.  Her research focused on the importance of fuel utilization pathways in pre-clinical models of diet and exercise-induced weight change. In her 10+ years as a biochemist working with metabolomics datasets, she has presented at international meetings as well as contributed to numerous publications and poster presentations. 

Emma Tallantyre 

Dr. Tallantyre graduated from medical school at the University of Nottingham in 2002 and undertook her postgraduate medical and neurological training in Nottingham, Derby, Australia and South Wales. As an MRC research fellow, she completed a PhD investigating imaging (Sir Peter Mansfield MR centre) and neuropathology (Nottingham University) of multiple sclerosis (MS). 

Dr. Tallantyre has been involved in the clinical care of people with MS since 2006. She completed her clinical training in 2015 and became a Clinical Senior Lecturer in Neurology in 2018, and a Clinical Reader in 2022. Her current research interests centre on the outcomes of neuroinflammatory disease. She is involved in clinical trials that investigate the optimum treatment approaches in multiple sclerosis and has an interest in combining real world clinical data with associated biological and imaging data to strengthen predictions of outcome and improve trial design. 

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