Project: A genotyping prognostic tool to predict course of multiple sclerosis (MS), improve its management and personalize treatment

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system and spinal cord. An abnormal immune response contributes to demyelination of areas of the white matter and the myelin sheath, leading to major neurological disability in young adults. When myelin is lost, the axons of the neurons can no longer effectively conduct action potentials. Although much is known about the mechanisms involved in the disease process, the cause reCOs unknown. A genetic predisposition, possibly infections, and different environmental risk factors are involved. MS is a "complex" disease of a polygenic and multifactorial nature._x000D__x000D_No curative therapy is available. Approximately 80% of individuals suffering from MS are ultimately severely disabled. The goal of treatment is to induce and COtain remission of the disease in order to prevent permanent disability. There are three CO subtypes, based on relapsing patterns: the commonest is the Relapsing-Remitting (RR) form, followed by the Secondary Progressive form (SP) and, less commonly, by the primary progressive (PP) form. However, a person with MS can suffer almost any neurological symptom or sign. The CO clinical measure of disability progression and symptom severity is the Expanded Disability Status Scale (EDSS). The scores on the EDSS scale can be related to the distribution of disability, resulting in the Multiple Sclerosis Severity Score. The most valuable diagnostic tool is magnetic resonance imaging (MRI) of the brain and spines since it demonstrate clearly the areas of demyelination (lesions or plaques). Other neuroimaging techniques, analysis of cerebrospinal fluid, and evoked potentials are used in assessing the patient status. _x000D__x000D_Epidemiological and familial studies support the concept that MS occurs as a result of the combination of both environmental and genetic factors. Advances in the polygenic nature of the disease have been slow in this complex disease. Recent DNA technologies such as genome wide screening with high throughput techniques are promising. A number of single nucleotide polymorphisms (SNPs) give raise to genetic variants that maybe involved in susceptibility to suffer from MS, determination of the course of the disease and prediction of treatment response. Knowledge on these SNPs has contributed to the discovery of new pathways of inflammation and new genes involved in disease predisposition. This has been possible due to new technology that has allowed the study of large groups of well defined patients with long-term follow-up. The application of this new knowledge to information on the total volume of brain lesions present and their spatial distribution, provided by MR, is likely to contribute to the understanding of clinical heterogeneity in MS. _x000D__x000D_The goal of this project is the creation of a “kit” composed of a SNP genotyping chip and a predictive model that, when used in combination with clinical and MRI data, will allow for disease prognosis, improving its management and introducing a personalized approach to the treatment. In this context, the project will develop and provide a technological solution that can be routinely used early in the diagnostic process to help prognosis, management and follow-up of Multiple Sclerosis. _x000D__x000D_To reach the objective of this project, Progenika Biopharma S.A. and two departments of the VU University Medical Center (VUmc), the Department of Neurology and the Department of Neuroimaging, will join efforts, expertise and technology. These are three of the leading groups in their respective fields. First, Progenika Biopharma, an international leader in personalized medicine, has great expertise in developing genotyping DNA chips for diagnosis and prognosis of complex multigenic diseases as well as pharmacogenomic tools for evaluation of drug effects and efficacy. Examples of genotyping chips already in use include LIPOchip®, BLOODchip®, PHARMAchip® and ARTchip®. Second, the Department of Neurology at the VU University Medical Center is one of the leading institutions in the World for research of Multiple Sclerosis, supported by many years of research and publications in many of the most representative journals in the field. Third, the Neuroimaging Department is a leader in MRI technology and application to MS research. Currently, the VUmc group is hypothesizing that spatial distribution of the lesions may reveal immunological patterns of inflammation driven by genetic predisposition, contributing to explaining clinical heterogeneity in MS. Research by this group has allowed the collection of a cohort of over 600 well-characterized samples from patients diagnosed with MS with long-term follow up that can be analyzed for the detection of brain and spinal cord lesions, an important preamble for the success of this project.

Acronym	PrognoseMS (Reference Number: 5090)
Duration	01/06/2010 - 31/05/2013
Project Topic	A predicting tool based on genomic information (MSchip) and its correlation with clinical variables and MRI of the brain and cord is being developed. The aim of this tool is to improve differential diagnosis of MS and predict long-term course and disability from an early phase of the disease.
Project Results (after finalisation)	This project has provided a set of single nucleotide polymorphisms (SNPs) significantly associated with the severity of multiple sclerosis (MS). We have developed a DNA chip able to detect this set of SNPs in a multiplex assay. As a result, we have set up a prototype MS chip; a DNA microarray that accurately detects the six SNPs included in the severity models. The MS chip has been validated technically. Thus we have developed a chip and user friendly software that makes fast, easy and reliable genotyping possible. Together with a set of probabilistic algorithms it can be used as a tool to predict the probability of developing cellular degeneration and central nervous inflammation in MS patients.
Network	Eurostars
Call	Eurostars Cut-Off 3

Project partner

Number	Name	Role	Country
2	Progenika Biopharma SA	Coordinator	Spain
2	VU University Medical Centre	Partner	Netherlands