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      Setting a research agenda for progressive multiple sclerosis: The International Collaborative on Progressive MS

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          Abstract

          Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.

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          Most cited references44

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          Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).

          J. Kurtzke (1983)
          One method of evaluating the degree of neurologic impairment in MS has been the combination of grades (0 = normal to 5 or 6 = maximal impairment) within 8 Functional Systems (FS) and an overall Disability Status Scale (DSS) that had steps from 0 (normal) to 10 (death due to MS). A new Expanded Disability Status Scale (EDSS) is presented, with each of the former steps (1,2,3 . . . 9) now divided into two (1.0, 1.5, 2.0 . . . 9.5). The lower portion is obligatorily defined by Functional System grades. The FS are Pyramidal, Cerebellar, Brain Stem, Sensory, Bowel & Bladder, Visual, Cerebral, and Other; the Sensory and Bowel & Bladder Systems have been revised. Patterns of FS and relations of FS by type and grade to the DSS are demonstrated.
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            Risk alleles for multiple sclerosis identified by a genomewide study.

            Multiple sclerosis has a clinically significant heritable component. We conducted a genomewide association study to identify alleles associated with the risk of multiple sclerosis. We used DNA microarray technology to identify common DNA sequence variants in 931 family trios (consisting of an affected child and both parents) and tested them for association. For replication, we genotyped another 609 family trios, 2322 case subjects, and 789 control subjects and used genotyping data from two external control data sets. A joint analysis of data from 12,360 subjects was performed to estimate the overall significance and effect size of associations between alleles and the risk of multiple sclerosis. A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis (P<1x10(-4)); of these SNPs, 38 were selected for the second-stage analysis. A comparison between the 931 case subjects from the family trios and 2431 control subjects identified an additional nonoverlapping 32 SNPs (P<0.001). An additional 40 SNPs with less stringent P values (<0.01) were also selected, for a total of 110 SNPs for the second-stage analysis. Of these SNPs, two within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with multiple sclerosis (P=2.96x10(-8)), as were a nonsynonymous SNP in the interleukin-7 receptor alpha gene (IL7RA) (P=2.94x10(-7)) and multiple SNPs in the HLA-DRA locus (P=8.94x10(-81)). Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis. Copyright 2007 Massachusetts Medical Society.
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              Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

              Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. 1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals; 2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk. 4 Modestly powered Genome-Wide Association Studies (GWAS) 5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility. 11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.
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                Author and article information

                Journal
                Mult Scler
                Mult. Scler
                MSJ
                spmsj
                Multiple Sclerosis (Houndmills, Basingstoke, England)
                SAGE Publications (Sage UK: London, England )
                1352-4585
                1477-0970
                November 2012
                November 2012
                : 18
                : 11
                : 1534-1540
                Affiliations
                [1 ]Mellen Center for Multiple Sclerosis, Neurological Institute, and Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, USA
                [2 ]Department of Brain Repair and Rehabilitation, University College London Institute of Neurology, Faculty of Brain Sciences, London, UK
                [3 ]Centre for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK
                [4 ]Multiple Sclerosis International Federation, London, UK
                [5 ]Multiple Sclerosis Society, London, UK
                [6 ]National MS Society, New York, NY, USA
                [7 ]Department of Neurology, Scientific Institute San Raffaele, Milan, Italy
                [8 ]Department of Psychiatry, University of Toronto, Canada
                [9 ]National Hospital for Neurology and Neurosurgery, London, UK
                [10 ]MS Society of Canada, Toronto, ON, Canada
                [11 ]Center for Neurology and Experimental Therapies, Sapienza University, Rome, Italy
                [12 ]Fast Forward, LLC, New York, NY, USA
                [13 ]Italian MS Society, Genoa, Italy
                [14 ]MS Research Foundation, Voorschoten, The Netherlands
                Author notes
                [*]Robert J. Fox, Mellen Center for Multiple Sclerosis, Neurological Institute, and Lerner College of Medicine, Cleveland Clinic, 9500 Euclid Ave, U-10, Cleveland Clinic, Cleveland, OH, 44122 USA. Email: foxr@ 123456ccf.org
                Article
                10.1177_1352458512458169
                10.1177/1352458512458169
                3573679
                22917690
                561f5c2b-4ad4-464c-9958-58ef282aa377
                © The Author(s) 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 June 2011
                : 18 July 2012
                : 22 July 2012
                Categories
                New Perspective

                Immunology
                multiple sclerosis,progressive multiple sclerosis,neuroprotection,rehabilitation,research agenda

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