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Molecular-based diagnosis of multiple sclerosis and its progressive stage
Author(s): ,
P Kosa
Affiliations:
Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
,
C Barbour
Affiliations:
Department of Mathematical Sciences, Montana State University, Bozeman, MT
,
M Komori
Affiliations:
Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
,
M Tanigawa
Affiliations:
Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
,
T Wu
Affiliations:
Clinical Trials Unit, National Institute of Neurological Disorders and Stroke
,
K Johnson
Affiliations:
Bioinformatics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda
,
R Herbst
Affiliations:
Department of Respiratory, Inflammation and Autoimmunity Research, MedImmune LLC, Gaithersburg, MD, United States
,
Y Wang
Affiliations:
Department of Respiratory, Inflammation and Autoimmunity Research, MedImmune LLC, Gaithersburg, MD, United States
,
K Tan
Affiliations:
Translational Medicine, Neuroscience Innovative Medicines, MedImmune Ltd, Cambridge, United Kingdom
,
M Greenwood
Affiliations:
Department of Mathematical Sciences, Montana State University, Bozeman, MT
B Bielekova
Affiliations:
Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
ECTRIMS Online Library. Kosa P. Sep 16, 2016; 147061; 219
Peter Kosa
Peter Kosa
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Abstract: 219

Type: Oral

Abstract Category: Pathology and pathogenesis of MS - Biomarkers

Background: Molecular taxonomy of cancers revolutionized oncology: biomarkers guide combination therapies specific for a patient"s disease process and patient preselection leads to economical clinical trials. In contrast, polygenic central nervous system (CNS) diseases like multiple sclerosis (MS) lack a molecular diagnosis. Despite multifaceted pathophysiology and pathological heterogeneity, each MS patient is treated with a single drug without understanding what molecular mechanism(s) drive his/her disability. Therefore, we sought to develop a molecular signature of MS and its progressive stage(s) using reliable proteomic assay.

Methods: Using 1128 Slow Off-rate Modified DNA Aptamers (SOMAscan) and statistical modeling we identified in the blinded cohort of untreated patients with CNS diseases and healthy volunteers (n=225) a combinatorial biomarker of 17 cerebrospinal fluid (CSF) proteins that differentiates MS from other CNS diseases, including inflammatory, with an independent cohort (n=85)-validated area under the receiver operating characteristic curve (AUC) of 0.95.

Results: Immunological biomarkers dominate the MS diagnostic test and over-representation of signaling lymphocytic activation molecule (SLAM) family members identifies these immunoregulatory molecules as a possible new therapeutic target. Primary- and secondary-progressive MS are biologically indistinguishable, with quantitatively comparable intrathecal inflammation to relapsing-remitting MS (RRMS). The molecular test that differentiates RRMS from progressive MS with a validated AUC=0.90 is based on 27 proteins and quantifies oligodendroglial and neuronal damage and LTA/LTB-related inflammation.

Conclusions: Validated molecular tests open opportunities for biomarker-supported drug development in MS, targeting processes poorly captured by imaging, such as neurodegeneration, compartmentalized inflammation in progressive MS and residual inflammation in partially-treated RRMS.

Disclosure:

Funding: The study was supported by the intramural research program of the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) and the Material Transfer Agreement (MTA) between NINDS and Medimmune, LLC (A member of the AstraZeneca Group) that funded the SOMAscan assay performed in the validation cohort.

Peter Kosa: nothing to disclose

Christopher Barbour: nothing to disclose

Mika Komori: nothing to disclose

Makoto Tanigawa: nothing to disclose

Tianxia Wu: nothing to disclose

Kory Johnson: nothing to disclose

Ronald Herbst: nothing to disclose

Yue Wang: nothing to disclose

Keith Tan: nothing to disclose

Mark Greenwood: nothing to disclose

Bibiana Bielekova: nothing to disclose

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