Contributions
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
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