Biomarkers for diagnosis and management of neuro-immunological diseases
Inventors
Bielekova, Bibiana • Komori, Mika • Kosa, Peter • Greenwood, Mark C. • Barbour, Christopher
Assignees
Montana State University Bozeman • US Department of Health and Human Services
Publication Number
US-10261098-B2
Publication Date
2019-04-16
Expiration Date
2035-08-17
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Biomarkers associated with neuroimmunological disease are described. The disclosed biomarkers are secreted proteins identified in cerebral spinal fluid (CSF) samples of patients with neurological disease. The disclosed biomarkers identify patients with intrathecal inflammation, distinguish multiple sclerosis (MS) patients from patients with other types of inflammatory neurological diseases and from subjects without MS, distinguish progressive MS patients from patients with relapsing-remitting MS, identify subjects with non-MS inflammatory neurological diseases, differentiate healthy subjects from patients with any type of neurological disease, and/or identify subjects with increased disability, CNS tissue damage and/or neurodegeneration. Process-specific biomarkers that can be used in place of a brain biopsy to identify immune cell infiltration and/or activation in the CNS are also described. Methods of treating subject with neurological disease, and methods of evaluating the efficacy of particular treatments, based on detection of the disclosed biomarkers are also described.
Core Innovation
Biomarkers associated with neuroimmunological diseases, specifically secreted proteins identified in cerebrospinal fluid (CSF), are disclosed as a means to reliably detect and differentiate various neurological disease states and inflammatory phenotypes. The invention encompasses biomarkers that can identify patients with intrathecal inflammation, distinguish multiple sclerosis (MS) patients from those with other types of inflammatory neurological diseases and from healthy or non-MS subjects, differentiate progressive MS from relapsing-remitting MS (RRMS), and further categorize subjects with non-MS inflammatory neurological diseases or other neurological conditions.
The problem addressed is the lack of reliable biomarkers for intrathecal inflammation, which is a significant challenge in neuroimmunology. Traditional laboratory measures, such as IgG index, oligoclonal bands, and CSF pleiocytosis, provide unsatisfactory sensitivity and specificity. As a result, diagnoses often require invasive procedures like brain biopsy or risky empirical treatments, both of which can expose patients to significant risks while sometimes resulting in inconclusive findings. There is a clear need for direct biomarkers of intrathecal inflammation and MS, particularly those that provide information on the specific phenotype of the inflammatory process.
The patent describes process-specific biomarkers and methods that can be used instead of brain biopsy to identify immune cell infiltration and/or activation in the CNS. Additionally, provided are methods for diagnosing, treating, and monitoring neurological diseases—including MS—based on the detection of these disclosed biomarkers. The methods also include evaluating the efficacy of particular therapies by assessing the presence and fluctuation of these biomarkers in the CSF, thereby enabling more precise and individualized management of neuroimmunological disorders.
Claims Coverage
There are three main inventive features covered by the independent claims of the patent.
Method for identifying multiple sclerosis using CSF biomarker profiles
This inventive feature introduces a method that comprises the following steps: 1. Measuring specific biomarkers in a CSF sample from a subject. The biomarkers include: - The ratio of FLT4 to TNFRSF17 - The ratio of TNFRSF17 to CD48 - The ratio of TNFRSF17 to IL16 - The ratio of TNFRSF17 to TNFRSF6B - The ratio of TNFRSF17 to CD163 - The ratio of TNFRSF17 to SHC1 - TNFRSF17 - The ratio of TNFRSF17 to UFC1 - The ratio of LY9 to IGHG1 - The ratio of LTA LTB to IGHG1 - MMP7 - SLAMF7 - TNFRSF1B - IGHG1 - CD48 - VCAM1 - CHIT1 - PLA2G5 2. Identifying the subject as having MS if there is an increase in specific biomarkers and a decrease in others compared to a control: - Increase: TNFRSF17, MMP7, SLAMF7, TNFRSF1B, CD48, VCAM1, CHIT1, PLA2G5, IGHG1, the ratio of TNFRSF17 to CD48, to IL16, to TNFRSF6B, to CD163, to SHC1, and to UFC1 - Decrease: the ratio of FLT4 to TNFRSF17, the ratio of LY9 to IGHG1, and the ratio of LTA LTB to IGHG1
Method for treating multiple sclerosis using biomarker measurements and immunomodulatory therapy
This inventive feature covers a method comprising: 1. Selecting a subject based on the presence of increased or decreased levels of the aforementioned CSF biomarkers relative to a control (decreased: ratio of FLT4 to TNFRSF17, ratio of LY9 to IGHG1, and ratio of LTA LTB to IGHG1; increased: TNFRSF17, MMP7, SLAMF7, TNFRSF1B, CD48, VCAM1, CHIT1, PLA2G5, IGHG1, and specified ratios involving TNFRSF17). 2. Administering to the subject an immunomodulatory therapy, such as a T cell depleting agent, a B cell depleting agent, or both, thereby treating MS in the subject.
Method for evaluating therapy effectiveness in treating multiple sclerosis by monitoring biomarker changes
This inventive feature provides a method that involves: 1. Measuring the same set of CSF biomarkers before and after the administration of treatment for MS. 2. Determining treatment effectiveness by observing: - A decrease in TNFRSF17, MMP7, SLAMF7, TNFRSF1B, CD48, VCAM1, CHIT1, PLA2G5, IGHG1, and the specified ratios involving TNFRSF17 (to CD48, IL16, TNFRSF6B, CD163, SHC1, UFC1) - An increase in the ratios of FLT4 to TNFRSF17, LY9 to IGHG1, and LTA LTB to IGHG1 in post-treatment samples compared to pre-treatment samples.
The inventive features are directed to methods for identifying MS via specific CSF biomarker profiles, treating MS based on CSF biomarker measurements with immunomodulatory therapies, and evaluating treatment effectiveness by monitoring defined biomarker changes.
Stated Advantages
Provides reliable biomarkers for intrathecal inflammation and MS, improving sensitivity and specificity over existing laboratory methods.
Enables differentiation of MS from other neurological diseases and between MS subtypes using non-invasive CSF analysis rather than invasive brain biopsy.
Facilitates individualized treatment decisions and monitoring of therapeutic effectiveness in neuroimmunological diseases using quantitative biomarker measurements.
Allows identification and management of progressive MS based on biomarker profiles, supporting better disease stratification.
Improves risk assessment and reduces unnecessary or harmful interventions by providing more precise diagnostic information.
Documented Applications
Identifying subjects as having multiple sclerosis, differentiating MS from other types of inflammatory neurological diseases, and distinguishing MS subtypes using CSF biomarkers.
Treating MS and other inflammatory neurological diseases by selecting and administering immunomodulatory therapies based on biomarker measurements.
Evaluating effectiveness of therapies for MS by measuring and comparing CSF biomarker profiles before and after treatment.
Differentiating healthy subjects from patients with any type of neurological disease using CSF biomarker analysis.
Identifying subjects with intrathecal inflammation and determining immune cell infiltration or activation in the CNS as a substitute for brain biopsy.
Interested in licensing this patent?