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-10877049-B2
Publication Date
2020-12-29
Expiration Date
2035-08-17
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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
The invention discloses biomarkers that are secreted proteins detected in the cerebral spinal fluid (CSF) of patients with neurological disease. These biomarkers are capable of identifying patients with intrathecal inflammation, distinguishing subjects with multiple sclerosis (MS) from those without MS, differentiating MS from other inflammatory neurological diseases, distinguishing progressive MS from relapsing-remitting MS (RRMS), identifying subjects with non-MS inflammatory neurological diseases, differentiating healthy subjects from those with any neurological disease, and/or identifying subjects with increased disability, central nervous system (CNS) tissue damage, and/or neurodegeneration.
Process-specific biomarkers are further described, which can be used instead of brain biopsy to identify immune cell infiltration and/or activation in the CNS. The invention provides methods for identifying various MS-related disease states and inflammatory conditions by detecting specific biomarkers in the CSF of a subject, using either immunoassays or aptamers for detection, and includes combinations and ratios of such biomarkers for diagnostic accuracy.
The problem addressed is the lack of reliable biomarkers for intrathecal inflammation, which is a critical impediment to therapeutic progress in neuroimmunology. Traditional techniques, such as IgG index, oligoclonal bands, or CSF pleiocytosis, yield unsatisfactory sensitivity and specificity ratios and fail to adequately inform clinicians regarding immune-mediated CNS disease. Alternatives like brain biopsy carry substantial risks and are frequently non-diagnostic. There is a need for direct biomarkers of intrathecal inflammation, including those specific to MS that provide information about the inflammatory process phenotype.
Claims Coverage
The patent claims a method with one main inventive feature related to identifying subjects with MS as having progressive MS or RRMS, as well as additional steps related to therapy and measurement approaches.
Identifying progressive MS or RRMS using ratios of specific biomarkers in CSF
A method involving measurement of a defined panel of biomarker ratios in a CSF sample, including: - Ratio of JAM3 to EDA2R - Ratio of TYRO3 to EDA2R - Ratio of EDA2R to ROBO2 - Ratio of F3 to ROBO2 - Ratio of EDA2R to STX1A - Ratio of EDA2R to EPHA5 - Ratio of LTA LTB to SERPING1 - Ratio of NTRK3 to EDA2R - Ratio of WIF1 to EDA2R - Ratio of EDA2R to ALCAM - Ratio of EDA2R to L1CAM - Ratio of TIE1 to EPHA5 - Ratio of EDA2R to EPHB2 - Ratio of CFD to F5 - Ratio of EDA2R to APP - Ratio of IL13RA1 to LTA LTB - Ratio of EPHA5 to DLL1 - Ratio of CADM1 to CDNF - Ratio of CDNF to IL20RA - SHH (Sonic Hedgehog) - Ratio of EDA2R to NRXN3 - Ratio of ROBO2 to IL17RC - Ratio of EDA2R to CADM1 - Ratio of EDA2R to RTN4R - LTA LTB The method includes: 1. Measuring these biomarkers in a CSF sample obtained from the subject. 2. Identifying the subject as having progressive MS if there is a decrease in LTA LTB, the ratio of JAM3 to EDA2R, the ratio of TYRO3 to EDA2R, the ratio of LTA LTB to SERPING1, the ratio of NTRK3 to EDA2R, the ratio of WIF1 to EDA2R, the ratio of EPHA5 to DLL1, the ratio of CADM1 to CDNF, and the ratio of ROBO2 to IL17RC, and an increase in SHH and other specified ratios, relative to a control. 3. Identifying the subject as having RRMS if the changes are in the opposite direction. Additional dependent claims include: - Administering an appropriate therapy (including immunomodulatory therapies such as T cell or B cell depleting agents) to the identified subject. - Utilizing a reference standard or average values from healthy subjects as controls. - Steps for obtaining the CSF sample. - Measurement using immunoassay or aptamers. - Measuring the level of IL-12p40 in the CSF sample.
The claim coverage centers on a method for identifying progressive MS versus RRMS based on measurement of specific biomarker ratios in CSF, as well as related steps for therapy selection and measurement techniques.
Stated Advantages
The disclosed biomarkers provide improved sensitivity and specificity for identifying intrathecal inflammation and differentiating subtypes of MS and other neuroimmunological diseases compared to traditional clinical laboratory tests.
The process-specific biomarkers and combinatorial biomarker ratios allow identification of immune cell infiltration and activation in the CNS without the need for invasive brain biopsies.
The methods enable tailored treatment decisions and allow rational drug or dose adjustments by accurately quantifying pathological processes in living subjects.
Measured biomarkers can be used to select patients for appropriate therapies and to evaluate the effectiveness of treatments, enabling improved patient care and facilitating therapeutic development.
Documented Applications
Identification of subjects as having MS, progressive MS, or RRMS based on CSF biomarker ratios.
Distinguishing MS patients from subjects without MS, from patients with other inflammatory neurological diseases, and from subjects with non-MS inflammatory neurological diseases.
Identification of subjects with intrathecal inflammation, CNS tissue injury, neurodegeneration, or increased disability.
Detection of immune cell infiltration or activation in CNS tissue using process-specific CSF biomarker ratios.
Guiding choice and adjustment of immunomodulatory therapies based on CSF biomarker measurements.
Evaluation of therapeutic effectiveness for treating MS and other neuroimmunological diseases by monitoring CSF biomarkers before and after treatment.
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