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Innate immune proteins as biomarkers for CNS injury

a technology of innate immune proteins and biomarkers, applied in the field of neurology, immunology, diagnostics, etc., can solve the problems of one-third of injury-related deaths, difficult to predict the severity and outcome of tbi and sci, and limited valu

Inactive Publication Date: 2015-07-02
UNIV OF MIAMI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is based on the discovery that NLRP1 inflammasome components are secreted into the cerebrospinal fluid after SCI and TBI in humans. The levels of inflammasome proteins in the CSF after injury correlate with the degree of neuroinflammation and the extent of inflammatory-induced damage. The CSF levels of inflammasome proteins can be used as acute biomarkers to predict patient prognosis and direct therapeutic interventions. The invention provides a method of evaluating a patient suspected of having a CNS injury, comprising measuring the level of at least one inflammasome protein in a biological sample from the patient and using the levels to prepare an inflammasome protein profile that is indicative of the presence or severity of CNS injury. The inflammasome protein profiles can be used to determine the prognosis of the patient with spinal cord or traumatic brain injury. The invention also includes kits for preparing an inflammasome protein profile associated with CNS injury.

Problems solved by technology

TBI affects an estimated 1.5 million people each year and causes one-third of injury-related deaths.
Predicting the severity and outcome of TBI and well as SCI is difficult, given the lack of objective, laboratory-based biomarkers.
Currently, the Glasgow Coma Scale (GCS) score (Teasdale et al., 1974) is the best available clinical predictor of injury severity; however, its value is limited in patients undergoing pharmacological paralysis for intubation, as a motor score cannot be obtained (Brain Trauma Foundation, American Association of Neurological Surgeons, 2000).
Predicting outcome is further complicated by the heterogeneity of pathology in patients with a similar GCS score.
Although, significant progress has been made regarding the verification and testing of various biomarkers after stroke and TBI, limited data are available regarding what biomarkers are appropriate for SCI.
Although some biomarkers show promising results, these do not yet provide a sensitive prognostic tool.

Method used

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  • Innate immune proteins as biomarkers for CNS injury
  • Innate immune proteins as biomarkers for CNS injury
  • Innate immune proteins as biomarkers for CNS injury

Examples

Experimental program
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example 1

Inflammasome Proteins are Secreted into Cerebrospinal Fluid after Spinal Cord Injury

[0043]To determine whether NLRP1 inflammasome proteins were present in cerebrospinal fluid (CSF) following spinal cord injury (SCI), CSF samples from seven patients with SCI or control patients were analyzed for levels of nucleotide-binding leucine-rich repeat pyrin domain containing protein 1 (NLRP1; also known as NAcht leucine-rich-repeat protein 1 (NALP-1)), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1. The American Spinal Cord Injury Association (ASIA) scale of the SCI patients at admission to the emergency department ranged from AIS A to B. Information regarding the diagnosis, procedures and outcomes of the patients is shown in Table 1. None of the patients had any complications. CSF from uninjured individuals was obtained as a control from three males and two females ranging from 67 to 91 years old.

[0044]For detection of inflammasome prote...

example 2

Immunohistochemical Expression of NLRP1 Inflammasome Proteins in Spinal Cords after Injury

[0047]Spinal cord sections were obtained from nine decedents (8 males and 1 female with ages ranging from 20 to 77 years) who had injury to the spinal cord due to vertebral fractures. The spinal cord injury was assessed microscopically, using bright field optics, by examining one H&E or H&E / DAB-stained section from the lesion center of each case or from cervical, thoracic and lumbar sections from control cases. The spinal cord injuries were classified on the basis of their histological appearance as “contusion / cyst,” massive compression, or laceration (Fleming et al., 2006). Contusional injuries were characterized by an intact pia and relative preservation of the anatomical relations of various elements of the spinal cord, and variable degrees of injury ranging from involvement of the entire cross-sectional area to large usually asymmetric areas of tissue damage. Massive compression injuries we...

example 3

Inflammasome Proteins in Cerebrospinal Fluid of Brain-Injured Patients are Biomarkers of Functional Outcome

[0054]To determine whether inflammasome proteins may serve as biomarkers for other types of central nervous system injury, a total of 45 CSF samples were collected from 23 traumatic brain injury (TBI) patients on the day of injury and up to three days after the injury and analyzed by immunoblot for levels of NALP-1 (also known as NLRP1), ASC, and caspase-1. Each of the patients presented with the following inclusion criteria: severe or moderate head trauma (Glasgow Coma Scale (GCS) score≦12), age 1 month to 65 years, and ventriculostomy. Twenty-two of the patients suffered severe brain trauma (GCS score≦8) and 1 suffered moderate brain trauma (moderate TBI GCS score range 9-12). Nine patients (5 men and 4 women) with a mean age of 66.3 years (range 29-91 years) served as controls. Control patients required a ventriculostomy for nontraumatic pathology. Patients with acute mening...

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Abstract

The present invention provides novel markers of the severity of a central nervous system injury, such as spinal cord injury or traumatic brain injury, in a patient. In particular, protein components of inflammasomes in the cerebrospinal fluid that can be used to assess the severity of central nervous system injury in a patient are disclosed. Methods of using such protein biomarkers to determine a prognosis, direct treatment and rehabilitation efforts, and monitor response to treatment for a patient with a central nervous system injury are also described.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 61 / 595,254, filed Feb. 6, 2012, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates generally to the fields of neurology, immunology, and diagnostics. In particular, the present invention relates to the identification of biomarkers in biological samples which can predict the severity of neuronal injury, such as spinal cord and traumatic brain injury, in patients. The identified biomarkers may also be used in determining prognosis, directing therapeutic and rehabilitation efforts, and monitoring response to treatment for patients with a central nervous system injury.BACKGROUND OF THE INVENTION[0003]Nucleotide-binding oligomerization domain (NOD)-containing protein-like receptors (NLRs) are a recently discovered class of innate immune receptors that play a crucial role in initiating inflammatory responses foll...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): G01N33/68A61F7/00
CPCG01N33/6896A61F7/00G01N2800/7095G01N2800/52G01N2800/28
Inventor KEANE, ROBERT W.DIETRICH, W. DALTONDE RIVERO VACCARI, JUAN PABLOADAMCZAK, STEPHANIEBULLOCK, M. ROSSLEVI, ALLANWANG, MICHAEL Y.
Owner UNIV OF MIAMI
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