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NZ757755B2 - Analysis and prediction of traumatic brain injury and concussion symptoms - Google Patents

Analysis and prediction of traumatic brain injury and concussion symptoms

Info

Publication number
NZ757755B2
NZ757755B2 NZ757755A NZ75775518A NZ757755B2 NZ 757755 B2 NZ757755 B2 NZ 757755B2 NZ 757755 A NZ757755 A NZ 757755A NZ 75775518 A NZ75775518 A NZ 75775518A NZ 757755 B2 NZ757755 B2 NZ 757755B2
Authority
NZ
New Zealand
Prior art keywords
mir
level
mirnas
mirna
human subject
Prior art date
Application number
NZ757755A
Other versions
NZ757755A (en
Inventor
Steven D Hicks
Frank A Middleton
Richard Uhlig
Original Assignee
Penn State Research Foundation
Quadrant Biosciences Inc
The Research Foundation For The State University Of New York
Filing date
Publication date
Application filed by Penn State Research Foundation, Quadrant Biosciences Inc, The Research Foundation For The State University Of New York filed Critical Penn State Research Foundation
Priority claimed from PCT/US2018/024111 external-priority patent/WO2018175941A1/en
Publication of NZ757755A publication Critical patent/NZ757755A/en
Publication of NZ757755B2 publication Critical patent/NZ757755B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Instruments for taking body samples for diagnostic purposes; Other methods or instruments for diagnosis, e.g. for vaccination diagnosis, sex determination or ovulation-period determination; Throat striking implements
    • A61B10/0045—Devices for taking samples of body liquids
    • A61B10/0051—Devices for taking samples of body liquids for taking saliva or sputum samples
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4058—Detecting, measuring or recording for evaluating the nervous system for evaluating the central nervous system
    • A61B5/4064—Evaluating the brain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/178—Oligonucleotides characterized by their use miRNA, siRNA or ncRNA

Abstract

Provided are methods for detecting or diagnosing a traumatic brain injury or TBI by detecting concentration levels miRNAs associated with TBI in saliva. Methods for controlled and normalized comparisons of salivary miRNA concentration levels are further provided. Assay kits comprising salivary miRNAs, probes and/or primers for detecting salivary miRNAs are also provided.

Claims (16)

1. A method for detecting or diagnosing a concussion, mild traumatic brain injury (mTBI), or other traumatic brain injury (TBI) in a human subject comprising: (a) determining abundance or concentration level(s) of one or more micro RNAs (miRNAs) in a saliva sample taken from the human subject, and (b) comparing the determined abundance or concentration level(s) of the one or more miRNAs against normal level(s) of the same one or more miRNAs, wherein the normal level is that found in a subject, or an average from two or more subjects, not having a concussion or mild traumatic brain injury; or is an abundance or concentration level(s) determined in the subject prior to an event that produces a concussion, mTBI or other TBI, and (c) selecting a subject having an abnormal level of said one or more miRNAs as having a concussion, mild traumatic brain injury or other traumatic brain injury; wherein the one or more miRNA and the abnormal level of said one or more miRNA is at least one of miR-29c-3p which is upregulated in the human subject as compared to the normal level; miR-26b-5p which is downregulated in the human subject as compared to the normal level; miR5p which is downregulated in the human subject as compared to the normal level; miR-320c which is downregulated in the human subject as compared to the normal level; or miR3p which is downregulated in the human subject as compared to the normal level.
2. The method of claim 1, wherein said miRNA expression levels are normalized to an expression level, or average expression level, of one or more housekeeping genes whose RNA expression level is substantially invariant; and/or adjusted to compensate for differences in age, sex or genetic background.
3. The method of claim 1 or claim 2, wherein (a) determining abundance or concentration of one or more miRNAs is done by RNA sequencing (RNA-seq), qPCR, a miRNA array, or multiplex miRNA profiling.
4. The method of any one of claims 1 to 3, wherein the saliva sample is taken from a human subject suspected of having a mTBI and the method comprises determining abundance or concentration levels of miR-29c-3p, miR-26b-5p, miR182-5p, miR-320c, and miR3p.
5. The method of any one of claims 1 to 3, wherein the saliva sample is taken from a human subject suspected of having a concussion and the method comprises determining abundance or concentration levels of miR-29c-3p, miR-26b-5p, miR5p, miR-320c, and miR3p.
6. The method of any one of claims 1 to 5, wherein the concentration level(s) of miRNAs in said saliva sample are compared to normal miRNA values in saliva taken at the same time of day under otherwise identical conditions.
7. The method of any one of claims 1 to 5, wherein the saliva sample is taken from the human subject at a different time of day than the time of day at which the normal level(s) of miRNAs were determined, further comprising adjusting or normalizing the value of the miRNA level(s) determined in the saliva sample using a regression model or other statistical analysis to compensate for age, sex, or genetic background.
8. The method of any one of claims 1 to 7, wherein the saliva sample is taken within 1 hour of waking, and before brushing or rinsing the mouth, before eating or drinking, and/or before exercise that elevates heart rate.
9. The method of any one of claims 1 to 8, wherein said selecting comprises selecting a subject having abnormal levels of four or more of said miRNAs, and calculating a Pearson correlation coefficient of said abnormal miRNA levels with at least one symptom of a concussion, mTBI or other TBI.
10. The method of any one of claims 1 to 9, wherein determining salivary miRNA levels is done by RNA sequencing (RNA-seq).
11. The method of claim 10, wherein the sequencing data raw read counts are quantile-normalized, mean-centered, and divided by the standard deviation of each variable; data are normalized to account for inter-sample count variations; and/or wherein data are normalized to expression of one or more invariant miRNAs to describe relative and/or absolute expression levels; and optionally further statistically analyzing the normalized data.
12. The method of any one of claims 1 to 11, wherein the method comprises determining abundance or concentration levels of miR-29c-3p.
13. The method of any one of claims 1 to 11, wherein the method comprises determining abundance or concentration levels of miR-26b-5p.
14. The method of any one of claims 1 to 11, wherein the method comprises determining abundance or concentration levels of miR5p.
15. The method of any one of claims 1 to 11, wherein the method comprises determining abundance or concentration levels of miR-320c.
16. The method of any one of claims 1 to 11, wherein the method comprises determining abundance or concentration levels of miR3p.
NZ757755A 2018-03-23 Analysis and prediction of traumatic brain injury and concussion symptoms NZ757755B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201762475698P 2017-03-23 2017-03-23
US201762480079P 2017-03-31 2017-03-31
US201762502107P 2017-05-05 2017-05-05
US201862623145P 2018-01-29 2018-01-29
PCT/US2018/024111 WO2018175941A1 (en) 2017-03-23 2018-03-23 Analysis and prediction of traumatic brain injury and concusion symptoms

Publications (2)

Publication Number Publication Date
NZ757755A NZ757755A (en) 2025-05-30
NZ757755B2 true NZ757755B2 (en) 2025-09-02

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