Biomarkers of traumatic brain injury

Abstract

Provided is a method of diagnosing and/or monitoring traumatic brain injury (TBI) in a subject. The method comprises determining a level of at least one miRNA in a fluid sample from the subject. The miRNA may be selected from miR-425-5p, miR-502, miR-21 and miR-335. The method may involve determining whether a subject is suffering from mild-TBI or moderate-to-severe TI. Also provided is a sensor element, a detection system, composition and a kit for diagnosing and/or monitoring TBI, and a method of determining an appropriate treatment for a subject with a suspected TBI.

1 . A method of treating traumatic brain injury (TBI) in a subject in need thereof, the method comprising:
 obtaining a fluid sample from the subject,   contacting the fluid sample with a probe comprising a nucleic acid able to bind to at least one miRNA selected from the group consisting of miR-335, miR-143, miR-425-5p, miR-502, and miR-21, or any combination thereof,   determining an amount of the at least one miRNA in the fluid sample,   identifying the subject as having TBI where the amount of miR-425-5p and/or miR-502 is decreased relative to a predetermined threshold value or relative to the amount of the miRNA in a reference sample, or   identifying the subject as having TBI where the amount of miR-143, miR-21 and/or miR-335 is increased relative to a predetermined threshold value or relative to the amount of the miRNA in a reference sample,   and   treating the subject identified as having TBI by administering to the subject one or more neuroprotective therapies selected from the group consisting of administering a neuroprotective drug, administering a sedative, avoiding hypertensive resuscitation, removing the subject from activity, admitting the subject to hospital, or surgery.   
     
     
         2 . The method of  claim 1 , wherein the at least one miRNA further comprises one or more miRNAs selected from the group consisting of:
 miR-505, miR-203, miR-654-3p, miR-655, miR-184, miR-301b, miR-let-7g, miR-126*, miR-193a-5p, miR-144*, miR-190, miR-194, miR-365, miR-590-3p, miR-624, miR-625*, miR-671-3p, hsa-let-7c-5p, hsa-let-7i-5p, miR-142-3p, miR-148a-3p, miR-15b-5p, miR-16-5p, miR-181a-5p, miR-20a-5p, miR-20b-5p, miR-221-3p, miR-24-3p, miR-27b-3p, miR-29a-3p, miR-29c-3p, miR-424-5p, miR-30a-5p; miR-107; miR-135b-5p; miR-199b-5p; miR-324-5p; miR-652-3p; miR-10a, miR-132, miR-223, miR-148b, miR-18a, miR-192, miR-429, miR-618, miR-95, miR-130a, miR-152, miR-27b, miR-301, miR-326, miR-345, miR-361, miR-422a, miR-579, miR-642, miR-99a, miR-520D-3p and miR-629, or any combination thereof.   
     
     
         3 . The method of  claim 2 , wherein the one or more miRNAs is selected from the group consisting of miR-505, miR-203, miR-654-3p, miR-655, miR-184, miR-301b, miR-let-7g, hsa-miR-126*, miR-193a-5p, miR-144*, miR-190, miR-194, miR-365, miR-590-3p, miR-624, miR-625*, and miR-671-3p, or any combination thereof. 
     
     
         4 . The method of  claim 3 , wherein the one or more miRNAs is selected from the group consisting of miR-505, miR-203, miR-654-3p, miR-655, miR-184, miR-301b, and miR-let-7g, or any combination thereof. 
     
     
         5 . The method of  claim 2 , wherein the one or more miRNAs is selected from the group consisting of let-7c-5p, let-7i-5p, miR-142-3p, miR-148a-3p, miR-15b-5p, miR-16-5p, miR-181a-5p, miR-20a-5p, miR-20b-5p, miR-221-3p, miR-24-3p, miR-27b-3p, miR-29a-3p, miR-29c-3p, and miR-424-5p; miR-30a-5p; miR-107; miR-135b-5p; miR-199b-5p; miR-324-5p; miR-652-3p, or any combination thereof. 
     
     
         6 . The method of  claim 2 , wherein the one or more miRNAs is selected from the group consisting of miR-10a, miR-132, miR-223, miR-148b, miR-18a, miR-192, miR-429, miR-618, miR-95, miR-130a, miR-152, miR-194, miR-27b, miR-301, miR-326, miR-345, miR-361, miR-422a, miR-579, miR-642, miR-99a, miR-520D-3p and miR-629, or any combination thereof. 
     
     
         7 - 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the method comprises determining the level amount of:
 (i) a first miRNA selected from miR-425-5p and miR-502; and   (ii) a second miRNA selected from miR-21 and miR-335.   
     
     
         13 . The method of  claim 12 , wherein the subject is identified as having mild TBI (mTBI) if the level of miR-425-5p or miR-502 is determined to be decreased relative to the threshold value or relative to the amount of the miRNA in the reference sample, and the subject is identified as having severe TBI (sTBI) if the level of miR-21 or miR-335 is determined to be increased relative to the threshold value or relative to the amount of the miRNA in the reference sample. 
     
     
         14 . The method of  claim 1 , wherein the fluid sample is obtained from the subject no more than 48 hours after injury. 
     
     
         15 . The method of  claim 1 , wherein the fluid sample comprises saliva, blood, plasma or serum. 
     
     
         16 . The method of  claim 15 , wherein the fluid sample is saliva. 
     
     
         17 . A sensor element for a detection system for diagnosing and/or monitoring TBI, the sensor element comprising a substrate functionalized with a probe specific for a target miRNA selected from the group consisting of miR-335, miR-143, miR-425-5p, miR-502, and miR-21, or any combination thereof. 
     
     
         18 . The sensor element of  claim 17 , wherein the probe comprises a nucleic acid. 
     
     
         19 . The sensor element of  claim 18 , wherein the nucleic acid comprises a sequence which is at least 80% identical to a sequence which is the complement of the sequence of the target miRNA. 
     
     
         20 . The sensor element of  claim 17 , wherein the substrate is formed from metal, plastic, glass, silica, silicon, graphite or graphene, or any combination thereof. 
     
     
         21 . A detection system for diagnosing and/or monitoring TBI, comprising:
 a sensor element according to  claim 17 ; and   a detection device that is capable of detecting the binding of the target miRNA to the probe.   
     
     
         22 . A kit for use in a method of diagnosing and/or monitoring traumatic brain injury (TBI) in a fluid sample from a subject, the kit comprising:
 a sensor element according to  claim 17 ; and   at least one probe specific for a target miRNA selected from the group consisting of miR-335, miR-143, miR-425-5p, miR-502, and miR-21, or any combination thereof.   
     
     
         23 - 27 . (canceled) 
     
     
         28 . A composition for use in a method of diagnosing and/or monitoring traumatic brain injury (TBI) in a subject, the composition comprising one or more probes specific for a target miRNA selected from the group consisting of miR-335, miR-143, miR-425-5p, miR-502, and miR-21, or any combination thereof. 
     
     
         29 . The composition of  claim 28 , comprising a plurality of probes. 
     
     
         30 - 31 . (canceled)