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 mat-425-5p, miR-502, milt-21 and miR-335. The method may involve determining whether a subject is suffering from mild-TBI or moderate-to-severe TBI. 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 diagnosing and/or monitoring traumatic brain injury (TBI) in a subject, the method comprising determining a level of at least one miRNA in a fluid sample from the subject. 
     
     
         2 . The method of  claim 1 , wherein the at least one miRNA is selected from the group consisting of:
 miR-505, miR-203, miR-654-3p, miR-655, miR-184, miR-301b, miR-425-5p, miR-502, miR-21, miR-let-7g, miR-335, 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-143, 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 1  or  claim 2 , wherein the at least one miRNA is selected from the group consisting of miR-505, miR-203, miR-654-3p, miR-655, miR-184, miR-301b, miR-425-5p, miR-502, miR-21, miR-let-7g, miR-335, 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 any one of  claims 1  to  3 , wherein the at least one miRNA is selected from the group consisting of miR-505, miR-203, miR-654-3p, miR-655, miR-184, miR-301b, miR-425-5p, miR-502, miR-21, miR-let-7g and miR-335, or any combination thereof. 
     
     
         5 . The method of  claim 1  or  claim 2 , wherein the at least one miRNA 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 1  or  claim 2 , wherein the at least one miRNA is selected from the group consisting of miR-10a, miR-132, miR-223, miR-143, 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 . The method of any one of  claims 1  to  4 , wherein the at least one miRNA is selected from the group consisting of: miR-425-5p; miR-502; miR-21; and miR-335, or any combination thereof. 
     
     
         8 . The method of  claim 7 , wherein the TBI is mild TBI (mTBI) and the miRNA is selected from the group consisting of: miR-425-5p and miR-502. 
     
     
         9 . The method of  claim 8 , wherein the subject is diagnosed as having mTBI if the level of miR-425-5p and/or miR-502 is determined to be below a predetermined threshold or decreased relative to a reference. 
     
     
         10 . The method of  claim 7 , wherein the TBI is severe TBI (sTBI) and the miRNA is selected from the group consisting of: miR-21 and miR-335. 
     
     
         11 . The method of  claim 10 , wherein the subject is diagnosed as having sTBI if the level of miR-21 and miR-335 is determined to be above a predetermined threshold or increased relative to a reference. 
     
     
         12 . The method of  claim 7 , wherein the method comprises determining the level 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 diagnosed as having a TBI of any severity if the level of miR-425-5p or miR-502 is determined to be below a predetermined threshold, or is decreased relative to a reference, and the level of miR-21 or miR-335 is determined to be above a predetermined threshold, or is increased relative to a reference. 
     
     
         14 . The method of any preceding claim, wherein the method is for diagnosing TBI and the level of the at least one miRNA is determined in a fluid sample obtained from the subject no more than 48 hours after injury. 
     
     
         15 . The method of any preceding claim, 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. 
     
     
         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 any one of  claims 17  to  19 , 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 any one of  claims 17  to  20 ; and   a detection device that is capable of detecting the binding of a 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 at least one probe specific for a target miRNA. 
     
     
         23 . A method for determining whether it is appropriate to administer to a subject a therapy for alleviating TBI, the method comprising:
 determining a level of at least one miRNA in a fluid sample from the subject; and   determining whether or not it is appropriate to administer a therapy for alleviating TBI, based on the level of the at least one miRNA.   
     
     
         24 . A method of determining an appropriate treatment of a subject suspected of suffering from a TBI, the method comprising identifying whether or not the subject has a TBI by determining a level of at least one miRNA in a fluid sample from the subject. 
     
     
         25 . The method of  claim 24 , wherein if the subject is identified as having a TBI, an appropriate treatment is determined to be at least one of: further evaluating the subject; removing the subject from activity; admitting the subject to a hospital or clinic; and administering a therapy for alleviating TBI to the subject. 
     
     
         26 . A therapy for alleviating TBI for use in a method of treating a subject in need thereof, wherein said subject is identified as having a TBI by determining a level of at least one miRNA in a fluid sample from the subject. 
     
     
         27 . The method of any one of  claims 24  to  26 , wherein the therapy for alleviating TBI is selected from at least one of: neuroprotective drugs, a sedative; and avoidance of the use of hypertensive resuscitation. 
     
     
         28 . A composition for use in a method of diagnosing and/or monitoring traumatic brain injury (TBI) in a subject, the composition comprising a probe specific for a target miRNA. 
     
     
         29 . The composition of  claim 28 , comprising a plurality of probes. 
     
     
         30 . The sensor element, detection system, kit, method or composition according to  claims 17  to  29 , wherein the miRNA is selected from the group consisting of: miR-505, miR-203, miR-654-3p, miR-655, miR-184, miR-301b, miR-425-5p, miR-502, miR-21, miR-let-7g, miR-335, 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-30a-5p; miR-107; miR-135b-5p; miR-199b-5p; miR-324-5p; miR-652-3p, miR-424-5p, miR-10a, miR-132, miR-223, miR-143, 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. 
     
     
         31 . The sensor element, detection system, kit, method or composition according to  claim 30 , wherein the miRNA is selected from the group consisting of miR-425-5p; miR-502; miR-21; and miR-335, or any combination thereof.