Granted Patent
B2
US 12,186,371 · App. 17/135,970 · Granted Jan 7, 2025
Biomarkers and treatment methods for traumatic brain injury-associated impairments
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Abstract
The present disclosure relates to methods, compositions, and kits for treating traumatic brain injury (TBI) and TBI-associated impairments in a subject. The methods include administering to the subject an interleukin-7 (IL-7) or IL-7 agonist, a tumor necrosis factor alpha (TNFα) inhibitor, or both. The present disclosure also relates to methods of using biomarkers for identifying a subject that is likely to respond to a treatment for TBI-associated impairments, and monitoring the subject's response to such treatment.
Claims (45)
1. A method of treating a traumatic brain injury (TBI)-associated impairment, in a subject that has sustained a TBI, comprising administering to the subject interleukin-7 (IL-7).
2. The method of claim 1 , wherein the method comprises an increase in a Glasgow Outcome Scale (GOS) score of the subject,
wherein the GOS score is assessed at least three distinct time points post-TBI,
wherein a first time point assessment occurs within 6 months post-TBI,
wherein a second time point assessment occurs within 12 months post-TBI,
wherein a third time point assessment occurs within 24 months post-TBI, and
wherein the GOS score increases from the first time point assessment to the second or third time point assessment.
3. The method of claim 2 , wherein the method comprises a reduction in a Disability Rating Scale (DRS) score of the subject,
wherein the DRS score is assessed at least three distinct time points post-TBI,
wherein a first time point assessment occurs within 6 months post-TBI,
wherein a second time point assessment occurs within 12 months post-TBI,
wherein a third time point assessment occurs within 24 months post-TBI, and
wherein the DRS score reduces from the first time point assessment to the second or third time point assessment.
4. The method of claim 1 , wherein the method comprises an increase in a serum IgM level in the subject,
wherein the serum IgM level is assessed at least three distinct time points,
wherein a first time point assessment occurs prior to treatment,
wherein a second time point assessment occurs within 1 month post-TBI,
wherein a third time point assessment occurs within 24 months post-TBI, and
wherein the serum IgM level increases from the first time point assessment to the second or third time point assessment.
5. The method of claim 1 , wherein the method comprises an increase in a serum IgM:IgG ratio in the subject,
wherein the serum IgM:IgG ratio is assessed at least three distinct time points,
wherein a first time point assessment occurs prior to treatment,
wherein a second time point assessment occurs within 1 month post-TBI,
wherein a third time point assessment occurs within 24 months post-TBI, and
wherein the serum IgM:IgG ratio increases from the first time point assessment to the second or third time point assessment.
6. The method of claim 1 , wherein the TBI-associated impairment is selected from the group consisting of cognitive deficits, psychological deficits, somatic symptoms, emotional symptoms, behavioral dysfunctions, physical dysfunctions, and neuroendocrine dysfunction.
7. The method of claim 1 , wherein the IL-7 is administered to the subject at the acute stage, at the post-acute stage and/or at the chronic stage of the TBI.
8. The method of claim 1 , wherein the IL-7 is a recombinant IL-7.
9. The method of claim 1 , wherein the method further comprises administering to the subject etanercept.
10. A method for treating a TBI-associated impairment in a subject that has sustained a TBI, comprising:
(a) determining a level of soluble tumor necrosis factor receptor (sTNFR) and a level of IL-7 in at least two samples obtained from the subject;
(b) comparing the level of sTNFR to a reference level of sTNFR and the level of IL-7 to a reference level of IL-7,
wherein the reference levels of sTNFR and IL-7 are predetermined levels
wherein the predetermined levels of sTNFR and IL-7 are from (i) a healthy individual or a population of healthy individuals free of the TBI-associated impairment or (ii) the same subject collected at an earlier time point,
wherein the reference level of IL-7 is about 25 pg/ml, and
wherein the reference level of sTNFR is about 1500 pg/ml;
(c) assigning trajectory group memberships to the subject by assessing the IL-7 and sTNFRI levels of the subject in relation to group-based trajectory analyses derived from a population with TBI,
wherein if the level of IL-7 is lower than the reference level of the IL-7 the subject is assigned a low IL-7 trajectory group membership,
wherein if the level of IL-7 is higher than the reference level of the IL-7 the subject is assigned a high IL-7 trajectory group membership,
wherein if the level of sTNFRI is lower than the reference level of sTNFRI the subject is assigned a low sTNFRI trajectory group membership,
wherein if the level of sTNFRI is higher than the reference level of sTNFRI the subject is assigned a high sTNFRI trajectory group membership; and
(c-i) treating the subject with IL-7 if the subject is assigned a low IL-7 trajectory group membership and a low sTNFR trajectory group membership,
(c-ii) treating the subject with IL-7 and etanercept if the subject is assigned a low IL-7 trajectory group membership and a high sTNFR trajectory group membership; or
(c-iii) treating the subject with etanercept if the subject is assigned a high IL-7 trajectory group membership and a high sTNFR trajectory group membership.
11. The method of claim 10 , wherein the dose of IL-7 is higher in (c-ii) than in (c-i).
Assignments (2)
CONFIRMATORY LICENSE
Recorded Jan 12, 2022
From: UNIVERSITY OF PITTSBURGH
To: THE GOVERNMENT OF THE UNITED STATES AS REPRESENTED BY THE SECRETARY OF THE ARMY
Reel/Frame 058708/0909 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Apr 19, 2021
From: WAGNER, AMY KATHLEEN
To: UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION
Reel/Frame 055955/0885 →
Continuity (3)
Continuation
PCTUS2019039879
· Jun 28, 2019
Provisional Application
62692364
· Jun 29, 2018
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