Treatment of gulf war illness
A method for treating Gulf War Illness (GWI) involves administering a therapeutically effective amount of a dominant negative tumor necrosis factor (DN-TNF) protein variant to a subject in need thereof. The DN-TNF variant is one that is modified with one to seven specific amino acid substitutions relative to the amino acid sequence of wtTNF and demonstrates a mechanism of selectively inhibiting soluble TNF (solTNF) without affecting transmembrane TNF (tmTNF) signaling. The method, exemplified by XPro1595 (pegipanermin), alleviates GWI symptoms, including depression, neuropathic pain, anxiety, and cognitive deficits, as shown in preclinical models. By targeting solTNF-driven neuroinflammation, this approach offers a novel therapeutic strategy for GWI.
1 . A method of treating gulf war illness in a subject, comprising:
administering to the subject in need thereof a therapeutically effective amount of a dominant negative tumor necrosis factor (DN-TNF) protein variant, the DN-TNF protein variant comprising the amino acid sequence of wild-type tumor necrosis factor according to SEQ ID NO. 3 modified with one to seven amino acid substitutions, wherein the substitutions are each selected from the group consisting of: V1M, Q21C, Q21R, E23C, N30D, R31C, R31I, R31D, R31E, R32D, R32E, R32S, A33E, N34E, N34V, A35S, D45C, L57F, L57W, L57Y, K65D, K65E, K65I, K65M, K65N, K65Q, K65T, K65S, K65V, K65W, G66K, G66Q, Q67D, Q67K, Q67R, Q67S, Q67W, Q67Y, C69V, L75E, L75K, L75Q, A84V, S86Q, S86R, Y87H, Y87R, V91E, I97R, 197T, C101A, A111R, A111E, K112D, K112E, Y115D, Y115E, Y115F, Y115H, Y115I, Y115K, Y115L, Y115M, Y115N, Y115Q, Y115R, Y115S, Y115T, Y115W, D140K, D140R, D143E, D143K, D143L, D143N, D143Q, D143R, D143S, F144N, A145D, A145E, A145F, A145H, A145K, A145M, A145N, A145Q, A145R, A145S, A145T, A145Y, E146K, E146L, E146M, E146N, E146R, E146S and S147R, whereby the subject is treated.
2 . The method of claim 1 , wherein the DN-TNF protein variant further comprises up to twenty amino acid insertions or deletions.
3 . The method of claim 2 , wherein the DN-TNF protein variant comprises pegipanermin.
4 . The method of claim 3 , wherein the method comprises administering pegipanermin in a dose between 0.1 mg/kg and 10.0 mg/kg.
5 . The method of claim 2 , wherein the DN-TNF protein variant is administered: intravenously; subcutaneously; orally; via aerosol; via topical application; or via gene therapy.
6 . The method of claim 5 , wherein the gene therapy comprises mesenchymal stem cells expressing a construct of the DN-TNF protein variant.
7 . The method of claim 1 , wherein the DN-TNF variant protein comprises the amino acid sequence of SEQ ID NO. 3 modified with the amino acid substitutions V1M, R31C, C69V, Y87H, C101A, and A145R.
8 . The method of claim 1 , wherein the DN-TNF variant protein comprises the amino acid sequence of SEQ ID NO. 3 modified with at least the amino acid substitutions I97T, and A145R.