WO2025076208A1 - Compositions and methods for treating pain disorders - Google Patents

Abstract

Provided are methods to treat, ameliorate, prevent, reverse, decrease the severity and/or duration of a pain-associated disease or condition comprising parenteral administration of a pharmaceutically acceptable formulation comprising a synthetic or recombinantly modified AP0A1BP (AIBP) polypeptide.

Description

Docket No. EPN-AC-RAFT.003PC PATENT COMPOSITIONS AND METHODS FOR TREATING PAIN DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS 5 This international application claims the benefit of pending U.S. Provisional Patent Application Serial No.63/587,608, filed October 3, 2023, the entire contents of which are hereby incorporated by reference herein. GOVERNMENT RIGHTS This invention was made with government support under grants NS102432, 10 HL135737 and NS113705 awarded by the National Institutes of Health (NIH). The US government has certain rights in the invention. SEQUENCE LISTING XML Incorporated by reference herein is a sequence listing in XML file format submitted via the USPTO patent electronic filing system complying with WIPO Standard 15 ST.26 requirements having the file name of EPN_AC_RAFT_003PC, file size 56 kB, created on 2024-10-02 using the WIPO Sequence Suite Version 2 software. TECHNICAL FIELD This invention generally relates to medicine, inflammation, pain control and cell biology. In particular, provided herein are methods to treat, ameliorate, prevent, reverse, 20 decrease the severity and/or duration of a pain-associated disease or condition including but not limited to a neuropathic pain, a CNS inflammation, an allodynia, a post nerve injury pain, a post-surgical pain, a hyperalgesia, and primary headaches such as migraines and cluster headaches by administering to a subject in need thereof of a pharmaceutically acceptable formulation comprising a synthetic or recombinantly modified mammalian or 25 human ApoA-I Binding Protein (AIBP) polypeptide as described herein. BACKGROUND OF THE INVENTION Medical conditions where pain is a major symptom of disease remains a significant problem to healthcare. By example, soft tissue or orthopedic surgeries, leads to upwards of 80-90% of patients experiencing pain requiring aggressive interventions for 30 intervals up to 2-4 days, with 40-60% showing symptoms at intervals of 5-9 days Docket No. EPN-AC-RAFT.003PC PATENT (Brattwell 2011, Tran 2015). Smaller populations may experience pain yet longer for periods greater than 3 months (Krakowski 2021). Migraine is a primary headache disorder, affecting one in nine adults worldwide (Stovner 2007). The Global Burden of Disease 2016 study ranks migraine as second in terms of years lived with disability, 5 particularly in young adult and middle-aged women and sixth leading cause for men of all ages (Vetvik 2017). With such prevalence in patient populations and deficiencies in existing medications, new pharmacotherapies are necessary to manage pain-associated diseases and conditions. SUMMARY OF THE INVENTION 10 In a principal aspect of the invention provided are methods and uses for treating, ameliorating, preventing, reversing or decreasing the severity or duration of, or decreasing the severity of symptoms of a disease or condition of a subject wherein the disease or condition is selected from the group consisting of: - neuropathic pain, 15 - inflammation-induced neuropathic pain, wherein in some aspects the inflammation-induced neuropathic pain comprises a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain, - nerve or CNS inflammation, 20 wherein in some aspects the nerve or CNS inflammation comprises a TLR4- mediated nerve or CNS inflammation, - allodynia, wherein in some aspects the allodynia comprises a TLR4-mediated allodynia, - a post nerve or tissue injury pain or neuropathic pain, 25 wherein in some aspects the post nerve or tissue injury pain or neuropathic pain is generated or caused by, or is a sequela to, trauma, - post-surgical pain or neuropathic pain, - a primary headache, wherein is some aspects is a migraine or a cluster headache, and 30 - hyperalgesia, wherein the method comprises administering to the subject: Docket No. EPN-AC-RAFT.003PC PATENT (a) a pharmaceutically acceptable formulation comprising at least one pharmaceutically acceptable excipient and: (i) a recombinant or synthetic ApoA-I Binding Protein (AIBP) polypeptide, comprised of an amino acid sequence of a wild-type AIPB polypeptide and an amino acid 5 sequence of at least 8-40 amino acid residues N-terminal to the amino acid sequence of the wild-type AIBP polypeptide (also referred to as a AIBP variant), or (ii) a recombinant or synthetic ApoA-I Binding Protein (AI-BP) polypeptide comprised of an amino acid sequence of a wild-type AIPB polypeptide lacking amino acids 1-24 (d24 AIBP) and an amino acid sequence of at least 8-40 amino acid residues 10 N-terminal to the amino acid sequence of the wild-type AIBP polypeptide lacking amino acids 1-24 (also referred to as a d24 AIBP variant), wherein the recombinant or synthetic AIBP polypeptide comprises the TLR4 binding cryptic domain of the wild-type AIBP polypeptide, wherein the TLR4 binding cryptic domain is comprised of or is homologous to amino acids 25-51 of the amino acid 15 sequence of human wild-type AIBP polypeptide, wherein the N-terminal amino acid sequence of the recombinant or synthetic AIBP polypeptide variant is comprised of at least 3 basic amino acid residues independently selected from the group consisting of His, Arg and Lys, wherein in some aspects the at least 3 basic amino acid residues comprise a His tag of six histidine 20 (HHHHHH (SEQ ID NO:1)) residues. In some aspects the N-terminal amino acid sequence of the recombinant or synthetic AIBP polypeptide is comprised of an amino acid sequence of a secretion signaling polypeptide having an enzymatically cleavable site that upon enzymatic cleavage under physiological conditions results in at least partial loss of the amino acid 25 sequence of the secretion signaling polypeptide, with the proviso that the at least partial loss of the amino acid sequence of the secretion signaling polypeptide does not result in loss of any of the at least 3 basic amino acid residues, which is some aspects one or more of the at least 3 basic amino acid residues were present in the secretion signaling polypeptide, 30 wherein in some aspects the enzymatically cleavable site comprises a thrombin cleavage site, and wherein in some aspects the amino acid sequence of the secretion signaling polypeptide is a fibronectin secretion signaling polypeptide, an immunoglobulin heavy Docket No. EPN-AC-RAFT.003PC PATENT chain secretion signaling polypeptide, an immunoglobulin kappa light chain secretory peptide, or an interleukin-2 signaling peptide, in particular a fibronectin secretion signaling polypeptide, wherein in some preferred aspects the N-terminal amino acid sequence of the 5 synthetic or recombinant AIBP polypeptide is: MSPIDPMGHHHHHHGRRRASVAAGILVPRGSPGLDGICSR (SEQ ID NO:2), wherein the amino acid sequence of the recombinant or synthetic AIBP polypeptide having the secretion signaling polypeptide as provided herein subsequent to said enzymatic action is capable under physiological conditions, of inducing unfolding or 10 exposing or making accessible said cryptic domain so that the cryptic domain is capable of binding to a TLR4 polypeptide in a suitable in vitro assay to inhibit TLR4 signaling, and wherein said administering is by parenteral administration, thereby treating, ameliorating, preventing, reversing or decreasing the severity or 15 duration of, or decreasing the severity of symptoms of a disease or condition of a subject wherein the disease or condition is selected from the group consisting of: - neuropathic pain, - inflammation-induced neuropathic pain, wherein in some aspects the inflammation-induced neuropathic pain comprises 20 a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain, - nerve or CNS inflammation, wherein in some aspects the nerve or CNS inflammation comprises a TLR4- mediated nerve or CNS inflammation, 25 - allodynia, wherein in some aspects the allodynia comprises a TLR4-mediated allodynia, - a post nerve or tissue injury pain or neuropathic pain, wherein in some aspects the post nerve or tissue injury pain or neuropathic pain is generated or caused by, or is a sequela to, trauma, 30 - post-surgical pain or neuropathic pain, - a primary headache, wherein is some aspects is a migraine or a cluster headache, and - hyperalgesia. Docket No. EPN-AC-RAFT.003PC PATENT In other aspects, the N-terminal amino acid sequence of the recombinant or synthetic AIBP polypeptide is comprised of an amino acid sequence of a secretion signaling polypeptide having an enzymatically cleavable site that is mutated so that it is no longer capable or is resistant to enzymatic cleavage under physiological conditions, 5 wherein in some aspects the enzymatically cleavable site comprises a mutated thrombin cleavage site. In some preferred aspects, the recombinant or synthetic ApoA-I Binding Protein is comprised of a human a wild-type-type AIBP amino acid sequence and an amino acid sequence N-terminus to the wild-type AIBP amino acid sequence as described herein; 10 In other preferred aspects, parenteral administration is by intravenous administration. In still other preferred aspects, parenteral administration is by subcutaneous administration. In another principal aspect of the invention, provided is a DNA sequence 15 encoding a recombinant or synthetic ApoA-I Binding Protein as described herein or a vector having contained therein the nucleic acid encoding the recombinant or synthetic ApoA-I Binding Protein. In other aspects of the invention the pharmaceutically acceptable formulation has the recombinant or synthetic ApoA-I Binding Protein attached non-covalently to or 20 contained within a carrier, preferably a nanoparticle liposome or lipoplex, a polymersome, a polyplex or a dendrimer, wherein in some aspects the carrier further comprises a cell or CNS penetrating moiety or peptide or a CNS targeting moiety or peptide. In alternative principal aspects, provided are kits comprising: a recombinant or 25 synthetic ApoA-I Binding Protein (APOA1BP, AIBP, or AI-BP) polypeptide; and/or a pharmaceutically acceptable formulation as used in a method as provided herein, and instructions on practicing a method as provided herein. In other alternative principal aspects of the invention, provided are uses of a pharmaceutically acceptable formulation as provided herein, in the manufacture of a 30 medicament. In still other alternative principal aspects of the invention, provided are uses of a pharmaceutically acceptable formulation as provided herein, in the manufacture of a medicament for treating, ameliorating, preventing, reversing or decreasing the severity or Docket No. EPN-AC-RAFT.003PC PATENT duration of, or decreasing the severity of symptoms of a disease or condition of a subject wherein the disease or condition is selected from the group consisting of: - neuropathic pain, - inflammation-induced neuropathic pain, 5 wherein in some aspects the inflammation-induced neuropathic pain comprises a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain, - nerve or CNS inflammation, wherein in some aspects the nerve or CNS inflammation comprises a TLR4- 10 mediated nerve or CNS inflammation, - allodynia, wherein in some aspects the allodynia comprises a TLR4-mediated allodynia, - a post nerve or tissue injury pain or neuropathic pain, wherein in some aspects the post nerve or tissue injury pain or neuropathic 15 pain is generated or caused by, or is a sequela to, trauma, - post-surgical pain or neuropathic pain, - a primary headache, wherein in some aspects isa migraine or a cluster headache, and - hyperalgesia. 20 In alternative aspects, provided are a pharmaceutically acceptable formulation as described herein, or a therapeutic combination comprising said formulation, for treating, ameliorating, preventing, reversing or decreasing the severity or duration of, or decreasing the severity of symptoms of a disease or condition in a subject, wherein the disease or condition is selected from the group consisting of: 25 - neuropathic pain, - inflammation-induced neuropathic pain, wherein in some aspects the inflammation-induced neuropathic pain comprises a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain, - nerve or CNS inflammation, 30 wherein in some aspects the nerve or CNS inflammation comprises a TLR4- mediated nerve or CNS inflammation, - allodynia, wherein in some aspects the allodynia comprises a TLR4-mediated allodynia, Docket No. EPN-AC-RAFT.003PC PATENT - a post nerve or tissue injury pain or neuropathic pain, wherein in some aspects the post nerve or tissue injury pain or neuropathic pain is generated or caused by, or is a sequela to, trauma, - post-surgical pain or neuropathic pain, 5 - a primary headache, wherein in some aspects a migraine or a cluster headache, and - hyperalgesia, wherein the pharmaceutically acceptable formulation or the therapeutic combination is intended for parenteral administration to the subject. 10 The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS 15 The drawings set forth herein are illustrative of embodiments provided herein and are not meant to limit the scope of the invention as encompassed by the claims. FIG.1 schematically illustrates a model of unfolding or exposing a cryptic N- terminal domain in the AIBP molecule; the diagram summarizes and illustrates results of experiments shown in Figures 2-4, which demonstrate that in native AIBP the N-terminal 20 domain is hidden or cryptic or not sufficiently exposed to mediate AIBP binding to TLR4 (top panel), extending the N-terminus with additional amino acids, at least three of which are positively charged under physiological conditions, changes the AIBP conformation and makes the cryptic domain of AIBP accessible for TLR4 binding (bottom panel). 25 FIG.2 illustrates an exemplary amino acid sequence of an engineered AIBP, as provided herein (Compound 7, SEQ ID NO: 24): the amino acid sequence of an extended AIBP molecule depicted in the bottom panel of FIG.1, amino acids 25-288 are from the wild-type AIBP sequence; the TLR4-binding sequence is amino acids 25-51 of the human AIBP sequence; with a sequence of 40 amino acids added to the N-terminus replacing 30 amino acids 1-24 of the AIBP sequence. Docket No. EPN-AC-RAFT.003PC PATENT FIG 3 schematically illustrates TLR4 binding of various exemplary engineered forms of AIBP: all proteins were expressed and purified from a baculovirus/insect cell system: His-d24AIBP: corresponds to the amino acid sequence shown in FIG.2, the 5 amino acid sequence (Compound 7, SEQ ID NO: 24) and shows the sequence of the “cleavable His tag”, all other Figures summarized herein show different modifications and corresponding changes in the amino acid sequence introduced to the AIBP molecule, the “N-terminal domain” box depicts the amino acid 25-51 sequence of native AIBP, the 10 column on the right shows the results of co-immunoprecipitation experiments of the AIBP variants with a recombinant ectodomain of TLR4, for “cleaved His-d24 AIBP”, (SEQ ID NO:36), for “5xD mut His-d24 AIPB” (SEQ ID NO:26), for “cleaved 5xD His-d24 AIPB” (SEQ ID NO:38), 15 for “2xD mut His-d24 AIBP (SEQ ID NO:29), and for “cleaved His-d24 AIBP” (SEQ ID NO:39). FIG.4 schematically illustrates TLR4 binding of various engineered forms of AIBP: all proteins were co-expressed with the full-length TLR4 in a mammalian system: SS, secretion signal, corresponding to the amino acids 1-24 in the human AIBP sequence; 20 the column on the right shows co-immunoprecipitation from cell lysates of the AIBP variants with TLR4, for Compound 3 (SEQ ID NO: 15) “Flag-full length” (SEQ ID NO:18). “Flag-d24 AIBP” (SEQ ID NO:21) and 25 “Flag-d24, d115-123 AIBP” (SEQ ID NO:43) FIG.5 schematically illustrates TLR4 binding of various engineered forms of AIBP: all proteins were expressed and purified from an E.coli, the column on the right shows the results of co-immunoprecipitation experiments of the AIBP variants with a recombinant ectodomain of TLR4. 30 FIG.6 demonstrates the efficacy of compound 7 in a pre-clinical model of surgical pain in rats. Paw incision in rats causes a reduction in tactile thresholds as measured by von Frey hairs. Administration of intravenous (IV) or intrathecal (IT) Docket No. EPN-AC-RAFT.003PC PATENT compound 7 leads to an increase in tactile threshold indicating the amelioration of pain. Compound 7 is more efficacious following IV administration. FIG.7 demonstrates the efficacy of compound 7 in a pre-clinical model of photophobia in mice, used as a recognized model of migraine. Administration of 5 compound 48/80 causes a light aversion increasing time spent in a dark box. Administration of intravenous (IV) compound 7 leads to an increase in time spent in the light box indicating the amelioration of photophobia. When a heat inactivated version of compound 7 is administered, there is no activity compared to control. Compound 7 is efficacious in both male and female mice. 10 FIG.8 demonstrates the efficacy of compound 7 in a pre-clinical model of migraine pain in mice, induced by stress. Mice when restrained develop a facial mechanical hypersensitivity as measured by a reduced mechanical threshold which recovers over time. This hypersensitivity is a recognized model of migraine pain. Follow on challenge with the priming agent, sodium nitroprusside (SNP) induces a follow-on 15 period of hypersensitivity. Administration of intravenous (IV) compound 7 leads to an increase in tactile thresholds in female mice in both the restrained and primed phases of this model indicating effective reduction of migraine pain. Like reference symbols in the various drawings indicate like elements. Reference will now be made in detail to various exemplary embodiments provided 20 herein, examples of which are illustrated in the accompanying drawings. The following detailed description is provided to give the reader a better understanding of certain details of aspects and embodiments of the invention, and should not be interpreted as a limitation on the scope of the invention. DETAILED DESCRIPTION 25 In alternative embodiments, provided are compositions and methods using pharmaceutical compounds and formulations comprising nucleic acids, polypeptides, and gene and polypeptide delivery vehicles for regulating or manipulating, including modification of amino acid sequence, adding, maintaining, enhancing or upregulating, the expression of recombinant ApoA-I Binding Protein (APOA1BP, AIBP, or AI-BP), and 30 kits comprising all or some of the components for practicing these compositions and methods. In alternative embodiments, provided are compositions and methods for altering AIBP sequence and structure and delivering therapeutic levels of recombinant Docket No. EPN-AC-RAFT.003PC PATENT AIBP to the body, including the brain and CNS, including use of delivery vehicles targeting and/or capable of penetrating the blood brain barrier, and nucleic acid (gene) delivery vehicles such as vectors and viruses such as an adeno-associated virus (AAV) delivery vehicle having contained within an AIBP expressing nucleic acid; and for direct 5 delivery of either AIBP polypeptide or AIBP-expressing nucleic acid directly via intrathecal (IT) administration. Example 1 describes studies using a mouse model of chemotherapy-induced peripheral neuropathy, where spinal microglia are characterized by the presence of inflammarafts - enlarged, cholesterol-enriched lipid rafts, which organize the 10 inflammatory response. Manipulation of specific mechanisms regulated cholesterol metabolism and normalized inflammarafts and reprogramed microglia, resulting in a long-lasting alleviation of neuropathic pain. We also show that a deletion mutant of AIBP that lacks the TLR4-binding domain does not reverse neuropathic pain in a mouse model of chemotherapy-induced peripheral 15 neuropathy. AIBP binding to TLR4 is important because this innate immune receptor is highly expressed in inflammatory cells and concentrates in lipid rafts on the cell surface and mediates inflammatory responses. Enlarged/clustered lipid rafts with increased content of TLR4 and the evidence of TLR4 dimerization are called “inflammarafts”. By virtue of binding to TLR4, AIBP targets inflammatory cells, disrupts inflammarafts and 20 inhibits inflammation – spinal neuroinflammation and neuropathic pain, and the effect is applicable to many inflammatory disease states mediated by TLR4. We also found that in native AIBP the N-terminal TLR4 binding domain is cryptic and the native AIBP does not bind to TLR4. The TLR4 binding domain in AIBP becomes exposed when the N-terminus is extended with additional amino acids, for example, as in 25 the recombinantly engineered forms of AIBP as provided herein, as illustrated in FIG.3. FIG.1 is a schematic representation of this model. In alternative embodiments, provided is an engineered AIBP comprising an amino acid sequence from the commercial pAcHLT-C vector (BD Biosciences). TLR4 receptors localize to and dimerize in membrane lipid rafts. The enlarged, 30 cholesterol-rich lipid rafts, harboring activated receptors and adaptor molecules – here designated as inflammarafts (Miller et al., 2020) – serve as an organizing platform to initiate inflammatory signaling and the cellular response. Regulation of cholesterol content in the plasma membrane can affect inflammarafts and TLR4 dimerization, Docket No. EPN-AC-RAFT.003PC PATENT signaling and inflammatory response in various cell types (Karasinska et al., 2013; Tall and Yvan-Charvet, 2015; Yvan-Charvet et al., 2008). In addition to TLR4, inflammarafts regulate activation of numerous other receptors and components of signaling pathways, as reviewed in (Miller et al., 2020). was Accordingly, pain states may be associated with 5 altered cholesterol dynamics in spinal microglia, leading to inflammaraft formation and persistent neuroinflammation in the spinal cord. Recombinant AIBP sequences In alternative embodiments, engineered protein sequences are disclosed comprised of a ApoA-I Binding Protein (AIBP) amino acid sequence and an amino acid sequence N- 10 terminal to the AIBP amino acid sequence, wherein the amino acid sequence N-terminal to the AIBP amino acid sequence comprises a peptide tag, wherein the peptide tag comprises a multi-histidine (multi-his) tag, in particular, the multi-his tag comprises six contiguous histidine residues (HHHHHH (SEQ ID NO:1)). In other embodiments, the heterologous amino terminus amino acid sequence 15 comprises the amino acid sequence MSPIDPMGHHHHHHGRRRASVAAGILVPRGSPGLDGICSR (SEQ ID NO:2) having mutation of its thrombin cleavage site so as to render it substantially or essentially inoperable. In some embodiments, provided is a peptide having an amino acid sequence 20 produced from the commercial pAcHLT-C vector (BD Biosciences), wherein the amino acid sequence is comprised of a ApoA-I Binding Protein (AIBP) amino acid sequence and an amino acid sequence N-terminal to the AIBP amino acid sequence, wherein the amino acid sequence N-terminal to the AIBP amino acid sequence comprises a peptide tag, wherein the peptide tag comprises a multi-histidine (multi-his) tag. 25 In alternative embodiments, provided are methods for administering in vivo a recombinant or synthetic ApoA-I Binding Protein (APOA1BP, AIBP, or AI-BP) polypeptide compound or composition having a heterologous amino terminus amino acid sequence of at least about ten amino acid, or between about 10 to 100 amino acids, or between about 20 to 80 amino acids, or between about 30 to 50 amino acids, or any 30 heterologous amino acid sequence sufficient to result in the unfolding and exposing of the cryptic (or hidden, unexposed) N-terminal TLR4 binding domain of the AIBP polypeptide. Docket No. EPN-AC-RAFT.003PC PATENT In alternative embodiments, murine AIBP is used, for example, a murine AIBP having a nucleic acid sequence encoded by SEQ ID NO:3, and/or an amino acid sequence of SEQ ID NO:4, which in some of these embodiments is supplemented with (i.e., further comprise) a fibronectin secretion signal (italic) at the N-terminus, and/or with the His tag 5 (underlined) at the C-terminus; the product is abbreviated as FIB-mAIBP-His: SEQ ID NO:3: ATG CTC AGG GGT CCG GGA CCC GGG CGG CTG CTG CTG CTA GCA GTC CTG TGC CTG GGG ACA TCG GTG CGC TGC ACC GAA ACC GGG AAG AGC AAG AGG CAGCAGAGTGTGTGTCGTGCAAGGCCCATCTGGTGGGGAACACAGCGCCGGG 10 GCTCGGAGACCATGGCGGGCGCTGCGGTGAAGTACTTAAGTCAGGAGGAGGC TCAGGCCGTGGACCAAGAGCTTTTTAACGAGTATCAGTTCAGCGTGGATCAA CTCATGGAGCTGGCCGGGTTGAGCTGTGCCACGGCTATTGCCAAGGCTTATCC CCCCACGTCTATGTCCAAGAGTCCCCCGACTGTCTTGGTCATCTGTGGCCCCG GAAATAACGGAGGGGATGGGCTGGTCTGTGCGCGACACCTCAAACTTTTTGG 15 TTACCAGCCAACTATCTATTACCCCAAAAGACCTAACAAGCCCCTCTTCACTG GGCTAGTGACTCAGTGTCAGAAAATGGACATTCCTTTCCTTGGTGAAATGCCC CCAGAGCCCATGATGGTGGACGAGCTGTATGAGCTGGTGGTGGACGCCATCT TCGGCTTCAGTTTCAAGGGTGACGTTCGGGAGCCATTCCACAGCATCCTGAGT GTCTTGAGTGGACTCACTGTGCCCATTGCTAGCATCGACATTCCCTCAGGATG 20 GGATGTAGAGAAGGGAAACCCTAGCGGAATCCAACCAGACTTACTCATCTCA CTGACGGCACCCAAGAAGTCTGCAACTCACTTTACTGGCCGATATCATTACCT TGGGGGTCGCTTTGTACCACCTGCTCTAGAGAAGAAGTACCAGCTGAACCTG CCATCTTACCCTGACACAGAGTGTGTCTACCGTCTACAGCATCATCATCATCA TCATTAA 25 SEQ ID NO:4: MLRGPGPGRLLLLAVLCLGTSVRCTETGKSKRQQSVCRARPIWWGTQRRGS ETMAGAAVKYLSQEEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPPTS MSKSPPTVLVICGPGNNGGDGLVCARHLKLFGYQPTIYYPKRPNKPLFTGLVTQC QKMDIPFLGEMPPEPMMVDELYELVVDAIFGFSFKGDVREPFHSILSVLSGLTVPI 30 ASIDIPSGWDVEKGNPSGIQPDLLISLTAPKKSATHFTGRYHYLGGRFVPPALEKK YQLNLPSYPDTECVYRLQHHHHHH Docket No. EPN-AC-RAFT.003PC PATENT In alternative embodiment, a variant of human AIBP (hAIBP) polypeptide as provided herein (for example, a human AIBP having heterologous amino acid sequence that results in exposure of a TLR4 (otherwise cryptic) binding site), or a nucleic acid encoding a variant AIBP as provided herein, is administered to a patient or an individual 5 in need thereof, or is used to manufacture a formulation or pharmaceutical, or is used to make a vector or expression vehicle for administration, or is included in a kit as provided herein, and the AIBP variant can comprise or be encoded by: Human AIBP-encoding nucleic acid (cDNA) (SEQ ID NO:5) GGGCCGGGCCGGGCCGGGGGCGCGCGCTCTGCGAGCTGGATGTCCAGGCTGC 10 GGGCGCTGCTGGGCCTCGGGCTGCTGGTTGCGGGCTCGCGCGTGCCGCGGAT CAAAAGCCAGACCATCGCCTGTCGCTCGGGACCCACCTGGTGGGGACCGCAG CGGCTGAACTCGGGTGGCCGCTGGGACTCAGAGGTCATGGCGAGCACGGTGG TGAAGTACCTGAGCCAGGAGGAGGCCCAGGCCGTGGACCAGGAGCTATTTAA CGAATACCAGTTCAGCGTGGACCAACTTATGGAACTGGCCGGGCTGAGCTGT 15 GCTACAGCCATCGCCAAGGCATATCCCCCCACGTCCATGTCCAGGAGCCCCCC TACTGTCCTGGTCATCTGTGGCCCGGGGAATAATGGAGGAGATGGTCTGGTCT GTGCTCGACACCTCAAACTCTTTGGCTACGAGCCAACCATCTATTACCCCAAA AGGCCTAACAAGCCCCTCTTCACTGCATTGGTGACCCAGTGTCAGAAAATGG ACATCCCTTTCCTTGGGGAAATGCCCGCAGAGCCCATGACGATTGATGAACTG 20 TATGAGCTGGTGGTGGATGCCATCTTTGGCTTCAGCTTCAAGGGCGATGTTCG GGAACCGTTCCACAGCATCCTGAGTGTCCTGAAGGGACTCACTGTGCCCATTG CCAGCATCGACATTCCCTCAGGATGGGACGTGGAGAAGGGAAATGCTGGAGG GATCCAGCCAGACTTGCTCATATCCCTCACAGCCCCCAAAAAATCTGCAACCC AGTTTACCGGTCGCTACCATTACCTGGGGGGTCGTTTTGTGCCACCTGCTCTG 25 GAGAAGAAGTACCAGCTGAACCTGCCACCCTACCCTGACACCGAGTGTGTCT ATCGTCTGCAGTGAGGGAAGGTGGGTGGGTATTCTTCCCAATAAAGACTTAG AGCCCCTCTCTTCCAGAACTGTGGATTCCTGGGAGCTCCTCTGGCAATAAAAG TCAGTGAATGGTGGAAGTCAGAGACCAACCCTGGGGATTGGGTGCCATCTCT CTAGGGGTAACACAAAGGGCAAGAGGTTGCTATGGTATTTGGAAACAATGAA 30 AATGGACTGTTAGATGCCAA Human AIBP polypeptide (SEQ ID NO:6) Docket No. EPN-AC-RAFT.003PC PATENT MSRLRALLGLGLLVAGSRVPRIKSQTIACRSGPTWWGPQRLNSGGRWDSEVMAS TVVKYLSQEEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPP TVLVICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIP FLGEMPAEPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSG 5 WDVEKGNAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPP YPDTECVYRLQ In some embodiments, a modified hAIBP is used, that retains the TLR4-binding domain and has N-terminal residues replaced with a native signal peptide, for example, the hAIBP comprises amino acids 25-288 of the hAIBP sequence, also known as 10 d24hAIBP (encoding nucleic acid): CAGACCATCGCCTGTCGCTCGGGACCCACCTGGTGGGGACCGCAGCGGCTGA ACTCGGGTGGCCGCTGGGACTCAGAGGTCATGGCGAGCACGGTGGTGAAGTA CCTGAGCCAGGAGGAGGCCCAGGCCGTGGACCAGGAGCTATTTAACGAATAC CAGTTCAGCGTGGACCAACTTATGGAACTGGCCGGGCTGAGCTGTGCTACAG 15 CCATCGCCAAGGCATATCCCCCCACGTCCATGTCCAGGAGCCCCCCTACTGTC CTGGTCATCTGTGGCCCGGGGAATAATGGAGGAGATGGTCTGGTCTGTGCTC GACACCTCAAACTCTTTGGCTACGAGCCAACCATCTATTACCCCAAAAGGCCT AACAAGCCCCTCTTCACTGCATTGGTGACCCAGTGTCAGAAAATGGACATCCC TTTCCTTGGGGAAATGCCCGCAGAGCCCATGACGATTGATGAACTGTATGAG 20 CTGGTGGTGGATGCCATCTTTGGCTTCAGCTTCAAGGGCGATGTTCGGGAACC GTTCCACAGCATCCTGAGTGTCCTGAAGGGACTCACTGTGCCCATTGCCAGCA TCGACATTCCCTCAGGATGGGACGTGGAGAAGGGAAATGCTGGAGGGATCCA GCCAGACTTGCTCATATCCCTCACAGCCCCCAAAAAATCTGCAACCCAGTTTA CCGGTCGCTACCATTACCTGGGGGGTCGTTTTGTGCCACCTGCTCTGGAGAAG 25 AAGTACCAGCTGAACCTGCCACCCTACCCTGACACCGAGTGTGTCTATCGTCT GCAG (SEQ ID NO:7) wherein the corresponding polypeptide is: QTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQ FSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLVCARHLK 30 LFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYELVVDAIF GFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLTAPK KSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO:8). Docket No. EPN-AC-RAFT.003PC PATENT In some embodiments, provided is a human AIBP in which a portion of the N- terminus of AIBP (amino acids 1-24, d24hAIBP) is replaced with (or further comprises) a fibronectin secretion signal (italic); the product is abbreviated as FIB-d24hAIBP and named Compound 1: 5 Human FIB-d24hAIBP (Compound 1)-encoding nucleic acid (cDNA): ATGCTCAGGGGTCCGGGACCCGGGCGGCTGCTGCTGCTAGCAGTCCTGTGCCTG GGGACATCGGTGCGCTGCACCGAAACCGGGAAGAGCAAGAGGCAGACCATCGC CTGTCGCTCGGGACCCACCTGGTGGGGACCGCAGCGGCTGAACTCGGGTGGC CGCTGGGACTCAGAGGTCATGGCGAGCACGGTGGTGAAGTACCTGAGCCAGG 10 AGGAGGCCCAGGCCGTGGACCAGGAGCTATTTAACGAATACCAGTTCAGCGT GGACCAACTTATGGAACTGGCCGGGCTGAGCTGTGCTACAGCCATCGCCAAG GCATATCCCCCCACGTCCATGTCCAGGAGCCCCCCTACTGTCCTGGTCATCTG TGGCCCGGGGAATAATGGAGGAGATGGTCTGGTCTGTGCTCGACACCTCAAA CTCTTTGGCTACGAGCCAACCATCTATTACCCCAAAAGGCCTAACAAGCCCCT 15 CTTCACTGCATTGGTGACCCAGTGTCAGAAAATGGACATCCCTTTCCTTGGGG AAATGCCCGCAGAGCCCATGACGATTGATGAACTGTATGAGCTGGTGGTGGA TGCCATCTTTGGCTTCAGCTTCAAGGGCGATGTTCGGGAACCGTTCCACAGCA TCCTGAGTGTCCTGAAGGGACTCACTGTGCCCATTGCCAGCATCGACATTCCC TCAGGATGGGACGTGGAGAAGGGAAATGCTGGAGGGATCCAGCCAGACTTG 20 CTCATATCCCTCACAGCCCCCAAAAAATCTGCAACCCAGTTTACCGGTCGCTA CCATTACCTGGGGGGTCGTTTTGTGCCACCTGCTCTGGAGAAGAAGTACCAGC TGAACCTGCCACCCTACCCTGACACCGAGTGTGTCTATCGTCTGCAG (SEQ ID NO:9) Compound 1 polypeptide sequence: 25 MLRGPGPGRLLLLAVLCLGTSVRCTETGKSKRQTIACRSGPTWWGPQRLNSGGRW DSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPP TSMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVT QCQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTV PIASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALE 30 KKYQLNLPPYPDTECVYRLQ (SEQ ID NO:10) In this embodiment, the hAIBP fragment comprises amino acids 25 to 288 (also known as d24hAIBP) and the N-terminal modification is: MLRGPGPGRLLLLAVLCLGTSVRCTETGKSKR (SEQ ID NO:11). Docket No. EPN-AC-RAFT.003PC PATENT In one embodiment, a secretion signal is added to ensure robust secretion of AIBP, for example, a fibronectin secretion signal is added to N terminus of AIBP (see italicized sequences in SEQ ID NO:3 and SEQ ID NO:4); or a nucleic acid encoding a secretion signal is added to the AIBP coding sequence. In alternative embodiments, a 5 secretion signal is a fibronectin secretion signal, an immunoglobulin heavy chain secretion signal or an immunoglobulin kappa light chain secretory peptide (see, for example, PLoS One.2015; 10(2): e0116878), or an interleukin-2 signal peptide (see, for example, J. Gene Med.2005 Mar;7(3):354-65). In alternative embodiments, the polypeptide coding sequences are operatively 10 linked to a promoter, for example, a constitutive, inducible, tissue specific (for example, nerve or brain tissue specific) or ubiquitous promoter or other transcriptional activating agent. In other embodiments, the product from post-translational modification of the fibronectin-hAIBP construct has an amino acid sequence (Compound 2): 15 TETGKSKRQTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVD QELFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDG LVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDEL YELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPD LLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ 20 (SEQ ID NO:12), wherein the hAIBP fragment is d24hAIBP and the N-terminal modification is TETGKSKR (SEQ ID NO:13), In other embodiments, the sequence of the AIBP polypeptide is modified at its C- terminus to incorporate additional peptidic fragments. This is exemplified by addition of a 25 C-terminal His Tag (underlined in the corresponding amino acid sequence): Compound 3 encoding nucleic acid sequence: ATGCTCAGGGGTCCGGGACCCGGGCGGCTGCTGCTGCTAGCAGTCCTGTGCCT GGGGACATCGGTGCGCTGCACCGAAACCGGGAAGAGCAAGAGGCAGACCAT CGCCTGTCGCTCGGGACCCACCTGGTGGGGACCGCAGCGGCTGAACTCGGGT 30 GGCCGCTGGGACTCAGAGGTCATGGCGAGCACGGTGGTGAAGTACCTGAGCC AGGAGGAGGCCCAGGCCGTGGACCAGGAGCTATTTAACGAATACCAGTTCAG CGTGGACCAACTTATGGAACTGGCCGGGCTGAGCTGTGCTACAGCCATCGCC AAGGCATATCCCCCCACGTCCATGTCCAGGAGCCCCCCTACTGTCCTGGTCAT Docket No. EPN-AC-RAFT.003PC PATENT CTGTGGCCCGGGGAATAATGGAGGAGATGGTCTGGTCTGTGCTCGACACCTC AAACTCTTTGGCTACGAGCCAACCATCTATTACCCCAAAAGGCCTAACAAGC CCCTCTTCACTGCATTGGTGACCCAGTGTCAGAAAATGGACATCCCTTTCCTT GGGGAAATGCCCGCAGAGCCCATGACGATTGATGAACTGTATGAGCTGGTGG 5 TGGATGCCATCTTTGGCTTCAGCTTCAAGGGCGATGTTCGGGAACCGTTCCAC AGCATCCTGAGTGTCCTGAAGGGACTCACTGTGCCCATTGCCAGCATCGACAT TCCCTCAGGATGGGACGTGGAGAAGGGAAATGCTGGAGGGATCCAGCCAGA CTTGCTCATATCCCTCACAGCCCCCAAAAAATCTGCAACCCAGTTTACCGGTC GCTACCATTACCTGGGGGGTCGTTTTGTGCCACCTGCTCTGGAGAAGAAGTAC 10 CAGCTGAACCTGCCACCCTACCCTGACACCGAGTGTGTCTATCGTCTGCAGTT GGTCCCTCGTGGAAGCCATCATCATCATCATCATTAA (SEQ ID NO:14) Amino acid sequence (Compound 3): MLRGPGPGRLLLLAVLCLGTSVRCTETGKSKRQTIACRSGPTWWGPQRLNSGGRW DSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPP 15 TSMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVT QCQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTV PIASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALE KKYQLNLPPYPDTECVYRLQLVPRGSHHHHH (SEQ ID NO:15). wherein the hAIBP fragment is d24hAIBP containing a His Tag (FIB-d24 AIBP- 20 His) and the N-terminal modification: MLRGPGPGRLLLLAVLCLGTSVRCTETGKSKR (SEQ ID NO:11), In other embodiments the post-translational modification of the signal peptide provides a compound (Compound 4): TETGKSKRQTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVD 25 QELFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDG LVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDEL YELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPD LLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQLVP RGSHHHHH (SEQ ID NO:16), 30 wherein the hAIBP fragment is d24hAIBP-His and the N-terminal modification is TETGKSKR (SEQ ID NO:13), Docket No. EPN-AC-RAFT.003PC PATENT In other embodiments, the polypeptide coding sequences are operatively linked to a promoter, e.g., a constitutive, inducible, tissue specific (e.g., nerve or brain tissue specific) or ubiquitous promoter or other transcriptional activating agent. In other embodiments, full length human AIBP is modified at its N-terminus, 5 wherein such modification facilitates TLR4 binding, for example Compound 5-encoding nucleic acid (cDNA): ATGGACTACAAAGACCATGACGGTGATTATAAAGATCATGACATCGATTACA AGGATGACGATGACAAGCTTGCGGCCGCGAATTCAGGGCCGGGGGCGCGCGC TCTGCGAGCTGGATGTCCAGGCTGCGGGCGCTGCTGGGCCTCGGGCTGCTGGT 10 TGCGGGCTCGCGCGTGCCGCGGATCAAAAGCCAGACCATCGCCTGTCGCTCG GGACCCACCTGGTGGGGACCGCAGCGGCTGAACTCGGGTGGCCGCTGGGACT CAGAGGTCATGGCGAGCACGGTGGTGAAGTACCTGAGCCAGGAGGAGGCCC AGGCCGTGGACCAGGAGCTATTTAACGAATACCAGTTCAGCGTGGACCAACT TATGGAACTGGCCGGGCTGAGCTGTGCTACAGCCATCGCCAAGGCATATCCC 15 CCCACGTCCATGTCCAGGAGCCCCCCTACTGTCCTGGTCATCTGTGGCCCGGG GAATAATGGAGGAGATGGTCTGGTCTGTGCTCGACACCTCAAACTCTTTGGCT ACGAGCCAACCATCTATTACCCCAAAAGGCCTAACAAGCCCCTCTTCACTGCA TTGGTGACCCAGTGTCAGAAAATGGACATCCCTTTCCTTGGGGAAATGCCCGC AGAGCCCATGACGATTGATGAACTGTATGAGCTGGTGGTGGATGCCATCTTTG 20 GCTTCAGCTTCAAGGGCGATGTTCGGGAACCGTTCCACAGCATCCTGAGTGTC CTGAAGGGACTCACTGTGCCCATTGCCAGCATCGACATTCCCTCAGGATGGG ACGTGGAGAAGGGAAATGCTGGAGGGATCCAGCCAGACTTGCTCATATCCCT CACAGCCCCCAAAAAATCTGCAACCCAGTTTACCGGTCGCTACCATTACCTGG GGGGTCGTTTTGTGCCACCTGCTCTGGAGAAGAAGTACCAGCTGAACCTGCC 25 ACCCTACCCTGACACCGAGTGTGTCTATCGTCTGCAGTGAGGGAAGGTGGGT GGGTATTCTTCCCAATAAAGACTTAGAGCCCCTCTCTTCCAGAACTGTGGATT CCTGGGAGCTCCTCTGGCAATAAAAGTCAGTGAATGGTGGAAGTCAGAGACC AACCCTGGGGATTGGGTGCCATCTCTCTAGGGGTAACACAAAGGGCAAGAGG TTGCTATGGTATTTGGAAACAATGAAAATGGACTGTTAGATGCCAA 30 (SEQ ID NO:17), This encodes the following amino acid sequence (Compound 5): MDYKDHDGDYKDHDIDYKDDDDKLAAANSMSRLRALLGLGLLVAGSRVPRIKS QTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQ Docket No. EPN-AC-RAFT.003PC PATENT FSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLVCARHLK LFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYELVVDAIF GFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLTAPK KSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO:18), 5 wherein, the hAIBP fragment is full length and the N-terminal modification: MDYKDHDGDYKDHDIDYKDDDDKLAAANS (SEQ ID NO:19), In other embodiments, hAIBP sequence which retains the cryptic TLR4 binding domain is modified at its N-terminus. Example sequences comprise DNA and peptide sequence for amino acids 25-288 of hAIBP (d24hAIBP): 10 Compound 6-encoding nucleic acid sequence: ATGGACTACAAAGACCATGACGGTGATTATAAAGATCATGACATCGATTACAAGGAT GACGATGACAAGCTTGCGGCCGCGAATTCACAGACCATCGCCTGTCGCTCGGGA CCCACCTGGTGGGGACCGCAGCGGCTGAACTCGGGTGGCCGCTGGGACTCAG AGGTCATGGCGAGCACGGTGGTGAAGTACCTGAGCCAGGAGGAGGCCCAGG 15 CCGTGGACCAGGAGCTATTTAACGAATACCAGTTCAGCGTGGACCAACTTAT GGAACTGGCCGGGCTGAGCTGTGCTACAGCCATCGCCAAGGCATATCCCCCC ACGTCCATGTCCAGGAGCCCCCCTACTGTCCTGGTCATCTGTGGCCCGGGGAA TAATGGAGGAGATGGTCTGGTCTGTGCTCGACACCTCAAACTCTTTGGCTACG AGCCAACCATCTATTACCCCAAAAGGCCTAACAAGCCCCTCTTCACTGCATTG 20 GTGACCCAGTGTCAGAAAATGGACATCCCTTTCCTTGGGGAAATGCCCGCAG AGCCCATGACGATTGATGAACTGTATGAGCTGGTGGTGGATGCCATCTTTGGC TTCAGCTTCAAGGGCGATGTTCGGGAACCGTTCCACAGCATCCTGAGTGTCCT GAAGGGACTCACTGTGCCCATTGCCAGCATCGACATTCCCTCAGGATGGGAC GTGGAGAAGGGAAATGCTGGAGGGATCCAGCCAGACTTGCTCATATCCCTCA 25 CAGCCCCCAAAAAATCTGCAACCCAGTTTACCGGTCGCTACCATTACCTGGGG GGTCGTTTTGTGCCACCTGCTCTGGAGAAGAAGTACCAGCTGAACCTGCCACC CTACCCTGACACCGAGTGTGTCTATCGTCTGCAG (SEQ ID NO:20), Amino acid sequence (Compound 6): MDYKDHDGDYKDHDIDYKDDDDKLAAANSQTIACRSGPTWWGPQRLNSGGRW 30 DSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPP TSMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVT QCQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTV Docket No. EPN-AC-RAFT.003PC PATENT PIASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALE KKYQLNLPPYPDTECVYRLQ (SEQ ID NO:21), wherein, the hAIBP fragment is d24hAIBP and the N-terminal modification is: MDYKDHDGDYKDHDIDYKDDDDKLAAANS (SEQ ID NO:19), 5 Compound 7-encoding nucleic acid sequence: ATG TCC CCT ATA GAT CCG ATG GGA CAT CAT CAT CAT CAT CAC GGA AGG AGA AGG GCC AGT GTT GCG GCG GGA ATT TTG GTC CCT CGT GGA AGC CCA GGA CTC GAT GGC ATA TGC TCG AGGCAGACCATCGCCTGTCGCTCGGGACCCACCTGGTGGGGACCGCAGCGGC TGAACTCGGGTGGCCGCTGGGACTCAGAGGTCATGGCGAGCACGGTGGTGAA 10 GTACCTGAGCCAGGAGGAGGCCCAGGCCGTGGACCAGGAGCTATTTAACGAA TACCAGTTCAGCGTGGACCAACTTATGGAACTGGCCGGGCTGAGCTGTGCTA CAGCCATCGCCAAGGCATATCCCCCCACGTCCATGTCCAGGAGCCCCCCTACT GTCCTGGTCATCTGTGGCCCGGGGAATAATGGAGGAGATGGTCTGGTCTGTG CTCGACACCTCAAACTCTTTGGCTACGAGCCAACCATCTATTACCCCAAAAGG 15 CCTAACAAGCCCCTCTTCACTGCATTGGTGACCCAGTGTCAGAAAATGGACAT CCCTTTCCTTGGGGAAATGCCCGCAGAGCCCATGACGATTGATGAACTGTATG AGCTGGTGGTGGATGCCATCTTTGGCTTCAGCTTCAAGGGCGATGTTCGGGAA CCGTTCCACAGCATCCTGAGTGTCCTGAAGGGACTCACTGTGCCCATTGCCAG CATCGACATTCCCTCAGGATGGGACGTGGAGAAGGGAAATGCTGGAGGGATC 20 CAGCCAGACTTGCTCATATCCCTCACAGCCCCCAAAAAATCTGCAACCCAGTT TACCGGTCGCTACCATTACCTGGGGGGTCGTTTTGTGCCACCTGCTCTGGAGA AGAAGTACCAGCTGAACCTGCCACCCTACCCTGACACCGAGTGTGTCTATCGT CTGCAG (SEQ ID NO:23), Amino acid sequence (Compound 7) 25 MSPIDPMGHHHHHHGRRRASVAAGILVPRGSPGLDGICSRQTIACRSGPTWWGP QRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLMELAGLSC ATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRP NKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDVREPFHS ILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTGRYHYLG 30 GRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO:24), wherein, the hAIBP fragment is d24hAIBP and the N-terminal modification is: MSPIDPMGHHHHHHGRRRASVAAGILVPRGSPGLDGICSR (SEQ ID NO:2), Compound 8- encoding nucleic acid sequence: Docket No. EPN-AC-RAFT.003PC PATENT ATG TCC CCT ATA GAT CCG ATG GGA CAT CAT CAT CAT CAT CAC GGA AGG AGA AGG GCC AGT GTT GCG GCG GGA ATT TTG GTC CCT CGT GGA AGC GAT GGA GAC GAT GGC GAT GAC GAC AGG CAGACCATCGCCTGTCGCTCGGGACCCACCTGGTGGGGACCGCAGCGGCTGA 5 ACTCGGGTGGCCGCTGGGACTCAGAGGTCATGGCGAGCACGGTGGTGAAGTA CCTGAGCCAGGAGGAGGCCCAGGCCGTGGACCAGGAGCTATTTAACGAATAC CAGTTCAGCGTGGACCAACTTATGGAACTGGCCGGGCTGAGCTGTGCTACAG CCATCGCCAAGGCATATCCCCCCACGTCCATGTCCAGGAGCCCCCCTACTGTC CTGGTCATCTGTGGCCCGGGGAATAATGGAGGAGATGGTCTGGTCTGTGCTC 10 GACACCTCAAACTCTTTGGCTACGAGCCAACCATCTATTACCCCAAAAGGCCT AACAAGCCCCTCTTCACTGCATTGGTGACCCAGTGTCAGAAAATGGACATCCC TTTCCTTGGGGAAATGCCCGCAGAGCCCATGACGATTGATGAACTGTATGAG CTGGTGGTGGATGCCATCTTTGGCTTCAGCTTCAAGGGCGATGTTCGGGAACC GTTCCACAGCATCCTGAGTGTCCTGAAGGGACTCACTGTGCCCATTGCCAGCA 15 TCGACATTCCCTCAGGATGGGACGTGGAGAAGGGAAATGCTGGAGGGATCCA GCCAGACTTGCTCATATCCCTCACAGCCCCCAAAAAATCTGCAACCCAGTTTA CCGGTCGCTACCATTACCTGGGGGGTCGTTTTGTGCCACCTGCTCTGGAGAAG AAGTACCAGCTGAACCTGCCACCCTACCCTGACACCGAGTGTGTCTATCGTCT GCAG (SEQ ID NO:25), 20 Compound 8 amino acid sequence: MSPIDPMGHHHHHHGRRRASVAAGILVPRGSDGDDGDDDRQTIACRSGPTWWG PQRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLMELAGLS CATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRP NKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDVREPFHS 25 ILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTGRYHYLG GRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO:26), wherein, the hAIBP fragment is d24hAIBP and the N-terminal modification is: MSPIDPMGHHHHHHGRRRASVAAGILVPRGSDGDDGDDDR (SEQ ID NO:27), (Compound 9-encoding nucleic acid sequence): 30 ATG TCC CCT ATA GAT CCG ATG GGA CAT CAT CAT CAT CAT CAC GGA AGG AGA AGG GCC AGT GTT GCG GCG GGA ATT TTG GTC CCT CGT GGA AGC GAT GGA GAC GAT GGC ATA TGC TCG AGG CAGACCATCGCCTGTCGCTCGGGACCCACCTGGTGGGGACCGCAGCGGCTGA Docket No. EPN-AC-RAFT.003PC PATENT ACTCGGGTGGCCGCTGGGACTCAGAGGTCATGGCGAGCACGGTGGTGAAGTA CCTGAGCCAGGAGGAGGCCCAGGCCGTGGACCAGGAGCTATTTAACGAATAC CAGTTCAGCGTGGACCAACTTATGGAACTGGCCGGGCTGAGCTGTGCTACAG CCATCGCCAAGGCATATCCCCCCACGTCCATGTCCAGGAGCCCCCCTACTGTC 5 CTGGTCATCTGTGGCCCGGGGAATAATGGAGGAGATGGTCTGGTCTGTGCTC GACACCTCAAACTCTTTGGCTACGAGCCAACCATCTATTACCCCAAAAGGCCT AACAAGCCCCTCTTCACTGCATTGGTGACCCAGTGTCAGAAAATGGACATCCC TTTCCTTGGGGAAATGCCCGCAGAGCCCATGACGATTGATGAACTGTATGAG CTGGTGGTGGATGCCATCTTTGGCTTCAGCTTCAAGGGCGATGTTCGGGAACC 10 GTTCCACAGCATCCTGAGTGTCCTGAAGGGACTCACTGTGCCCATTGCCAGCA TCGACATTCCCTCAGGATGGGACGTGGAGAAGGGAAATGCTGGAGGGATCCA GCCAGACTTGCTCATATCCCTCACAGCCCCCAAAAAATCTGCAACCCAGTTTA CCGGTCGCTACCATTACCTGGGGGGTCGTTTTGTGCCACCTGCTCTGGAGAAG AAGTACCAGCTGAACCTGCCACCCTACCCTGACACCGAGTGTGTCTATCGTCT 15 GCAG (SEQ ID NO:28), Amino acid sequence (Compound 9): MSPIDPMGHHHHHHGRRRASVAAGILVPRGSDGDDGICSR QTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQ FSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLVCARHLK 20 LFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYELVVDAIF GFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLTAPK KSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO:29), wherein, the hAIBP fragment is d24hAIBP and the N-terminal modification is: MSPIDPMGHHHHHHGRRRASVAAGILVPRGSDGDDGICSR (SEQ ID NO:30), 25 In other embodiments, provided are compositions for a recombinant, synthetic ApoA-I Binding Protein (APOA1BP, AIBP, or AI-BP) polypeptide compound or composition having a heterologous amino terminus amino acid sequence of at least about eight amino acid, or between about 8 to 100 amino acids, or between about 8 to 40 amino acids, or between about 30 to 50 amino acids, or any heterologous amino acid sequence30 sufficient to result in the unfolding and exposing of the cryptic (or hidden, unexposed) N- terminal TLR4 binding domain of the AIBP polypeptide. Docket No. EPN-AC-RAFT.003PC PATENT In alternative embodiments, the amino acid N-terminal sequence comprises between 3 and 12 basic amino acids selected from histidine (H), lysine (K) or arginine (R). In other embodiments, compounds described herein may be further modified to 5 improve properties for bioactivity, for example by removal of putative peptide cleavage sites. Example sequences are represented by: Compound 10 (encoding nucleic acid sequence): ATG TCC CCT ATA GAT CCG ATG GGA CAT CAT CAT CAT CAT CAC GGA AGG AGA AGG GCC AGT GTT GCG GCG GGA ATT TTG GTC CCT GCT GCA AGC CCA GGA CTC GAT GGC ATA TGC TCG 10 AGG CAGACCATCGCCTGTCGCTCGGGACCCACCTGGTGGGGACCGCAGCGG CTGAACTCGGGTGGCCGCTGGGACTCAGAGGTCATGGCGAGCACGGTGGTGA AGTACCTGAGCCAGGAGGAGGCCCAGGCCGTGGACCAGGAGCTATTTAACGA ATACCAGTTCAGCGTGGACCAACTTATGGAACTGGCCGGGCTGAGCTGTGCT ACAGCCATCGCCAAGGCATATCCCCCCACGTCCATGTCCAGGAGCCCCCCTAC 15 TGTCCTGGTCATCTGTGGCCCGGGGAATAATGGAGGAGATGGTCTGGTCTGTG CTCGACACCTCAAACTCTTTGGCTACGAGCCAACCATCTATTACCCCAAAAGG CCTAACAAGCCCCTCTTCACTGCATTGGTGACCCAGTGTCAGAAAATGGACAT CCCTTTCCTTGGGGAAATGCCCGCAGAGCCCATGACGATTGATGAACTGTATG AGCTGGTGGTGGATGCCATCTTTGGCTTCAGCTTCAAGGGCGATGTTCGGGAA 20 CCGTTCCACAGCATCCTGAGTGTCCTGAAGGGACTCACTGTGCCCATTGCCAG CATCGACATTCCCTCAGGATGGGACGTGGAGAAGGGAAATGCTGGAGGGATC CAGCCAGACTTGCTCATATCCCTCACAGCCCCCAAAAAATCTGCAACCCAGTT TACCGGTCGCTACCATTACCTGGGGGGTCGTTTTGTGCCACCTGCTCTGGAGA AGAAGTACCAGCTGAACCTGCCACCCTACCCTGACACCGAGTGTGTCTATCGT 25 CTGCAG (SEQ ID NO:31), Compound 10 (Amino acid sequence): MSPIDPMGHHHHHHGRRRASVAAGILVPAASPGLDGICSRQTIACRSGPTWWGP QRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLMELAGLSC ATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRP 30 NKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDVREPFHS ILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTGRYHYLG GRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO:32), Docket No. EPN-AC-RAFT.003PC PATENT wherein, the hAIBP fragment is d24hAIBP and the N-terminal modification is: MSPIDPMGHHHHHHGRRRASVAAGILVPAASPGLDGICSR (SEQ ID NO:33). The thrombin cleavage site LVPRGS (SEQ ID NO:34) described in compound 7 incorporates an amino acid mutation to LVPAAS (SEQ ID NO.: 46) in compound 10 that 5 prevents cleavage and unexpected loss of TLR4 binding activity as described in Example 1 and figures 3, 4 and 5. It should be acknowledged that these sequences are illustrative and are not limiting to the invention. In other embodiments, any of the amino acids in the N-terminal modification of 10 hAIBP may be unnatural and inserted by methods known to those skilled in the art. Products of Manufacture, Kits Also provided are products of manufacture such as implants or pumps, kits and pharmaceuticals for practicing the methods as provided herein. In alternative embodiments, provided are products of manufacture, kits and/or pharmaceuticals 15 comprising all the components needed to practice a method as provided herein. In alternative embodiments, kits also comprise instructions for practicing a method as provided herein. Formulations and pharmaceutical compositions In alternative embodiments, provided are pharmaceutical formulations or 20 compositions comprising nucleic acids and polypeptides for practicing methods and uses as provided herein to regulate neuropathic pain, the methods comprising upregulating the expression of recombinant ApoA-I Binding Protein (APOA1BP, AIBP, or AI-BP). In alternative embodiments, provided are pharmaceutical formulations or compositions for use in in vivo, in vitro or ex vivo methods to treat, prevent, reverse and/or ameliorate 25 neuropathic pain. In alternative embodiments, pharmaceutical compositions and formulations used to practice methods and uses as provided herein comprise recombinant APOA1BP nucleic acids and polypeptides that are administered to an individual in need thereof in an amount sufficient to treat, prevent, reverse and/or ameliorate, for example, post-operative pain, a neuropathic pain or a headache such as migraine. In alternative 30 embodiments, pharmaceutical compositions and formulations used to practice methods and uses as provided herein comprise recombinant APOA1BP nucleic acids and polypeptides that are administered to an individual in need thereof in an amount sufficient Docket No. EPN-AC-RAFT.003PC PATENT to prevent or decrease the intensity of and/or frequency of for example, post-operative pain, the neuropathic pain or the headache such as migraine. In alternative embodiments, the pharmaceutical compositions used to practice methods and uses as provided herein are administered parenterally. The pharmaceutical 5 compositions are formulated in any way and administered in a variety of unit dosage forms depending upon the condition or disease and the degree of illness, the general medical condition of each patient, the resulting preferred method of administration and the like. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, for example, the latest edition of Remington's 10 Pharmaceutical Sciences, Maack Publishing Co., Easton PA (“Remington’s”). For example, in alternative embodiments, the compositions used to practice methods and uses as provided herein are formulated in a buffer, in a saline solution, in a vesicle, in a liposome, in a nanoparticle, in a nanolipoparticle and the like. In alternative embodiments, the compositions are formulated and applied in a variety of concentrations 15 and forms depending on the desired in vivo, in vitro or ex vivo conditions, a desired in vivo, in vitro or ex vivo method of administration and the like. Details on techniques for in vivo, in vitro or ex vivo formulations and administrations are well described in the scientific and patent literature. In alternative embodiments, formulations and pharmaceutical compositions used 20 to practice methods and uses as provided herein can comprise a solution of compositions (which include peptidomimetics, racemic mixtures or racemates, isomers, stereoisomers, derivatives and/or analogs of compounds) disposed in or dissolved in a pharmaceutically acceptable carrier, for example, acceptable vehicles and solvents that are typically employed include water and Ringer's solution, an isotonic sodium chloride. In one 25 embodiment, solutions and formulations used to practice methods and uses as provided herein are sterile and are manufactured to be generally free of undesirable matter. In one embodiment, these solutions and formulations are sterilized by conventional, well known sterilization techniques. In some embodiments, the solutions and formulations used to practice methods 30 and uses as provided herein auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of active agent in these formulations vary, and are Docket No. EPN-AC-RAFT.003PC PATENT selected primarily based on fluid volumes, viscosities and the like, in accordance with the particular mode of in vivo, in vitro or ex vivo administration selected and the desired results. The compositions and formulations used to practice methods and uses as provided 5 herein in some embodiments are delivered by the use of liposomes. By using liposomes, particularly where the liposome surface carries ligands specific for target cells (for example, an injured or diseased neuronal cell or CNS tissue), or are otherwise preferentially directed to a specific tissue or organ type, one can focus the delivery of the active agent into a target cell in an in vivo, in vitro or ex vivo application. 10 Nanoparticles, Nanolipoparticles and Liposomes Also provided are nanoparticles, nanolipoparticles, vesicles and liposomal membranes comprising compounds used to practice methods and uses as provided herein, for example, to deliver compositions comprising recombinant APOA1BP polypeptides in vivo, for example, to the CNS and brain. In alternative embodiments, these compositions 15 are designed to target specific molecules, including biologic molecules, such as polypeptides, including cell surface polypeptides, for example, for targeting a desired cell type or organ, for example, a nerve cell or the CNS, and the like. Provided are multilayered liposomes comprising compounds used to practice methods and uses as provided herein, for example, as described in Park, et al., U.S. Pat. 20 Pub. No.20070082042. The multilayered liposomes are sometimes prepared using a mixture of oil-phase components comprising squalane, sterols, ceramides, neutral lipids or oils, fatty acids and lecithins, to about 200 to 5000 nm in particle size, to entrap a composition used to practice methods and uses as provided herein. Liposomes are typically made using a method as described in Park, et al., U.S. 25 Pat. Pub. No.20070042031, including method of producing a liposome by encapsulating an active agent (for example, recombinant APOA1BP nucleic acids and polypeptides), the method comprising providing an aqueous solution in a first reservoir; providing an organic lipid solution in a second reservoir, and then mixing the aqueous solution with the organic lipid solution in a first mixing region to produce a liposome solution, where the 30 organic lipid solution mixes with the aqueous solution to substantially instantaneously produce a liposome encapsulating the active agent; and immediately then mixing the liposome solution with a buffer solution to produce a diluted liposome solution. Docket No. EPN-AC-RAFT.003PC PATENT In one embodiment, liposome compositions used to practice methods and uses as provided herein comprise a substituted ammonium and/or polyanions, for example, for targeting delivery of a compound (for example, a recombinant APOA1BP nucleic acid and polypeptide) to a desired cell type (for example, an endothelial cell, a nerve cell, or 5 any tissue or area, for example, a CNS, in need thereof), as described for example, in U.S. Pat. Pub. No.20070110798. Provided are nanoparticles comprising compounds (for example, recombinant APOA1BP nucleic acids and polypeptides used to practice methods provided herein) in the form of active agent-containing nanoparticles (for example, a secondary nanoparticle), 10 as described, for example, in U.S. Pat. Pub. No.20070077286. In one embodiment, provided are nanoparticles comprising a fat-soluble active agent or a fat-solubilized water-soluble active agent to act with a bivalent or trivalent metal salt. In one embodiment, solid lipid suspensions are used to formulate and to deliver compositions used to practice methods and uses as provided herein to mammalian cells in 15 vivo, for example, to the CNS, as described, for example, in U.S. Pat. Pub. No. 20050136121. Delivery vehicle modifications and modification of AIBP In alternative embodiments, recombinant AIBP peptides or polypeptides, or AIBP-comprising nanoparticles, liposomes and the like (for example, comprising or 20 having contained therein recombinant APOA1BP polypeptides used to practice methods provided herein) are modified to facilitate intrathecal injection, for example, delivery into the cerebrospinal fluid or brain. For example, in alternative embodiments, AIBP peptides or polypeptides, or recombinant AIBP-comprising nanoparticles, liposomes and the like, are engineered to comprise a moiety that allows the AIBP peptides or polypeptides, or 25 AIBP-comprising nanoparticles, liposomes and the like, to bind to a receptor or cell membrane structure that facilitates delivery into the CNS or brain, for example, where the moiety can comprise a mannose-6-phosphate receptor, a melanotransferrin receptor, a LRP receptor or any other receptor that is ubiquitously expressed on the surface of any CNS or brain cell. For example, conjugation of mannose-6-phosphate moieties allows the 30 AIBP peptides or polypeptides, or recombinant AIBP-comprising nanoparticles, liposomes and the like, to be taken up by a CNS cell that expresses a mannose-6- phosphate receptor. In alternative embodiments, any protocol or modification of the AIBP peptides or polypeptides, or AIBP-comprising nanoparticles, liposomes and the Docket No. EPN-AC-RAFT.003PC PATENT like, that facilitates entry or delivery into the CNS or brain in vivo are used, for example, as described in USPN 9,089,566. In alternative embodiments, recombinant AIBP peptides or polypeptides, or AIBP-comprising nanoparticles, liposomes and the like (for example, comprising or 5 having contained therein recombinant APOA1BP nucleic acids or polypeptides used to practice methods provided herein) are directly or indirectly linked or conjugated to any blood brain barrier (BBB)-targeting agent, for example, a transferrin, an insulin, a leptin, an insulin-like growth factor, a cationic peptide, a lectin, a Receptor-Associated Protein (RAP) (a 39 kD chaperone localized to the endoplasmic reticulum and Golgi, a 10 lipoprotein receptor-related protein (LRP) receptor family ligand), an apolipoprotein B- 100 derived peptide, an antibody (for example, a peptidomimetic monoclonal antibody) to a transferrin receptor, an antibody (for example, a peptidomimetic monoclonal antibody) to the insulin receptor, an antibody (for example, a peptidomimetic monoclonal antibody) to the insulin-like growth factor receptor, an antibody (for example, a peptidomimetic 15 monoclonal antibody) to the leptin receptor and the like. In alternative embodiments, protocols for modifications of the synthetic or recombinant AIBP polypeptides, or AIBP- comprising nanoparticles, liposomes and the like, that facilitates crossing of the BBB are used, for example, as described in US Pat App Pub Nos.20050142141; 20050042227. For example, to enhance CNS or brain delivery of a composition used to practice methods 20 as provided herein, various protocols are available, for example: modification of synthetic or recombinant AIBP polypeptides as described herein with CNS penetrating amino acid sequences, or AIBP-comprising nanoparticles, liposomes and the like to alter tissue distribution Delivery cells and delivery vehicles 25 In alternative embodiments, a delivery vehicle is used to practice the methods or uses as provided herein, for example, to deliver compositions (for example, recombinant APOA1BP polypeptides) to a CNS or a brain in vivo. For example, delivery vehicles comprising polycations, cationic polymers and/or cationic peptides, such as polyethyleneimine derivatives, are used for example as described, for example, in U.S. 30 Pat. Pub. No. 20060083737. In one embodiment, a delivery vehicle is a transduced cell engineered to express or overexpress and then secrete an endogenous or exogenous AIBP. Docket No. EPN-AC-RAFT.003PC PATENT In one embodiment, a dried polypeptide-surfactant complex is used to formulate a composition used to practice methods as provided herein, for example as described, for example, in U.S. Pat. Pub. No.20040151766. In one embodiment, a composition used to practice methods and uses as provided 5 herein are applied to cells using vehicles with cell membrane-permeant peptide conjugates, for example, as described in U.S. Patent Nos.7,306,783; 6,589,503. In one aspect, the composition to be delivered is conjugated to a cell membrane-permeant peptide. In one embodiment, the composition to be delivered and/or the delivery vehicle are conjugated to a transport-mediating peptide, for example, as described in U.S. Patent 10 No.5,846,743, describing transport-mediating peptides that are highly basic and bind to poly-phosphoinositides. In one embodiment, cells that will be subsequently delivered to a CNS or a brain are transfected or transduced with an AIBP-expressing nucleic acid, for example, a vector, for example, by electro-permeabilization, which is sometimes used as a primary or 15 adjunctive means to deliver the composition to a cell, for example, using any electroporation system as described for example in U.S. Patent Nos.7,109,034; 6,261,815; 5,874,268. Dosage and Administration Thereof The pharmaceutical compositions and formulations used to practice methods and 20 uses as provided herein are administered for prophylactic and/or therapeutic treatments. In therapeutic applications, compositions are administered to a subject already suffering from a disease, condition, infection or defect in an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of the disease, condition, infection or disease and its complications (a “therapeutically effective amount”), including for example, a 25 neuropathic pain. For example, in alternative embodiments, recombinant APOA1BP polypeptide-comprising pharmaceutical compositions and formulations as provided herein are administered to an individual in need thereof in an amount sufficient to treat, prevent, reverse and/or ameliorate a neuropathic pain, an inflammation-induced neuropathic pain, an inflammation-induced neuropathic pain, a nerve or CNS 30 inflammation, a allodynia, a post nerve injury pain or neuropathic pain, a post-surgical pain or neuropathic pain, a migraine, or a hyperalgesia. The amount of pharmaceutical composition adequate to accomplish this is defined as a "therapeutically effective dose." The dosage schedule and amounts effective for this Docket No. EPN-AC-RAFT.003PC PATENT use, i.e., the “dosing regimen,” will depend upon a variety of factors, including the stage of the disease or condition, the severity of the disease or condition, the general state of the patient's health, the patient’s physical status, age and the like. In calculating the dosage regimen for a patient, the mode of parenteral administration also is taken into 5 consideration. In alternative embodiments these dosages are administered once a day, once a week, or any variation thereof as needed to maintain in vivo expression levels of recombinant AIBP, which are monitored by measuring actually expression of AIBP or by monitoring of therapeutic effect, for example, diminishing of pain. The dosage regimen 10 also takes into consideration pharmacokinetics parameters well known in the art, i.e., the active agents’ rate of absorption, bioavailability, metabolism, clearance, and the like (see, for example, Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol.58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci.84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; 15 Brophy (1983) Eur. J. Clin. Pharmacol.24:103-108; the latest Remington’s, supra). The state of the art allows the clinician to determine the dosage regimen for each individual patient, active agent and disease or condition treated. Guidelines provided for similar compositions used as pharmaceuticals are typically used as guidance to determine the dosage regiment, i.e., dose schedule and dosage levels, administered practicing the 20 methods as provided herein are correct and appropriate. Single or multiple administrations of formulations are given depending on the dosage and frequency as required and tolerated by the patient. The formulations should provide a sufficient quantity of active agent to effectively treat, prevent or ameliorate a conditions, diseases or symptoms as described herein. For example, alternative 25 exemplary pharmaceutical formulations for parenteral administration of compositions used to practice methods as provided herein are in a daily amount of between about 0.1 to 0.5 to about 20, 50, 100 or 1000 or more ug per kilogram of body weight per day. In an alternative embodiment, dosages are from about 1 mg to about 4 mg per kg of body weight per patient per day are used. Lower dosages are sometimes administered into the 30 blood stream, into a body cavity or into a lumen of an organ. Typical methods for preparing parenterally administrable formulations will be known or apparent to those skilled in the art and are described in more detail in such publications as Remington's, supra. Docket No. EPN-AC-RAFT.003PC PATENT The methods as provided herein sometimes further comprise co-administration with other drugs or pharmaceuticals, for example, compositions for treating any neurological or neuromuscular disease, condition, infection or injury, including related inflammatory and autoimmune diseases and conditions, and the like. For example, the 5 methods and/or compositions and formulations as provided herein in some embodiments are co-formulated with and/or co-administered with, fluids, antibiotics, cytokines, immunoregulatory agents, anti-inflammatory agents, pain alleviating compounds, complement activating agents, such as peptides or proteins comprising collagen-like domains or fibrinogen-like domains (for example, a ficolin), carbohydrate-binding 10 domains, and the like and combinations thereof. Kits and Instructions Provided are kits comprising compositions (including the devices as described herein) and/or instructions for practicing methods as provided herein to for example, treat, ameliorate or prevent a neuropathic pain. In alternative embodiments, provided are kits 15 comprising: a composition used to practice a method as provided herein, or a composition, a pharmaceutical composition or a formulation as provided herein, and in some embodiments comprising instructions for use thereof. The invention will be further described with reference to the examples described herein; however, it is to be understood that the invention is not limited to such examples. 20 EXAMPLES Figure 1 postulates a model for exposure of the TLR4 binding site of AIBP in a modified AIBP sequence: Figure 1. Model of unfolding or exposing a cryptic N-terminal domain in the AIBP molecule. The diagram summarizes and illustrates results of experiments shown in Figs.2-4, which demonstrate that in native AIBP the N-terminal 25 domain is hidden or cryptic or not sufficiently exposed to mediate AIBP binding to TLR4 (top panel). Extending the N-terminus with additional amino acids changes the AIBP conformation and makes the N-terminal domain of AIBP accessible for TLR4 binding (bottom panel). The amino acid sequence of an extended AIBP molecule depicted in the bottom panel of Fig.1. Figure 2. One example of the amino acid sequence of an 30 exemplary engineered AIBP as provided herein, wherein amino acids 25-288 are from the native AIBP sequence also referred to as YjeF_N; the TLR4-binding sequence is amino Docket No. EPN-AC-RAFT.003PC PATENT acids 25-51 of the human AIBP sequence; with a sequence of 40 amino acids added to the N-terminus replacing amino acids 1-24 of the AIBP sequence. Figure 3 demonstrates TLR4 binding of certain modified AIBP sequences derived from a baculovirus expression system: 5 Figure 3. TLR4 binding of various engineered forms of AIBP. All proteins were expressed and purified from a baculovirus/insect cell system. The top drawing for His- d24AIBP corresponds to the amino acid sequence shown in Fig.2. The amino acid sequence below the top drawing shows the sequence of the “cleavable His tag,” (SEQ ID NO: 2) All other drawings show different modifications and corresponding changes in the 10 amino acid sequence introduced to the AIBP molecule. The “N-terminal domain” box depicts the amino acid 25-51 sequence of native AIBP. The column on the right shows the results of co-immunoprecipitation experiments of the AIBP variants with a recombinant ectodomain of TLR4. Figure 4 demonstrates TLR4 binding of certain modified AIBP sequences from a 15 mammalian expression system: TLR4 binding of various engineered forms of AIBP. All proteins were co- expressed with the full-length TLR4 in a mammalian system. SS, secretion signal, corresponding to the amino acids 1-24 in the human AIBP sequence. The column on the right shows the results of co-immunoprecipitation from cell lysates of the AIBP variants 20 with TLR4. Figure 5. TLR4 binding of various engineered forms of AIBP. All proteins were expressed and purified from an E.coli. The column on the right shows the results of co- immunoprecipitation experiments of the AIBP variants with a recombinant ectodomain of TLR4, there was no TLR4 binding using the AIBP variants d24 AIBP-his or d51 AIBP- 25 his consistent with results described in Figures 1-4. Example 1. Structural determinants of AIBP binding to TLR4 This Example summarizes results of pull-down experiments to test binding of different AIBP variants expressed in insect, mammalian or bacterial systems to the ectodomain of TLR4. Results for this example are unexpected in that the depictions for 30 activity in Figures 3 and 4 demonstrate that not all N-terminal modifications expose the TLR4 binding domain. By example, the putative cleavage products of N-terminal His- tags containing a cleavage site do not demonstrate TLR4 binding. These unexpected data Docket No. EPN-AC-RAFT.003PC PATENT suggest that N-terminal modifications to AIBP polypeptides have specific amino acid composition requirements. A pulldown assay was performed using compounds as provided herein. Compounds 3, 7, 8 or 9 and other constructs described in Figures 3 and 4 were purified 5 from either a baculovirus (BD Bioscience) or CHO (ExpiCHO, Expression Systems, ThermoFisher) cell expression system and incubated with TLR4 protein (Sino biological). In addition to these compounds the following sequences were expressed: His-d51AIBP (Figure 3): MSPIDPMGHHHHHHGRRRASVAAGILVPRGSPGLDGICSRMASTVVKYLS 10 QEEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVIC GPGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEM PAEPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVE KGNAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDT ECVYRLQ (SEQ ID NO:35), 15 Cleaved His-d24 AIBP (Figure 3): GSPGLDGICSRQTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQ EEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGP GNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPA EPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKG 20 NAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTEC VYRLQ (SEQ ID NO:36), d24 AIB-His (Figure 3): QTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQEL FNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLVC 25 ARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYEL VVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLIS LTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQLVPRGS HHHHH (SEQ ID NO:37), Cleaved 5xD His-d24 AIBP (Figure 3): 30 GSDGDDGDDDRQTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYLS QEEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICG PGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMP AEPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEK Docket No. EPN-AC-RAFT.003PC PATENT GNAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTE CVYRLQ (SEQ ID NO:38), Cleaved 2xD His-d24 AIBP (Figure 3): GSDGDDGICSRQTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQ 5 EEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGP GNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPA EPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKG NAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTEC VYRLQ (SEQ ID NO:39), 10 Cleaved His-d24 AIBP (C29A: Figure 3): GSPGLDGICSRQTIAARSGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQ EEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGP GNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPA EPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKG 15 NAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTEC VYRLQ (SEQ ID NO:40), Cleaved His-d24 AIBP (R30A: Figure 3): GSPGLDGICSRQTIACASGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQ EEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGP 20 GNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPA EPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKG NAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTEC VYRLQ (SEQ ID NO:41), Cleaved His-d24 AIBP (C29R30A: Figure 3): 25 GSPGLDGICSRQTIAAASGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQ EEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGP GNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPA EPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKG NAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTEC 30 VYRLQ (SEQ ID NO:42), Flag-d24, d115-123 AIBP (Figure 4): MDYKDHDGDYKDHDIDYKDDDDKLAAANSQTIACRSGPTWWGPQRLNS GGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLMELAGLSCATAIA Docket No. EPN-AC-RAFT.003PC PATENT KAYPPTSMSRSPPTVLVIGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQK MDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASI DIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQ LNLPPYPDTECVYRLQ (SEQ ID NO:43), 5 Flag-d51 AIBP (Figure 4): MDYKDHDGDYKDHDIDYKDDDDKLAAANSMASTVVKYLSQEEAQAVD QELFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDG LVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDEL YELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPD 10 LLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO:44), and Flag-full length ACR (28-30aa: Figure 4): MDYKDHDGDYKDHDIDYKDDDDKLAAANSMSRLRALLGLGLLVAGSR VPRIKSQTISGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQELFNE 15 YQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLVCAR HLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYELVV DAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLT APKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO:45). 20 Pull-down was performed with anti-AIBP antibody described. Bound TLR4 to AIBP was detected by western blot with an anti-his antibody (both modified AIBP and TLR4 have his-tag). Detailed experimental information is provided in example 1 as to pull down method. An alternate assay used transfection of modified AIBP and TLR4 into HEK293 25 cells. For this study, transfected Flag-AIBP (exemplified for compounds 5 and 6) and Flag-TLR4-his constructs were expressed, transfected cells harvested, and lysed. Cell lysates were co-immunoprecipitated with anti-TLR4 antibody then immunoblotted with an anti-flag antibody. Example 2. Co-immunoprecipitation assays for TLR4 binding. 30 Pull down assay of eTLR4 and wt-AIBP or mut-AIBP in test tube was performed by mixing 1µg of eTLR4 (Sino Biological) and the AIBP in PBS containing 0.5% Triton X-100 and incubating for 1 hour at room temperature. Samples were precleared by adding Protein A/G Sepharose beads at room temperature for 30min, followed by addition of 1µg Docket No. EPN-AC-RAFT.003PC PATENT of BE-1 monoclonal anti-AIBP antibody and incubation for 2 hours. Protein A/G Sepharose beads were added and incubated for an additional one hour, followed by 5 washes with PBS containing 0.5% Triton X-100 and immunoblot of samples. HEK293 cells (RRID:CVCL_0045) were transfected with Flag-eTLR4 and a 5 Flag-AIBP (wild type or one of the mutants) construct. Thirty-six hours after transfection, cells were harvested and lysed with an ice-cold lysis buffer (50mM Tris-HCl, pH7.5, 1% NP-40, 150mM NaCl, 1mM EDTA, 1mM EGTA, 5mM Na3VO4, 1mM NaF, and a protease inhibitor cocktail from Sigma). Cell lysates were preincubated with protein A/G Sepharose beads for 30 min at 4℃ and immunoprecipitated with a mouse anti-TLR4 10 antibody (Abcam) overnight at 4℃. Next day, the lysates were incubated with protein A/G beads for 1 hour at 4℃. Unbound proteins were removed by washing with lysis buffer, and the beads were run on a Bolt Bis-Tris gel (Invitrogen); the bound AIBP was detected by immunoblotting with an anti-Flag antibody (Sigma). Example 3: Production of Compound 7. 15 In brief, Compound 7 was expressed in a baculovirus/insect cell system to ensure posttranslational modification and endotoxin-free preparation and purified by affinity chromatography using a Ni-NTA agarose column, followed by ion exchange chromatography and buffer replacement. The product was greater than 90% pure, with no detectable aggregates (HPLC-SEC) and residual endotoxin less than 0.2 EU/mg. Storage- 20 stability study of Compound 7 for up to 6 months at -80°C or for 1 week at 4°C did not show any loss of its titer or purity. Example 4: Efficacy of Compound 7 in a model of surgical (or post-operative) pain in rats. Rats were anesthetized by inhalation of 3% isoflurane and the skin of one hind 25 paw cleaned and prepped with betadine and isopropyl alcohol. A surgical incision was made on the plantar surface and the subcutaneous tissue bluntly dissected. The skin was sutured to using 4-0 vicryl and the animal allowed to recover on a warming pad. In those animals where drugs were administered by intrathecal (IT) injection, the animals received a percutaneous injection in the L2-3 intervertebral space while under isoflurane 30 anesthesia either 30 minutes prior to or following the surgical incision. Intravebous (IV) administration was made by injection into the tail vein. Animals received a standardized battery of behavioral tests to monitor behavioral alterations after surgical treatment. Docket No. EPN-AC-RAFT.003PC PATENT Behavioral tests were conducted in a quiet room at 22^oC. To test mechanical sensitivity, rats were placed on a wire mesh, loosely restrained in a cage (12 x 20 x 15 cm) open from below and allowed to accommodate for at least 10 min. A series of von Frey monofilaments ( 0.4 – 15.0g) were applied in ascending order. Each filament was 5 applied to the mid-plantar side of each hind paw from beneath for 1 second and repeated five times at an interval of 2 seconds. This causes no apparent stress. Example 5: Efficacy of Compound 7 in a pre-clinical model of photophobia. All behavioral tests were conducted at fixed times (9:00 a.m.–5:00 p.m.). Light aversive behavior was performed using a light and dark box. This test system is 10 composed of two equally sized compartments A and B (each measuring 90 x 90 x 165 cm), animals can move freely from one to the other through a small portal. One of the chambers was illuminated with light (7000 lux) and the other chamber painted dark. During the testing period, the box is covered with an opaque lid. The animals were acclimatized for 20 min in the chamber one day before testing. On the day of testing, 15 baseline values were obtained prior to the injection with saline, intraperitoneal 48/80 or compound 7 (IV). Each testing period lasted for 15 min. Following the administration of saline or compound 48/80, animals were tested at 15 min, 1 h, 2 h, and 4 h. Time spent in each chamber was measured by the animal’s obscuration of the light path of three red LED lights mounted close to the floor in each chamber. Time in each chamber was 20 collected automatically and placed in spread sheets.2 Molecular Pain Percentage of time spent in the light chamber was then calculated and plotted on a graph. In this example, compound 7 increased the time spent in the light box for male and female mice treated with compound 48/80, compared to 48/80 alone (Figure 8). Administration of a heat inactivated (hi) compound 7 did not differ from control. 25 Example 6: Efficacy of Compound 7 in a pre-clinical model of stress-induced migraine pain. Animals were subjected to restraint stress 24 hours after baseline. Sensory threshold values were determined with von Frey filaments. Animals were placed in cylindrical tail access rodent restrainers designed for animals 15 to 30 g (Stoelting 30 51338). Animals were placed in these restraint devices so that their tail was threaded through the moveable disk and their faces project out of the hole in the acrylic front face of the tube. Animals were introduced to the tube by placing the restrainer in front of the animals on the first day of stress and guiding them into the restrainer with the animal Docket No. EPN-AC-RAFT.003PC PATENT facing the acrylic front. Once the animal was in position, the tail was threaded through the moveable disk, and the disk was moved toward the animal and tightened to ensure that the animal was incapable of movement. Care was taken to avoid any trauma to the mice due to injuries from moving the disk or from threading the tail. Mice were also restrained 5 at a level that still allowed normal respiration. Animals were placed in the restraint tube so that the moveable disk faced upward and an opening on the tube was on the bottom. The animals were restrained for 2 hours a day for 3 consecutive days unless otherwise noted. Restraint stress started no earlier than 9:30 AM and stress ended before 12:00 PM in all cases to account for natural rising in corticosterone levels that have been shown 10 occur in rodents in the afternoon starting at 1:00 PM. Sham animals were left in their home cages without access to water or food to ensure that water/food deprivation alone did not contribute to the stress responses. Sham animals were kept in a separate room from stressed animals for the duration of stress. Once animals were in restraint devices, checks were made every 15 to 20 minutes to ensure that animals had not altered their 15 position; if an animal altered their position, they were readjusted by the experimenter by loosening the movable disk without completely removing the animal from the restrainer. Animal weight was taken into consideration to ensure that all animals were restrained equivalently. Animals above 34 g were not used for stress due to the maximum weight of the restrainer and animals that weighed under 22 g had a custom 3D printed 1 mm thick 20 plastic insert fit into the restrainer. Animals weighing 18 g or less were not used for restraint stress because in pilot studies, animals at this weight were capable of exiting through the hole in the acrylic front of the restrainer. Animals subjected to stress were not cohoused with sham animals to avoid the transfer of a stressed phenotype between mice. Mice were handled for a single 5-minute session at 24 hours before habituation to 25 the behavior chambers. During each session of habituation, animals were placed in 4 oz paper cups (Choice) for 2 hours a day for 3 consecutive days as previously described. Habituation was done in the rooms where all further behavioral testing occurred to acclimate animals to the room and light conditions. von Frey testing of the periorbital skin was used to assess baseline values after habituation before stress as well as 30 mechanical hypersensitivity that resulted from restraint stress and drug treatments. von Frey thresholds were not measured on the days that animals were subjected to restraint stress. Testing began 24 hours after the third day of restraint unless otherwise noted. Before stress, mice were subjected to baseline tests of cutaneous facial sensitivity for Docket No. EPN-AC-RAFT.003PC PATENT approximately 3 to 4 days. Baselined animals were defined as animals that exhibited a withdrawal threshold approximately 0.5 to 0.6 g. Filaments greater than 0.6 g were not used. Mice with a baseline threshold lower than 0.5 g at the end of 4 days were excluded from experiments. Mechanical thresholds were determined by applying von Frey 5 filaments to the periorbital region of the face (the midline of the forehead at the level of the eyes) in an ascending/ descending manner starting from the 0.07 g filament. Briefly, if an animal did not respond, increasing filament forces were applied until the 0.6 g filament was reached or until a response was observed. If the animal responded to a specific filament, decreasing filament forces were applied until the 0.008 g filament was reached 10 or until there were no responses. A response was defined as a mouse actually removing/swiping the filament away from its face during application. All animals were numbered and randomly allocated to experimental groups by drawing from prelabeled paper slips. All data here are shown as mean ± SEM. These data were analyzed among groups 15 for each time point using two-way repeated-measures (RM) analysis of variance (ANOVA) and then followed by Bonferroni post hoc analysis. All graphs were analyzed in 2 phases: 1. A two-way RM ANOVA was conducted on the initial acute phase starting from baseline to the return to baseline after stress.2. Another two-way RM ANOVA was conducted only on the time points during the priming phase. Data were analyzed using 20 Prism 8.0 (GraphPad Software). Significance was set at P , 0.05 for all analyses. In this example, periorbital tactile hypersensitivity was measured after restraint- induced stress and following intraperitoneal administration of priming agent sodium nitroprusside (SNP: 0.1mg/Kg dissolved in PBS). Effects of compound 7 were assessed after IV administration of 50 µg/mouse to female animals. Compound 7 afforded a 25 statistically significant increase in tactile thresholds in female mice in both the restrained and primed phases of this model indicating effective reduction of migraine pain. A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of 30 the claims recited herein. Docket No. EPN-AC-RAFT.003PC PATENT CITATIONS 1. Brattwall M, Warrén Stomberg M, Rawal N, Segerdahl M, Jakobsson J, Houltz E. Patients' assessment of 4-week recovery after ambulatory surgery. Acta Anaesthesiol Scand.2011; 55:92-98. 5 2. Tran TT, Kaneva P, Mayo NE, Fried GM, Feldman LS. Short-stay surgery: what really happens after discharge? Surgery.2014; 156:20-27. 3. Krakowski JC, Hallman MJ, Smeltz AM. Persistent Pain After Cardiac Surgery: Prevention and Management. Semin Cardiothorac Vasc Anesth. 2021:10892532211041320. 10 4. Stovner L, Hagen K, Jensen R, Katsarava Z, Lipton R, Scher A, Steiner T, Zwart J-A. The Global Burden of Headache: A Documentation of Headache Prevalence and Disability Worldwide. Cephalalgia.2007;27:193-210 5. Vetvik KG, MacGregor EA. Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. Lancet Neurol.2017;16:76-87. 15 6. Miller, Y.I., Navia-Pelaez, J.M., Corr, M., and Yaksh, T.L. (2020). Lipid rafts in glial cells: role in neuroinflammation and pain processing. J Lipid Res 61, 655-666. 7. Karasinska JM, de Haan W, Franciosi S, Ruddle P, Fan J, Kruit JK, Stukas S, Lütjohann D, Gutmann DH, Wellington CL, Hayden MR. (2013). ABCA1 influences neuroinflammation and neuronal death. Neurobiol Dis.54: 445-55. 20 8. Tall AR, Yvan-Charvet L. (2015). Cholesterol, inflammation and innate immunity. Nat Rev Immunol.15(2):104-16. 9. Yvan-Charvet, L., Welch, C., Pagler, T.A., Ranalletta, M., Lamkanfi, M., Han, S., Ishibashi, M., Li, R., Wang, N., and Tall, A.R. (2008). Increased inflammatory gene expression in ABC transporter-deficient macrophages: free cholesterol accumulation, 25 increased signaling via toll-like receptors, and neutrophil infiltration of atherosclerotic lesions. Circulation 118, 1837-1847. 10. Hidalgo-Aragones MI, Purohit A, Parish D, Sahm UG, Pouton CW, Potter BV, Reed MJ. (1996). Pharmacokinetics of oestrone-3-O-sulphamate. J Steroid Biochem Mol Biol. 58(5-6):611-7. 30 11. Groning R, Braun FJ. (1996). Three-dimensional solubility parameters and their use in characterising the permeation of drugs through the skin. Pharmazie.51(5):337-41. Docket No. EPN-AC-RAFT.003PC PATENT 12. Fotherby K. (1996). Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy. Contraception 54:59-69. 13. Johnson ME, Blankschtein Langer DR. (1995). Permeation of steroids through human skin. J. Pharm. Sci.84:1144-1146. 5 14. Rohatagi S, Hochhaus G, Möllmann H, Barth J, Derendorf H. (1995). Pharmacokinetic interaction between endogenous cortisol and exogenous corticosteroids. Pharmazie 50:610-613. 15. Brophy TR, McCafferty J, Tyrer JH, Eadie MJ. (1983). Bioavailability of oral dexamethasone during high dose steroid therapy in neurological patients. Eur. J. Clin. 10 Pharmacol.24:103-108.

Claims

Docket No. EPN-AC-RAFT.003PC PATENT WHAT IS CLAIMED IS: 1. A method of treating a pain-associated disease or condition comprising parenteral administration of a pharmaceutically acceptable formulation to a subject in 5 need thereof, wherein the pharmaceutically acceptable formulation is comprised of at least one pharmaceutically acceptable excipient and (i) a recombinant or synthetic ApoA-I Binding Protein (AIBP) polypeptide, comprised of an amino acid sequence of a wild-type AIPB polypeptide and an amino acid sequence of at least 8-40 amino acid residues N-terminal to the amino acid sequence of 10 the wild-type AIBP polypeptide (a AIBP variant), or (ii) a recombinant or synthetic ApoA-I Binding Protein (AIBP) polypeptide, comprised of an amino acid sequence of a wild-type AIPB polypeptide lacking amino acids 1-24 (d24 AIBP) and an amino acid sequence of at least 8-40 amino acid residues N-terminal to the amino acid sequence of the wild-type AIBP polypeptide lacking amino 15 acids 1-24 (d24 AIBP variant), wherein the recombinant or synthetic AIBP polypeptide comprises the Toll-like Receptor 4 (TLR4) binding cryptic domain of the wild-type AIBP polypeptide, wherein the TLR4 binding cryptic domain is comprised of or is homologous to amino acids 25-51 of the amino acid sequence of human wild-type AIBP polypeptide, 20 wherein the N-terminal amino acid sequence of the recombinant or synthetic AIBP polypeptide is comprised of at least 3 basic amino acid residues independently selected from the group consisting of His, Arg and Lys; and provided that the recombinant or synthetic AIBP polypeptide is capable of binding to a TLR4 polypeptide in vivo to inhibit TLR4 signaling as determined by a suitable in 25 vitro assay . 2. The method of claim 1, wherein the pain-associated disease or condition is mediated at least in part by human Toll-like Receptor 4 (hTLR4). 30 3. The method of claim 1 or 2, wherein the pain-associated disease or condition is selected from the group consisting of: - neuropathic pain, - inflammation-induced neuropathic pain, Docket No. EPN-AC-RAFT.003PC PATENT - nerve or CNS inflammation, - allodynia, - a post nerve or tissue injury pain or neuropathic pain, - post-surgical pain or neuropathic pain, 5 - a primary headache, and - hyperalgesia, 4. The method of claim 3, wherein the post nerve or tissue injury pain or neuropathic pain is generated or caused by, or is a sequela to, trauma, or surgery and 10 wherein the primary headache is migraine or a cluster headache. 5. The method of any one of claims 1-4, wherein the recombinant or synthetic AIBP polypeptide is an AIBP variant, in particular a human AIBP variant. 15 6. The method of any one of claims 1-4, wherein the recombinant or synthetic AIBP polypeptide is a d24 AIBP variant, in particular, a human d24 AIBP variant. 7. The method of any one of claims 1-4, wherein the at least 3 basic amino 20 acid residues form a His tag of six histidine (SEQ ID NO:1) residues. 8. The method of any one of claims 1-6, wherein the N-terminal amino acid sequence of the synthetic or recombinant AIBP polypeptide is comprised of an amino acid sequence of a secretion signaling polypeptide having an enzymatically cleavable site 25 that upon enzymatically cleavage upon under physiological conditions results in at least partial loss of the amino acid sequence of the secretion signaling polypeptide, with the proviso that the at least partial loss of the amino acid sequence of the secretion signaling polypeptide does not result in loss of any of the at least 3 basic amino acid residues; and 30 wherein the N-terminal amino acid sequence subsequent to said enzymatic cleavage is capable under physiological conditions of inducing unfolding or exposing or making accessible said TLR4 cryptic domain so that this cryptic domain is capable of binding to a TLR4 polypeptide in a suitable in vitro assay to inhibit TLR4 signaling. Docket No. EPN-AC-RAFT.003PC PATENT 9. The method of any one of claims 1-7, wherein the N-terminal amino acid sequence of the synthetic or recombinant AIBP polypeptide is comprised of an amino acid sequence of a secretion signaling polypeptide having a mutated enzymatically 5 cleavable site that is inoperable by being substantially or essentially resistant to enzymatic cleavage under physiological conditions. 10. The method of claim 8 wherein the enzyme cleavage site comprises a thrombin cleavage site. 10 11. The method of claim 8, wherein said enzymatically cleavable site has the amino acid sequence of: LVPRGS (SEQ ID NO:34). 15 12. The method of claim 9, wherein said mutated enzymatically cleavable site has the amino acid sequence of: LVAAGS (SEQ ID NO:46). 13. The method of any one of claims 8-12, wherein the amino acid sequence 20 of the secretion signaling polypeptide is comprised of one or more of the at least 3 basic amino acid residues. 14. The method of any one of claims 8-13, wherein the amino acid sequence of the secretion signaling polypeptide is selected from the group consisting of a 25 fibronectin secretion or an immunoglobulin heavy chain secretion signaling polypeptide, or an immunoglobulin kappa light chain secretory peptide, an interleukin-2 secretion signaling polypeptide and mutated variants thereof having a cleavable site that is inoperable by being substantially or essentially resistant to enzymatic cleavage under physiological conditions. 30 15. The method of claim 8, wherein the amino acid sequence of the secretion signaling polypeptide is a fibronectin secretion signaling polypeptide comprised of SEQ ID NO.:34. Docket No. EPN-AC-RAFT.003PC PATENT 16. The method of any one of claims 8, wherein the amino acid sequence of the secretion signaling polypeptide is a mutated fibronectin secretion signaling polypeptide comprised of SEQ ID No:46. 5 17. The method of claim 8, wherein the amino acid sequence of the fibronectin secretion signaling polypeptide is: MLRGPGPGRLLLLAVLCLGTSVRCTETGKSKR (SEQ ID NO.: 11). 10 18. The method of any one of claims 1-7, wherein the synthetic or recombinant AIBP polypeptide is comprised of the N-terminal amino acid sequence of: MSPIDPMGHHHHHHGRRRASVAAGILVPRGSPGLDGICSR (SEQ ID NO:2). 19. The method of any one of claims 1-6, wherein the synthetic or 15 recombinant AIBP polypeptide is comprised of the N-terminal amino acid sequence of: TETGKSKR (SEQ ID NO:13). 20. The method of any one of claims 1-6, wherein the synthetic or recombinant AIBP polypeptide is comprised of the N-terminal amino acid sequence of: 20 MDYKDHDGDYKDHDIDYKDDDDKLAAANS (SEQ ID NO:19) 21. The method of any one of claims 1-7, wherein the synthetic or recombinant AIBP polypeptide is comprised of the N-terminal amino acid sequence of: MSPIDPMGHHHHHHGRRRASVAAGILVPRGSDGDDGICSR (SEQ ID 25 NO:30). 22. The method of any one of claims 1-7, wherein the synthetic or recombinant AIBP polypeptide is comprised of the N-terminal amino acid sequence of: MSPIDPMGHHHHHHGRRRASVAAGILVPAASPGLDGICSR (SEQ ID 30 NO.:32). Docket No. EPN-AC-RAFT.003PC PATENT 23. The method of claim 1, wherein the synthetic or recombinant AIBP polypeptide is an AIBP variant having the N-terminal amino acid sequence of SEQ ID NO:2, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:19, SEQ ID NO:30, SEQ ID NO:32. 5 24. The method of claim 1, wherein the synthetic or recombinant AIBP polypeptide is a d24 AIBP variant having the N-terminal amino acid sequence of SEQ ID NO:2, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:19, SEQ ID NO:30, or SEQ ID NO:32. 10 25. The method of claim 23, wherein the synthetic or recombinant AIBP polypeptide is further comprised of the wild-type AIBP amino acid sequence of: MSRLRALLGLGLLVAGSRVPRIKSQTIACRSGPTWWGPQRLNSGGRWD SEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPPT SMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQ 15 CQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPI ASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALEKK YQLNLPPYPDTECVYRLQ (SEQ ID NO.: 6). 26. The method of claim 24, wherein the synthetic or recombinant AIBP 20 polypeptide is further comprised of the d24 AIBP amino acid sequence of: QTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQEL FNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLVC ARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYEL VVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLIS 25 LTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO.:8). 27. The method of any one of claims 1-4, wherein the synthetic or recombinant AIBP polypeptide has the amino acid sequence of: 30 MLRGPGPGRLLLLAVLCLGTSVRCTETGKSKRQTIACRSGPTWWGPQRLN SGGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLMELAGLSCATAI AKAYPPTSMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPL FTALVTQCQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDVREPFHSILSV Docket No. EPN-AC-RAFT.003PC PATENT LKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRF VPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO.:10). 28. The method of claim 8, wherein the synthetic or recombinant AIBP 5 polypeptide has the amino acid sequence of: TETGKSKRQTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQEEA QAVDQELFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNN GGDGLVCARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMT IDELYELVVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGG 10 IQPDLLISLTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO.: 12). 29. The method of any one of claims 1-4, wherein the synthetic or recombinant AIBP polypeptide has the amino acid sequence of: 15 MDYKDHDGDYKDHDIDYKDDDDKLAAANSMSRLRALLGLGLLVAGSR VPRIKSQTIACRSGPTWWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQE LFNEYQFSVDQLMELAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLV CARHLKLFGYEPTIYYPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYEL VVDAIFGFSFKGDVREPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLIS 20 LTAPKKSATQFTGRYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO:18). 30. The method of any one of claims 1-4, wherein the synthetic or recombinant AIBP polypeptide has the amino acid sequence of: 25 MDYKDHDGDYKDHDIDYKDDDDKLAAANSQTIACRSGPTWWGPQRLNS GGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLMELAGLSCATAIA KAYPPTSMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIYYPKRPNKPLFT ALVTQCQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDVREPFHSILSVLK GLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTGRYHYLGGRFVP 30 PALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO:21). 31. The method of any one of claims 1-4, wherein the synthetic or recombinant AIBP polypeptide has the amino acid sequence of: Docket No. EPN-AC-RAFT.003PC PATENT MSPIDPMGHHHHHHGRRRASVAAGILVPRGSPGLDGICSRQTIACRSGPT WWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLMEL AGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIY YPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDV 5 REPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTG RYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO.:24). 32. The method of any one of claims 1-4, wherein the synthetic or recombinant AIBP polypeptide has the amino acid sequence of: 10 MSPIDPMGHHHHHHGRRRASVAAGILVPRGSDGDDGDDDRQTIACRSGP TWWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLME LAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIY YPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDV REPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTG 15 RYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO:26). 33. The method of any one of claims 1-4, wherein the synthetic or recombinant AIBP polypeptide has the amino acid sequence of: MSPIDPMGHHHHHHGRRRASVAAGILVPRGSDGDDGICSR QTIACRSGP 20 TWWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLME LAGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIY YPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDV REPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTG RYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO:29). 25 34. The method of any one of claims 1-4, wherein the synthetic or recombinant AIBP polypeptide has the amino acid sequence of: MSPIDPMGHHHHHHGRRRASVAAGILVPAASPGLDGICSRQTIACRSGPT WWGPQRLNSGGRWDSEVMASTVVKYLSQEEAQAVDQELFNEYQFSVDQLMEL 30 AGLSCATAIAKAYPPTSMSRSPPTVLVICGPGNNGGDGLVCARHLKLFGYEPTIY YPKRPNKPLFTALVTQCQKMDIPFLGEMPAEPMTIDELYELVVDAIFGFSFKGDV REPFHSILSVLKGLTVPIASIDIPSGWDVEKGNAGGIQPDLLISLTAPKKSATQFTG RYHYLGGRFVPPALEKKYQLNLPPYPDTECVYRLQ (SEQ ID NO:32). Docket No. EPN-AC-RAFT.003PC PATENT 35. The method of any one of claims 1-34, wherein parenteral administration is by intravenous administration. 5 36. The method of any one of claims 1-34, wherein parenteral administration is by subcutaneous administration. 37. The method of any one of claims 1-4, wherein administration is by intravenous administration and the synthetic or recombinant AIBP polypeptide is a 10 human d24 AIBP variant. 38. The method of any one of claims 1-4, wherein administration is by intravenous administration and the synthetic or recombinant AIBP polypeptide has the amino acid sequence of SEQ ID NO.:24 (Compound 7). 15 39. The method of any one of claims 1-38, wherein the subject is a human. 40. The method of any one of claims 1-39, wherein the pharmaceutically acceptable formulation has the recombinant or synthetic ApoA-I Binding Protein attached 20 non-covalently to or contained within a carrier, in particular, a nanoparticle liposome or lipoplex, a polymersome, a polyplex or a dendrimer. 41. The method of claim 40, wherein the carrier further comprises a cell or CNS penetrating moiety or peptide or a CNS targeting moiety or peptide. 25 42. A kit comprising a pharmaceutically acceptable formulation of any one of claims 1-41 and instructions on administering said pharmaceutically acceptable formulation to a subject in need thereof for treating a pain-associated disease or condition, in particular a pain-associated disease or condition is mediated by human Toll-like 30 Receptor 4 (hTLR4), preferably post-surgical pain. 43. Use of a pharmaceutically acceptable formulation of any one of claims 1- 41 in the manufacture of a medicament for treating a pain-associated disease or condition, Docket No. EPN-AC-RAFT.003PC PATENT in particular, a pain-associated disease or condition is mediated by human Toll-like Receptor 4 (hTLR4), preferably post-surgical pain. 44. A pharmaceutically acceptable formulation for treating, ameliorating, 5 preventing, reversing or decreasing the severity or duration of, or decreasing the severity of symptoms of a disease or condition in a subject, of a pain-associated disease or condition, in particular, a pain-associated disease or condition is mediated by human Toll- like Receptor 4 (hTLR4), preferably a disease or condition is selected from the group consisting of: 10 - neuropathic pain, - inflammation-induced neuropathic pain, wherein optionally the inflammation-induced neuropathic pain comprises a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain, - nerve or CNS inflammation, 15 wherein optionally the nerve or CNS inflammation comprises a TLR4- mediated nerve or CNS inflammation, - allodynia, wherein optionally the allodynia comprises a TLR4-mediated allodynia, - a post nerve or tissue injury pain or neuropathic pain, 20 wherein optionally the post nerve or tissue injury pain or neuropathic pain is generated or caused by, or is a sequela to, trauma, - post-surgical pain or neuropathic pain, - a primary headache, optionally a migraine or a cluster headache, - hyperalgesia, 25 wherein the pharmaceutically acceptable formulation is intended for parenteral administration to the subject, and is comprised of at least one pharmaceutically acceptable and a recombinant or synthetic ApoA-I Binding Protein (AIBP) polypeptide capable of inhibiting TLR4 signaling. 30 45. The pharmaceutically acceptable formulation of claim 44, wherein the recombinant or synthetic ApoA-I Binding Protein (AIBP) polypeptide is comprised of: Docket No. EPN-AC-RAFT.003PC PATENT (i) an amino acid sequence of a wild-type AIPB polypeptide and an amino acid sequence of at least 8-40 amino acid residues N-terminal to the amino acid sequence of the wild-type AIBP polypeptide (a AIBP variant), or (ii) of an amino acid sequence of a wild-type AIPB polypeptide lacking amino 5 acids 1-24 (d24 AIBP) and an amino acid sequence of at least 8-40 amino acid residues N-terminal to the amino acid sequence of the wild-type AIBP polypeptide lacking amino acids 1-24 (d24 AIBP variant), wherein the recombinant or synthetic AIBP polypeptide comprises the Toll-like Receptor 4 (TLR4) binding cryptic domain of the wild-type AIBP polypeptide, wherein 10 the TLR4 binding cryptic domain is comprised of or is homologous to amino acids 25-51 of the amino acid sequence of human wild-type AIBP polypeptide, wherein the N-terminal amino acid sequence of the recombinant or synthetic AIBP polypeptide is comprised of at least 3 basic amino acid residues independently selected from the group consisting of His, Arg and Lys. 15