Alpha1-antitrypsin for use in the treatment of nervous system diseases or disorders such as chronic inflammatory demyelinating polyneuropathy

Abstract

The present invention relates to an alpha1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments and / or corresponding nucleotide sequences for use in the treatment of diseases or disorders of the nervous system such as chronic inflammatory demyelinating polyneuropathy. The present invention further relates to combinations with IgG antibodies such as immunoglobulin therapy for use in these diseases or disorders.

Description

【Technical Field】 【0001】 The present invention relates to alpha1 - antitrypsin (AAT) protein, its variants, isoforms and / or fragments and / or corresponding nucleotide sequences for use in the treatment of nervous system diseases or disorders such as chronic inflammatory demyelinating polyneuropathy. The present invention further relates to combinations with IgG antibodies such as immunoglobulin therapy for use in these diseases or disorders. 【0002】 Nervous system diseases or disorders are diseases or disorders that can dramatically affect the peripheral and / or central nervous system (PNS / CNS). In the past decade, neuroinflammation has become increasingly central to our understanding of neurological disorders. Inflammation itself can directly or indirectly induce diseases, but surely contributes to the etiology of diseases throughout the peripheral nervous system (PNS) and central nervous system (CNS). 【0003】 Peripheral neuritis constitutes a very diverse group of disorders mainly composed of damage to the myelin sheath after its abnormal development (hypomyelination) in the genetic types (CMT1A - F and - X) or direct in acquired types such as chronic inflammatory demyelinating polyneuropathy. 【0004】 Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease that specifically targets the myelin sheath in the peripheral nerves, causing progressive weakness and sensory loss. Swelling of the nerve roots is also characteristic of this disease. CIDP can occur at any age regardless of gender, but is more common in young adults and more common in men than in women. 【0005】 Untreated CIDP is characterized by the accumulation of disabilities that require physical and occupational therapy, corrective devices, and long-term treatment. Early intervention can prevent permanent damage and disability. Current treatment methods for CIDP include the administration of corticosteroids (e.g., prednisone), which can be prescribed alone or in combination with immunosuppressive drugs. Immunosuppressive drugs may also be given in the absence of steroids. 【0006】 Myelin is produced by Schwann cells (SCs) in the PNS and is important for the proper transmission of electrical impulses in nerves. In the complex neuron / glia cross-communication required for proper myelin regulation (Rao and Pearse 2016), several diverse signaling pathways are involved, including growth factors, integrins, and cell adhesion molecules, but more importantly, the extremely important neuregulin 1 type III (NRG1-III) that signals via the ERBB2 / 3 receptor and its proteolytic shedase modulator, tumor necrosis factor-α converting enzyme, TACE (also known as ADAM17). TACE / ADAM17 is a transmembrane protein containing an extracellular zinc-dependent protease domain. In the context of the PNS, ADAM17 is known for its inhibitory effect on SC-mediated myelination by cleaving NRG1-III in the epidermal growth factor domain in a ligand-independent manner (La Marca, R., 2011, Nat Neurosci 14(7):857-865.). Conflicting evidence has been reported in the literature regarding the role of human protease alpha-1-antitrypsin (AAT), specifically, in 2013, it was shown that AAT does not interact with TACE (van’t Wout E.F. et al., 2014, Hum Mol Genet.;23(4):929-4), which is in contrast to a previous report in 2010 that the claimed AAT actually interacts with TACE and inhibits its activity in a dose-dependent manner (Bergin, D.A. et al., 2010, J Clin Invest 120(12):4236-4250). 【0007】 A biologically common feature of many PNS and CNS neurodegenerative diseases is a persistent acute inflammatory response caused by cytokine release (also called "cytokine storm") organized in a feed-forward loop. Therefore, the suppression of the inflammatory response exists as a central target of treatment strategies. However, the intricacy of the inflammatory mechanism underlying its multiple mediators is not fully understood. 【0008】 Therefore, there is a need for improved therapies for diseases or disorders of the nervous system, particularly chronic inflammatory demyelinating polyneuropathy. 【0009】 The above technical problems are solved by the embodiments disclosed herein and defined in the claims. 【0010】 Therefore, the present invention relates, inter alia, to the following embodiments. 1. A pharmaceutical for use in the treatment of an inflammatory disease or disorder, a) alpha1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having ADAM17 inhibitory activity, or small molecules having ADAM17 inhibitory activity, and / or b) a nucleic acid encoding AAT, its variants, isoforms, and / or fragments having inhibitory activity A pharmaceutical for use, comprising. 2. The pharmaceutical for use according to embodiment 1, wherein the inflammatory disease or disorder is an autoimmune inflammatory disease. 3. The pharmaceutical for use according to embodiment 1 or 2, wherein the inflammatory disease or disorder is an inflammatory disease or disorder of the nervous system, preferably the neuropathic pain caused by an inflammatory disease or disorder of the nervous system. 4. The pharmaceutical for use according to any one of embodiments 1 to 3, wherein the inflammatory disease is chronic inflammatory demyelinating polyneuropathy. 5. The pharmaceutical for use according to embodiment 1 or 2, wherein the inflammatory disease is complex regional pain syndrome. 6. A pharmaceutical for use according to any one of embodiments 1 to 3, wherein the inflammatory disease or disorder is inflammatory pain. 7. A kit for use in the treatment of a disease or disorder of the nervous system, comprising: i) a) Alpha1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof having inhibitory activity, or small molecules having ADAM17 inhibitory activity, and / or b) a nucleic acid encoding AAT, variants, isoforms, and / or fragments thereof having inhibitory activity; ii) a plurality of IgG antibodies, isoforms, fragments, and / or IgG variants thereof; and 10. A kit for use. 8. A pharmaceutical composition for use in the treatment of a disease or disorder of the nervous system, comprising: i) a) Alpha1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof having inhibitory activity, or small molecules having ADAM17 inhibitory activity, and / or b) a nucleic acid encoding AAT, variants, isoforms, and / or fragments thereof having inhibitory activity; ii) a plurality of IgG antibodies, IgG variants, isoforms and / or fragments thereof; iii) at least one pharmaceutically acceptable carrier; and 22. A pharmaceutical composition for use. 9. A method of treatment comprising administering to a subject an effective amount of a pharmaceutical composition, wherein the subject is suffering from a disease or disorder of the nervous system and has received a therapy comprising administration of a plurality of IgG antibodies, isoforms, fragments, and / or IgG variants thereof, and the pharmaceutical composition comprises: a) AAT protein, variants, isoforms and / or fragments thereof having inhibitory activity, or small molecules having ADAM17 inhibitory activity, and / or b) a nucleic acid encoding AAT, variants, isoforms, and / or fragments thereof having inhibitory activity. 30. A method of treatment. 10. A method of treatment comprising administering to a subject an effective amount of a pharmaceutical compound comprising a plurality of IgG antibodies, their isotypes, fragments thereof, and / or IgG variants, wherein the subject is suffering from a disease or disorder of the nervous system, and the subject is a) an AAT protein, its variants, isotypes and / or fragments having inhibitory activity, or a small molecule having ADAM17 inhibitory activity, and / or b) a nucleic acid encoding an AAT, its variants, isotypes, and / or fragments having inhibitory activity and is undergoing a therapy comprising administration of. 11. The kit for use according to embodiment 7, the pharmaceutical composition for use according to embodiment 8, the method of treatment according to embodiment 9 or 10, wherein the disease or disorder of the nervous system is pain caused by a disease or disorder of the nervous system, preferably chronic pain caused by a disease or disorder of the nervous system. 12. The kit for use according to embodiment 7 or 11, the pharmaceutical composition for use according to embodiment 8 or 11, the method of treatment according to embodiments 9 to 11, wherein the disease or disorder of the nervous system is an autoimmune disease or disorder of the nervous system. 13. The kit for use according to embodiment 12, the pharmaceutical composition for use according to embodiment 12, the method of treatment according to embodiment 12, wherein the nervous system disease or disorder is chronic inflammatory demyelinating polyneuropathy. 14. The pharmaceutical for use according to embodiment 4 or 6, the kit for use according to embodiment 13, the pharmaceutical composition for use according to embodiment 13, the method of treatment according to embodiment 13, wherein the subject to be treated has a history of at least one symptom of chronic inflammatory demyelinating polyneuropathy or at least one symptom of chronic inflammatory demyelinating polyneuropathy. 15. The kit for use according to any one of embodiments 7, 11 to 14, the pharmaceutical composition for use according to any one of embodiments 8, 11 to 14, the method of treatment according to any one of embodiments 9 to 14, wherein the plurality of IgG antibodies, their isotypes, fragments thereof, and / or IgG variants are plasma-derived IgG antibodies, their isotypes, fragments thereof, and / or IgG variants. 16. The use of a plurality of IgG antibodies, their isotypes, their fragments, and / or IgG variants, which are recombinant IgG antibodies, their isotypes, their fragments, and / or IgG variants, in the parts kit according to any one of embodiments 7, 11 to 14, the pharmaceutical composition for use according to any one of embodiments 8, 11 to 14, and the treatment method according to any one of embodiments 9 to 14. 17. The use of a plasma-derived IgG antibody, its isotype, its fragment, and / or IgG variant, which is formulated for intravenous administration, in the parts kit according to any one of embodiments 7, 11 to 16, the pharmaceutical composition for use according to any one of embodiments 8, 11 to 16, and the treatment method according to any one of embodiments 9 to 16. 18. The use of a plasma-derived IgG antibody, its isotype, its fragment, and / or IgG variant, which is formulated for subcutaneous administration, in the parts kit according to any one of embodiments 7, 11 to 16, the pharmaceutical composition for use according to any one of embodiments 8, 11 to 16, and the treatment method according to any one of embodiments 9 to 16. 19. The pharmaceutical product for use according to any one of embodiments 1 to 6, the parts kit for use according to any one of embodiments 7, 11 to 18, the pharmaceutical composition for use according to any one of embodiments 8, 11 to 18, and the treatment method according to any one of embodiments 9 to 18, wherein the AAT protein is recombinant AAT. 20. The pharmaceutical product for use according to any one of embodiments 1 to 6, the parts kit for use according to any one of embodiments 7, 11 to 18, the pharmaceutical composition for use according to any one of embodiments 8, 11 to 18, and the treatment method according to any one of embodiments 9 to 18, wherein the AAT protein is plasma-derived AAT. 21. a) An alpha1-antitrypsin (AAT) protein, its variant, isotype and / or fragment having inhibitory activity, or a small molecule having ADAM17 inhibitory activity, and / or b) A nucleic acid encoding AAT, its variants, isoforms, and / or fragments having inhibitory activity A pharmaceutical for use according to any one of embodiments 1 to 6, 19 or 20, a parts kit for use according to any one of embodiments 7, 11 to 20, a pharmaceutical composition for use according to any one of embodiments 8, 11 to 20, or a treatment method according to any one of embodiments 9 to 20, wherein is formulated for intravenous administration. 22. a) An alpha1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having inhibitory activity, or a small molecule having ADAM17 inhibitory activity, and / or b) A nucleic acid encoding AAT, its variants, isoforms, and / or fragments having inhibitory activity A pharmaceutical for use according to any one of embodiments 1 to 6, 19 or 20, a parts kit for use according to any one of embodiments 7, 11 to 20, a pharmaceutical composition for use according to any one of embodiments 8, 11 to 20, or a treatment method according to any one of embodiments 9 to 20, wherein is formulated for subcutaneous administration. 【0011】 Accordingly, in one embodiment, the present invention relates to a pharmaceutical for use in the treatment of an inflammatory disease or disorder, the pharmaceutical comprising: a) an alpha1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having inhibitory activity, or a small molecule having ADAM17 inhibitory activity, and / or b) a nucleic acid encoding AAT, its variants, isoforms, and / or fragments having inhibitory activity. 【0012】 As used herein, the term "inflammatory disease or disorder" refers to a disease, disorder or condition characterized by an increase in inflammation in a tissue, organ or system as compared to the corresponding tissue, organ or system of a healthy reference subject. Inflammation is characterized by dysregulation of inflammatory markers and / or an increase in infiltration, activation, proliferation, and / or differentiation of immune cells in blood and / or tissue. An inflammatory marker is a marker that indicates inflammation in a subject. In certain embodiments, the inflammatory markers described herein are markers selected from the group consisting of CRP, erythrocyte sedimentation rate (ESR), and procalcitonin (PCT), interleukins (e.g., IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-33, IL-32, IL-33, IL-35 or IL-36), tumor necrosis factors (e.g., TNF-alpha, TNF-beta), interferons (e.g., interferon gamma), MIP-I, MCP-I, RANTES, other chemokines and / or other cytokines. Inflammatory markers can also be detected indirectly, for example, by detection of inhibitors (e.g., binding factors and / or antagonists) of inflammatory markers. In some embodiments, inflammatory markers are measured in cells involved in inflammation, in cells affected by cells involved in inflammation, in cerebrospinal fluid, and / or in blood. In some embodiments, inflammatory markers indicate infiltration, activation, proliferation and / or differentiation of immune cells. Detection of an inflammatory marker or the ratio of two or more inflammatory markers is detected outside the normal range. The normal range of inflammatory markers and whether the marker (ratio) should be below or above a threshold to indicate inflammation are known to those of skill in the art. In some embodiments, the gene expression level, RNA transcript level, protein expression level, protein activity level and / or enzyme activity level of at least one inflammatory marker is detected.In some embodiments, at least one inflammatory marker is detected quantitatively and / or qualitatively to determine an inflammatory disease or disorder in a subject in need of treatment and / or prevention. 【0013】 In some embodiments, the inflammatory diseases or disorders described herein are characterized by acute inflammation, i.e., the duration of the inflammatory symptoms typically ranges from a few minutes (e.g., 2, 5, 10, 15, 30, 45 minutes) to several days (e.g., 2, 3, 5, 7, 10, or 14 days). In some embodiments, the inflammatory disease or disorder is characterized by chronic inflammation, i.e., the duration of the inflammatory symptoms typically takes at least about several days (e.g., 2, 3, 5, 7, 10, or 14 days) or the inflammatory symptoms recur at least once (e.g., one or more times, two or more times, or three or more times). In some embodiments, the inflammatory disease or disorder is characterized by chronic low-grade inflammation. Chronic low-grade inflammation can occur in the absence of clinical symptoms. In certain embodiments, the inflammatory disease described herein is an inflammatory disease characterized by Schwann cell (SC) phenotype or an increase in inflammation affecting health. In certain embodiments, the inflammatory disease described herein is an inflammatory disease characterized by an increase in inflammatory microglia and / or an increase in the microglial inflammatory phenotype. 【0014】 The inventor has found that AAT can inhibit TACE / ADAM17 in a dose-dependent manner, which, without being bound by theory, rescues myelin production by SC and thus prevents, delays, and / or reverses the progression of inflammatory diseases. Further, alpha 1-antitrypsin (AAT) protein and its variants attenuate the reactive oxygen species (ROS) response of SC when stimulated with the pro-inflammatory cytokine TNFα (TNF-α). This indicates that AAT and its derivatives exert a novel therapeutic effect by acting directly on Schwann cells (SC) and rescuing these cells back from their inflammatory state to their native wild-type state, for example, by rescuing the SC's ability to restore myelination around axons. Thus, this anti-inflammatory effect on SC in the PNS or microglia in the CNS is surprisingly effective in the treatment of inflammatory diseases involving these cells. 【0015】 Accordingly, the present invention is based at least in part on the anti-inflammatory effects of AAT and its variants, isoforms, and / or fragments. 【0016】 In certain embodiments, the present invention relates to a pharmaceutical for use in the present invention, wherein the inflammatory disease or disorder is an autoimmune inflammatory disease. 【0017】 As used herein, the term "autoimmune inflammatory disease" refers to a group of diseases or disorders in which tissue damage is associated with a humoral immune response and / or a cell-mediated immune response against a body constituent, or, in a broader sense, an immune response against oneself. The pathological immune response can be systemic or organ-specific. In certain embodiments, the autoimmune diseases described herein are diseases selected from the group consisting of multiple sclerosis, myasthenia gravis, pernicious anemia, arthritis, Sjogren's syndrome, systemic lupus erythematosus, complex regional pain syndrome, and type 1 diabetes. 【0018】 In certain embodiments, the present invention relates to a pharmaceutical for use of the present invention, wherein the inflammatory disease or disorder is an inflammatory disease or disorder of the nervous system. In certain embodiments, the present invention relates to a pharmaceutical for use of the present invention, wherein the inflammatory disease or disorder is neuropathic pain. 【0019】 In certain embodiments, the present invention relates to a kit, a pharmaceutical composition and a treatment method for use of the present invention, wherein the disease or disorder of the nervous system is neuropathic pain. 【0020】 In certain embodiments, the present invention relates to a pharmaceutical for use of the present invention, wherein the inflammatory disease or disorder is neuropathic pain caused by an inflammatory disease or disorder of the nervous system. 【0021】 As used herein, the term "inflammatory disease or disorder of the nervous system" refers to a disease, disorder or condition characterized by an increase in inflammation in the nervous system as compared to a healthy reference subject. 【0022】 In certain embodiments, the present invention relates to a pharmaceutical for use of the present invention, wherein the inflammatory disease or disorder, preferably an inflammatory disease or disorder of the nervous system, is selected from the group consisting of inflammatory pain, neuropathic pain, autoimmune inflammatory diseases, complex regional pain syndrome and chronic inflammatory demyelinating polyneuropathy. In certain embodiments, the present invention relates to a pharmaceutical for use of the present invention, wherein the inflammatory disease or disorder, preferably an inflammatory disease or disorder of the nervous system, is selected from the group consisting of autoimmune inflammatory diseases, complex regional pain syndrome and chronic inflammatory demyelinating polyneuropathy. In certain embodiments, the present invention relates to a pharmaceutical for use of the present invention, wherein the inflammatory disease or disorder, preferably an inflammatory disease or disorder of the nervous system, is selected from the group consisting of complex regional pain syndrome and chronic inflammatory demyelinating polyneuropathy. 【0023】 As used herein, the term "neuropathic pain" refers to pain caused by injury or disease that affects the somatosensory system, and preferably, the pain is caused by an inflammatory disease or disorder. As used herein, the term "neuropathic pain caused by an inflammatory disease or disorder of the nervous system" refers to pain induced by injury to the nerve, where the injury is caused by an inflammatory disease or disorder. In certain embodiments, the pain described herein is considered to be "caused by" a disease if the disease and pain are present and the disease is known to have pain as a symptom, and preferably, the disease is the most likely cause of the subject's pain. 【0024】 In certain embodiments, the invention relates to a pharmaceutical for use in the invention, wherein the inflammatory disease is complex regional pain syndrome. 【0025】 In certain embodiments, the invention relates to a kit of parts, pharmaceutical composition and treatment method for use in the invention, wherein the disease or disorder of the nervous system is complex regional pain syndrome. 【0026】 As used herein, the term "complex regional pain syndrome" refers to a syndrome characterized by excessive and long-term pain and inflammation following an injury, typically to an upper or lower limb. 【0027】 In certain embodiments, the invention relates to a pharmaceutical for use in the invention, wherein the inflammatory disease or disorder is inflammatory pain. 【0028】 In certain embodiments, the invention relates to a kit of parts, pharmaceutical composition and treatment method for use in the invention, wherein the disease or disorder of the nervous system is inflammatory pain. 【0029】 As used herein, the term "inflammatory pain" is pain that occurs in response to tissue damage and inflammation. Thus, inflammatory pain is pain that is neither nociceptive pain nor neuropathic pain. In certain embodiments, the inflammatory pain described herein is caused by an inflammatory disease. 【0030】 As used herein, the term "pain" refers to the term used in the art. In certain embodiments, the pain described herein is chronic pain that occurs for more than 2 weeks, more than 4 weeks, more than 6 weeks, more than 8 weeks, or more than 12 weeks. In certain embodiments, the pain described herein is breakthrough pain in a subject having chronic pain, or a subject undergoing pain reduction therapy (such as pharmacological pain treatment), or a subject having chronic pain undergoing pain reduction therapy. In certain embodiments, the pain described herein occurs without a history of injury or surgery. In certain embodiments, the pain described herein is self-reported pain. The numeric rating scale (NRS) is the most commonly used pain scale for evaluating pain on a scale of 0 to 10. In certain embodiments, the pain described herein is pain evaluated as greater than 1, greater than 2, greater than 3, greater than 4, greater than 5, greater than 6, greater than 7, greater than 8, or greater than 9 on the NRS. 【0031】 In certain embodiments, the invention relates to a pharmaceutical for use in the treatment of pain caused by a disease or disorder of the nervous system, comprising a) an alpha1-antitrypsin (AAT) protein, a variant, isoform and / or fragment thereof having inhibitory activity, or a small molecule having ADAM17 inhibitory activity, and / or b) a nucleic acid encoding AAT, a variant, isoform and / or fragment thereof having inhibitory activity. 【0032】 Oxidative stress has been well established to be associated with neuropathic pain. The inventors have found that oxidative stress is downregulated by AAT and its peptide derivatives, particularly in SCs that reduce pain. 【0033】 Accordingly, the present invention is based at least in part on the effects of AAT and its variants, isoforms and / or fragments against oxidative stress. 【0034】 In certain embodiments, the present invention relates to a pharmaceutical for use in the treatment of chronic inflammatory demyelinating polyneuropathy, comprising a) an alpha1-antitrypsin (AAT) protein, its variant, isoform and / or fragment having inhibitory activity, or a small molecule having ADAM17 inhibitory activity, and / or b) a nucleic acid encoding AAT, its variant, isoform and / or fragment having inhibitory activity. 【0035】 Thus, the pharmaceutical described herein may comprise an alpha1-antitrypsin (AAT) protein, a variant of AAT having ADAM17 inhibitory activity, an isoform of AAT having ADAM17 inhibitory activity, or a fragment of AAT having ADAM17 inhibitory activity, or any combination thereof. Additionally or alternatively, it may comprise a small molecule having ADAM17 inhibitory activity. 【0036】 The terms "peptide", "protein", "polypeptide", "polypeptidic" and "peptidic" are used interchangeably herein and refer to a series of amino acid residues linked to other amino acid residues by peptide bonds between the alpha-amino and carboxy groups of adjacent residues. 【0037】 As used herein, the term "alpha1 - antitrypsin protein" or "AAT" refers to a protease inhibitor belonging to the serpin superfamily. Preferably, AAT is mammalian AAT, more preferably human AAT. hAAT and human AAT are used interchangeably herein and refer to plasma - derived human AAT. In humans, AAT is encoded by the SERPINA1 gene. The term AAT includes natural variants, post - translationally modified AAT, and preferably isoforms of AAT produced by alternative splicing. Sequences of AAT from different species and origins can be found in protein and nucleic acid databases such as UniProt, Genbank, DDBJ, and EMBL. In a highly preferred embodiment, the term "AAT" includes variants as disclosed in protein and nucleic acid databases. In a highly preferred embodiment, the term "AAT" refers to a protein having the amino acid sequence defined by SEQ ID NO: 1, or a nucleotide sequence encoding a protein having the amino acid sequence defined by SEQ ID NO: 1. In some embodiments, the AAT described herein is a protein, peptide, or polypeptide. The AAT protein can be obtained by isolation from blood (e.g., human blood) or produced recombinantly. 【0038】 The term "variant" refers to a protein, peptide or polypeptide having an amino acid sequence that is somewhat different from the AAT native sequence peptide, preferably SEQ ID NO:1, which is an amino acid sequence different from the AAT native sequence, preferably SEQ ID NO:1, by amino acid substitution, whereby one or more amino acids are substituted by another amino acid having the same characteristics and conformational role. Preferably, the variants described herein are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acids of SEQ ID NO:1. Amino acid sequence variants may have substitutions, deletions and / or insertions at specific positions within the amino acid sequence of the native amino acid sequence (e.g., N-terminal or C-terminal sequences or within the amino acid sequence). The substitution may be conservative, in which case a conservative amino acid substitution is defined herein as an exchange within one of the following five groups. I. Small aliphatic, non-polar or slightly polar residues: Ala, Ser, Thr, Pro, Gly II. Polar, positively charged residues: His, Arg, Lys III. Polar, negatively charged residues: and their amides: Asp, Asn, Glu, Gln IV. Large aromatic residues: Phe, Tyr, Trp V. Large aliphatic non-polar residues: Met, Leu, Ile, Val, Cys. 【0039】 In some embodiments, the AAT variants described herein have protease inhibitory activity, preferably AAT variants having a disintegrin and metalloprotease 17 (ADAM17) inhibitory activity. "Disintegrin and metalloprotease 17 (ADAM17) inhibitory activity" is preferably measured by a recombinant human ADAM-17 kit (recombinant human TACE / ADAM17 protein, CF: 930-ADB-010 and Mca-PLAQAV-Dpa-RSSSR-NH2 fluorescent peptide substrate: ES003; R&D Systems, preferably under the conditions described in Example 22). "Disintegrin and metalloprotease 17 (ADAM17) inhibitory activity" is at least about 30% reduction in ADAM17 activity at 200 uM, preferably at least about 30% reduction in ADAM17 activity at 100 uM, and / or at least about 45% reduction in ADAM17 activity at 200 uM, more preferably at least about 45% reduction in ADAM17 activity at 15 uM. In these embodiments, the concentration in uM units may be the concentration of the AAT variant. In certain embodiments, the AAT variant described herein is Ac-VKFNKPFVFLNleIEQNTK-NH2. In certain embodiments, the AAT variant described herein is a sequence related to Ac-VKFNKPFVFLNleIEQNTK-NH2, which has 5 or fewer, 4 or fewer, 3 or fewer, or 1 or fewer amino acid substitutions compared to Ac-VKFNKPFVFLNleIEQNTK-NH2, preferably, this amino acid substitution is a conservative amino acid substitution. The sequence related to Ac-VKFNKPFVFLNleIEQNTK-NH2 may further include one or more terminal insertions. In certain embodiments, preferably, in embodiments where the AAT variant described herein is Ac-VKFNKPFVFLNleIEQNTK-NH2 or a sequence related to Ac-VKFNKPFVFLNleIEQNTK-NH2, the AAT variant is not used in the treatment of acute nociceptive pain, inflammatory pain, and neuropathic pain.In certain embodiments, the Ac-VKFNKPFVFLNleIEQNTK-NH2 or sequences related to Ac-VKFNKPFVFLNleIEQNTK-NH2 described herein are used in the treatment of chronic inflammatory demyelinating polyneuropathy or its symptoms. 【0040】 As used herein, an "isoform" of an AAT protein, peptide or polypeptide of the invention refers to a splice variant resulting from alternative splicing of AAT mRNA. In some embodiments, the AAT isoforms described herein have ADAM17 inhibitory activity, preferably have ADAM17 inhibitory activity, more preferably are AAT isoforms having disintegrin and metalloprotease 17 (ADAM17) inhibitory activity. 【0041】 As used herein, a "fragment" of an AAT protein, peptide or polypeptide of the invention refers to a sequence of amino acids that is shorter in length than the AAT protein, peptide or polypeptide of the invention, particularly a sequence of amino acids that is shorter than the sequence of AAT set forth in SEQ ID NO: 1. Fragments are preferably functional fragments, e.g., fragments having the same biological activity as the AAT protein set forth in SEQ ID NO: 1. Functional fragments are preferably derived from the AAT protein set forth in SEQ ID NO: 1. Any AAT fragment can be used as long as it exhibits the same properties as the native AAT sequence from which it is derived (i.e., is biologically active). In some embodiments, the AAT fragments described herein have protease inhibitory activity, preferably have ADAM17 inhibitory activity, more preferably are AAT fragments having disintegrin and metalloprotease 17 (ADAM17) inhibitory activity. 【0042】 Preferably, the (functional) fragment shares about 5 contiguous amino acids, at least about 7 contiguous amino acids, at least about 15 contiguous amino acids, at least about 20 contiguous amino acids, at least about 25 contiguous amino acids, at least about 20 contiguous amino acids, at least about 30 contiguous amino acids, at least about 35 contiguous amino acids, at least about 40 contiguous amino acids, at least about 45 contiguous amino acids, at least about 50 contiguous amino acids, at least about 55 contiguous amino acids, at least about 60 contiguous amino acids, at least about 100 contiguous amino acids, at least about 150 contiguous amino acids, at least about 200 contiguous amino acids, at least about 300 contiguous amino acids, or more of the native human AAT amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the (functional) fragments described herein include an expression optimization signal protein. In certain embodiments, the fragments described herein are derived from the C-terminus of AAT, and thus the fragment shares about 5 contiguous amino acids, at least about 7 contiguous amino acids, at least about 15 contiguous amino acids, at least about 20 contiguous amino acids, at least about 25 contiguous amino acids, at least about 20 contiguous amino acids, at least about 30 contiguous amino acids, at least about 35 contiguous amino acids, at least about 40 contiguous amino acids, at least about 45 contiguous amino acids, at least about 50 contiguous amino acids, at least about 55 contiguous amino acids, at least about 60 contiguous amino acids, at least about 100 contiguous amino acids, at least about 150 contiguous amino acids, or more of the native human AAT amino acid sequence set forth in SEQ ID NO: 2. In highly preferred embodiments, this fragment is derived from the C-terminus of AAT, and thus this fragment shares at least about 200 or more of the native human AAT amino acid sequence set forth in SEQ ID NO: 2. In highly preferred embodiments, the fragment has the sequence of SEQ ID NO: 2. 【0043】 As used herein, a "small molecule" having ADAM17 inhibitory activity refers to a molecule having a molecular weight of less than 1500 kD, less than 1400 kD, less than 1300 kD, less than 1200 kD, less than 1100 kD, less than 1000 kD, less than 900 kD, less than 800 kD, less than 700 kD, less than 600 kD, less than 500 kD, or less than 400 kD. In certain embodiments, the small molecules described herein are peptides having a molecular weight of 1500 kD to 500 kD, preferably 1300 kD to 600 kD, more preferably 1100 kD to 700 kD. Examples of such peptides are provided as Peptide 9 and Peptide 8 in Example 22. In certain embodiments, the small molecule is a variant of Peptide 9 and Peptide 8, with one or two amino acids replaced, inserted, or removed, preferably replaced by conservative amino acid substitutions. In certain embodiments, the small molecules described herein are molecules having a molecular weight of 1000 kD to 50 kD, preferably 600 kD to 100 kD, more preferably 400 kD to 200 kD. An example of such a small molecule is provided in Example 22 (peptidomimetic 14). Those skilled in the art will recognize methods for identifying additional small molecules for use in the present invention, for example, by screening for ADAM17 inhibitory activity as described in Example 22, following the teachings of Lior, Yotam et al. (European Journal of Medicinal Chemistry 228 (2022): 113969). 【0044】 In some embodiments, the amino acid sequence of AAT, its variant, isoform, or fragment as described herein is at least 80% identical to the corresponding amino acid sequence of SEQ ID NO: 1. In some embodiments, the amino acid sequence of AAT, its variant, isoform, or fragment is 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding amino acid sequence of SEQ ID NO: 1. 【0045】 The terms "nucleic acid", "polynucleotide", and "oligonucleotide" are used interchangeably and refer to any kind of deoxyribonucleotide (e.g., DNA, cDNA, etc.) or ribonucleotide (e.g., RNA, mRNA, etc.) polymer, in single-stranded or double-stranded form, in linear or circular conformation, or a combination of deoxyribonucleotides and ribonucleotides (e.g., DNA / RNA) polymer. These terms should not be construed as limiting with respect to the length of the polymer and can include known analogs of natural nucleotides, as well as nucleotides modified in the base, sugar, and / or phosphate moieties (e.g., phosphorothioate backbone). Generally, an analog of a particular nucleotide has the same base pairing specificity, i.e., an analog of A forms a base pair with T. 【0046】 As used herein, the term "treatment" (and its grammatical variations such as "treat" or "treating") refers to a clinical intervention in an attempt to alter the natural course of the individual being treated and can be performed either for prophylaxis or during the course of a clinical pathology. Desirable effects of treatment include, but are not limited to, prevention of the occurrence or recurrence of a disease, alleviation of symptoms, reduction of any direct or indirect pathological consequences of the disease, decrease in the rate of disease progression, improvement or palliation of the diseased state, and remission or improvement of prognosis. In some embodiments, the antibodies of the invention are used to delay the onset of a disease or to slow the progression of a disease. 【0047】 CIDP is an acquired polyneuropathy within the peripheral nervous system with a presumed autoimmune-mediated etiology. CIDP is characterized by symmetrical weakness in both proximal and distal muscles that progresses gradually. This condition is usually, but not always, associated with sensory disturbances, absence or reduction of tendon reflexes, elevation of cerebrospinal fluid protein levels, and changes in electrophysiological parameters. Nerve biopsy specimens are characterized by signs of demyelination. The clinical course can be relapsing or chronic and progressive (see, for example, Mathey E K, et al. J Neurol Neurosurg Psychiatry 2015;86:973-985; Koller H, et al. N Engl J Med. 2005;352(13):1343-1356), with the former being far more common in young adults. CIDP is a rare disease with an estimated prevalence of about 1.6 - 8.9 per 100,000 adults and about 0.5 per 100,000 children. CIDP can be diagnosed as described by the Joint Task Force of the EFNS and the PNS (Journal of the Peripheral Nervous System 15:1-9(2010)). 【0048】 The following conditions are considered to be the same as, or essentially the same as, CIDP and are thus encompassed by the term "CIDP": "chronic relapsing polyneuritis", "chronic idiopathic demyelinating polyneuritis", "chronic inflammatory demyelinating polyradiculoneuritis", and "chronic acquired demyelinating polyneuropathy" ("CADP"). 【0049】 The inventors have found that AAT can reduce the neuropathological pathway (Figures 2 - 4, Tables 1 - 10). This reduction of the neuropathological pathway is observed in resting cells (Figure 4B) and stimulated cells (Figure 4C) and is thus useful for preventing and / or treating diseases or disorders of the nervous system and their symptoms. 【0050】 TACE / ADAM17 activity regulation is involved in myelin regulation and is characteristic of the inflammation in chronic inflammatory demyelinating polyneuropathy. 【0051】 The inventor has found that AAT can inhibit TACE / ADAM17 in a dose-dependent manner, which, without being bound by theory, rescues SC-mediated myelin production and thus prevents, delays, and / or reverses the progression of chronic inflammatory demyelinating polyneuropathy. Thus, the combination of the anti-inflammatory effect and the neuroprotective / regenerative effect is surprisingly effective in the treatment of chronic inflammatory demyelinating polyneuropathy. 【0052】 Accordingly, the present invention is based at least in part on the finding that it is useful, at least in part, for treating the nervous system diseases or disorders described herein. 【0053】 According to some embodiments, the treatment described herein comprises a single administration of the total amount of AAT. According to certain embodiments, an effective amount of AAT is about 10 mg to about 1000 mg / kg body weight of AAT per week, preferably about 10 mg to about 500 mg / kg body weight of AAT per week (or an equivalent amount of an AAT variant, fragment, isoform, and / or corresponding nucleic acid). According to certain embodiments, an effective amount of AAT is about 30 mg to about 240 mg / kg body weight of AAT per week, preferably about 60 mg to about 120 mg / kg body weight of AAT per week (or an equivalent amount of an AAT variant, fragment, isoform, and / or corresponding nucleic acid). According to certain embodiments, an effective amount of AAT (or an equivalent amount of an AAT variant, fragment, isoform, and / or corresponding nucleic acid) is about 10 mg / kg / week to about 1000 mg / kg / week, preferably about 10 mg / kg / week to about 500 mg / kg / week. According to certain embodiments, an effective amount of AAT (or an equivalent amount of an AAT variant, fragment, isoform, and / or corresponding nucleic acid) exceeds about 100 mg / kg / day, preferably about 100 mg / kg / day to about 1000 mg / kg / day, more preferably about 100 mg / kg / day to about 500 mg / kg / day, more preferably about 150 mg / kg / day to about 250 mg / kg / day, more preferably about 150 mg / kg / day to about 210 mg / kg / day. 【0054】 According to other embodiments, the treatment described herein comprises multiple administrations of multiple partial doses to reach the total cumulative dose of AAT. According to certain embodiments, each partial dose comprises from about 5 mg / kg to about 500 mg / kg, preferably from about 15 mg / kg to about 240 mg / kg. According to other embodiments, each partial dose comprises about 10, about 20, about 40, about 60, about 80, about 120 or about 240 mg AAT / kg (or an equivalent amount of an AAT variant, fragment, isoform and / or corresponding nucleic acid or small molecule). Each possibility represents a separate embodiment of the invention. 【0055】 In one embodiment, the invention is a kit for use in the treatment of a disease or disorder of the nervous system, comprising: i) a) an alpha1-antitrypsin (AAT) protein, a variant, isoform and / or fragment thereof having inhibitory activity, and / or b) a nucleic acid encoding an AAT, a variant, isoform and / or fragment thereof having ADAM17 inhibitory activity; and ii) a plurality of IgG antibodies, isoforms thereof, fragments thereof and / or IgG variants. 【0056】 As used herein, the term "plurality of IgG antibodies" refers to at least two different, at least three different, at least four different, at least five different, at least six different, at least seven different, at least eight different, at least nine different, or at least ten different IgG antibodies. In certain embodiments, the plurality of IgG antibodies identify at least two different epitopes or antigens. In certain embodiments, the plurality of IgG antibodies comprises IgG antibodies of several IgG subclasses. In certain embodiments, the plurality of IgG antibodies are polyclonal antibodies. In certain embodiments, the plurality of IgG antibodies are not monoclonal antibodies. In certain embodiments, the plurality of IgG antibodies described herein comprise IgG antibody human plasma-derived IgG antibodies, preferably pooled IgG antibodies. Isoforms of IgG antibodies, fragments of IgG antibodies and / or IgG variants may be further combined with the plurality of IgG antibodies (e.g., added, or not separated). In certain embodiments, these isoforms, fragments and variants are naturally occurring isoforms, fragments and / or variants. In other embodiments, the isoforms, fragments and / or variants are produced separately and added to the IgG antibodies. 【0057】 In general, the term "antibody" is used herein in its broadest sense and encompasses various antibody structures including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), fully human antibodies, and antibody fragments, so long as they exhibit the desired antigen-binding activity. In some embodiments, the IgG antibodies described herein are derived from the IgG1, IgG2, IgG3, and / or IgG4 subclasses. In some embodiments, the IgG antibodies described herein include polyclonal IgG antibodies. In some embodiments, the IgG antibodies described herein are part of an immunoglobulin therapy. As used herein, the term "immunoglobulin therapy" generally refers to a therapeutic method of administering a composition of IgG immunoglobulin to a patient intravenously, subcutaneously, or intramuscularly to treat some conditions such as immunodeficiency, inflammatory diseases, and autoimmune diseases. IgG immunoglobulins are typically pooled and prepared from plasma. Whole antibodies or fragments can be used. IgG immunoglobulins can be formulated at high concentrations (e.g., greater than 10%) for subcutaneous administration or formulated for intramuscular administration. This is particularly common for special IgG preparations that are prepared to be higher than the average titer against specific antigens (e.g., Rho D factor, pertussis toxin, tetanus toxin, botulinum toxin, rabies, etc.). The preparation of immunoglobulin therapy is known in the art (see, e.g., US8940877(B2)). Immunoglobulin therapy can be derived from mammalian, preferably human, plasma. In certain embodiments, the plasma of multiple (generally 1000 or more) healthy donors is pooled and optionally further processed. The term "healthy individual" means an individual who meets the current (at the time of donation) standard eligibility criteria for providing blood, and it should be noted that such eligibility criteria are subject to continuous improvement and change. In some embodiments, the immunoglobulin fraction is concentrated from the pooled plasma. Preferably, the immunoglobulin is purified from the pooled plasma. More preferably, the immunoglobulin is purified and concentrated. In various embodiments, purified and concentrated immunoglobulin G (IgG) is used.In certain embodiments, the immunoglobulin therapy may contain trace amounts of immunoglobulins of different Ig classes, such as IgA or IgM. In certain embodiments, the IgA concentration is 50 μg or less per 100 mg of immunoglobulin. In preferred embodiments, the IgA concentration is 25 μg or less per 100 mg of immunoglobulin. Low IgA is desirable to avoid adverse events in patients with IgA deficiency. In one embodiment, the IgM concentration is 10 μg or less per 100 mg of immunoglobulin. In preferred embodiments, the IgM concentration is 5 μg or less per 100 mg of immunoglobulin. In various embodiments, the immunoglobulin therapy exhibits a protein fraction purity of >90% IgG, more preferably >95% IgG, even more preferably >98% IgG. In various embodiments, the immunoglobulin therapy exhibits an immunoglobulin monomer and dimer content of >90%, more preferably >95%, even more preferably >98%. The immunoglobulin therapy preferably exhibits a natural IgG subclass distribution. In one embodiment, the immunoglobulin subclass distribution in the immunoglobulin therapy is 62% - 74% IgG1, 22% - 34% IgG2, 2% - 5% IgG3, and 1% - 3% IgG4. The immunoglobulin therapy may contain stabilizers, such as amino acids like proline or glycine, or additional components such as sucrose, maltose, sorbitol, albumin nicotinamide, PEG, polysorbate 80, etc. A preferred stabilizer is an amino acid, particularly proline. In various embodiments, the immunoglobulin therapy contains 10% (w / v) - 30% (w / v) immunoglobulin. In certain embodiments, the immunoglobulin therapy is provided as a solution containing at least 10% (w / v) immunoglobulin, more preferably at least 15% (w / v) immunoglobulin, most preferably approximately 20% (w / v) immunoglobulin. The immunoglobulin therapy may also contain approximately 30% (w / v) immunoglobulin. The immunoglobulin therapy is virus-safe against enveloped viruses (e.g., HIV, HBV, and HCV) and non-enveloped viruses (e.g., HAV and parvovirus B19). The immunoglobulin therapy may be provided as a liquid product or a lyophilized product.In a preferred embodiment, the immunoglobulin therapy is provided as a liquid product. Such a liquid product is in a usable state, i.e., there is no need to reconstitute the product prior to administration. The liquid product is convenient to use as it does not require reconstitution. Thus, the liquid product is particularly suitable for self - administration by patients. In some embodiments, the dosage of the IgG antibody is individually adjusted or is a fixed dosage. In some embodiments, the IgG antibodies described herein are selected from the range of about 0.1 g / kg to about 0.4 g / kg of patient body weight, from the range of about 0.1 g / kg to about 0.3 g / kg of patient body weight, from the range of about 0.15 g / kg to about 0.25 g / kg of patient body weight, from the range of about 0.18 g / kg to about 0.22 g / kg of patient body weight, or a dosage of about 0.2 g / kg of patient body weight per 5 to 10 days or per 6 to 8 days or per week, preferably a dosage selected from the range of about 0.18 g / kg to about 0.22 g / kg of patient body weight per 6 to 8 days. In some embodiments, the dosage of the IgG antibody is administered as a single dose or is divided and administered 2, 3, 4, 5, 6 or 7 times a week. 【0058】 The term "nervous system disease or disorder", as used herein, refers to a group of diseases or disorders in which the pathological condition involves the nervous system. In some embodiments, the nervous system diseases or disorders described herein are 12q14 microdeletion syndrome, 15q13.3 microdeletion syndrome, 15q24 microdeletion syndrome, 22q11.2 deletion syndrome, 22q13.3 deletion syndrome, 2-methylbutyryl-CoA dehydrogenase deficiency, 2q23.1 microdeletion syndrome, 2q37 deletion syndrome, 3-alpha-hydroxyacyl-CoA dehydrogenase deficiency, 3MC syndrome, XXXY syndrome, XYYY syndrome, XXXXY syndrome, 5q14.3 microdeletion syndrome, 6-pyruvoyl-tetrahydrobiopterin synthase deficiency, Aarskog syndrome, abetalipoproteinemia, Abri amyloidosis, agenesis of the septum pellucidum, aceruloplasminemia, agenesis of the corpus callosum, acro-fronto-facial dysostosis Catania type, acro-fronto-facial dysostosis Rodriguez type, acute cerebellar ataxia, acute cholinergic autonomic neuropathy, acute CNS demyelinating event, acute disseminated encephalomyelitis, acute inflammatory demyelinating polyneuropathy, acute intermittent porphyria, acute motor sensory axonal neuropathy syndrome, ADCY5-related dystonia, adenosine monophosphate deaminase 1 deficiency, adenylosuccinate lyase deficiency, Adie syndrome, adrenomyeloneuropathy, adult polyglucosan body disease, adult-onset nemaline myopathy, advanced sleep phase syndrome, agenesis of the corpus callosum, age-related peripheral neuropathy, age-related peripheral neuropathy, agnosia, Aicardi syndrome, Ecardie Guthrie syndrome, AIDS dementia complex, Al Gazali AzizSalem syndrome, Alaninuria, leukodystrophy-deafness syndrome, alcohol-nutritional induced sensory and motor deficit disorder, alcoholic neuropathy, alcoholic peripheral neuropathy, Alexander disease, ALG11-CDG (CDG-Ip), ALG12-CDG (CDG-Ig), ALG13-CDG, ALG1-CDG (CDG-Ik), ALG2-CDG (CDG-Ii), ALG3-CDG (CDG-Id), ALG6-CDG (CDG-Ic), ALG8-CDG (CDG-Ih), ALG9-CDG (CDG-IL), Alan-Herndon-Dudley syndrome, Moynahan's alopecia-epilepsy-mental retardation syndrome, alopecia, epilepsy, alveolar pyorrhea, mental weakness, alopecia-contraction-dwarfism-mental developmental delay syndrome, alopecia-mental developmental delay syndrome, Alpers syndrome, alpha-ketoglutaric dehydrogenase deficiency, alpha-mannosidosis, X-linked alpha-sarcopenia-mental retardation syndrome, infantile alternating hemiplegia, Alzheimer's disease type 4, Alzheimer's disease, Alzheimer's disease without neurofibrillary changes, aminoacylase 1 deficiency, aminolevulinic acid dehydrogenase-deficient porphyria, Amish type severe microcephaly, Amish nemaline myopathy, amyloid neuropathy, amyopathic dermatomyositis, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis type 6, amyotrophic lateral sclerosis / Parkinson's dementia complex 1, amyotrophic lateral sclerosis, anaplastic astrocytoma, anaplastic ganglioglioma, anaplastic oligodendroglioma, Andermann syndrome, Andersen-Tawil syndrome, sideroblastic anemia ataxia, spinocerebellar degeneration, anencephaly, hereditary neurocutaneous angioma (Angioma hereditaryNeurocutaneous), aniridia, aniridia - renal agenesis - psychomotor retardation syndrome, anti - synthetase syndrome, aortic arch anomaly, apraxia, arachnoid cyst, arachnoiditis, aromatic L - amino acid decarboxylase deficiency, congenital multiple arthrogryposis, distal, X - linked, arthrogryposis - renal dysfunction - cholestasis syndrome, Arts syndrome, aspartylglycosaminuria, ataxia, ataxia - telangiectasia, ataxia - oculomotor apraxia type 1, ataxia - oculomotor apraxia type 2, ataxia - oculomotor apraxia type 4, vitamin E - only deficiency ataxia, ataxia - telangiectasia, osteogenesis imperfecta type 2, osteogenesis imperfecta type 3, atkin syndrome, atypical Rett syndrome, aseptic meningitis, autism with wine - stain spots, autosomal dominant central core myopathy, autosomal dominant cerebellar ataxia with deafness and narcolepsy, autosomal dominant Charcot - Marie - Tooth disease type 2 with giant axons, autosomal dominant deafness - onychodystrophy syndrome, autosomal dominant intermediate Charcot - Marie - Toothdisease), autosomal dominant leukodystrophy with autonomic neuropathy, autosomal dominant neuronal ceroid lipofuscinosis 4B, autosomal dominant nocturnal frontal lobe epilepsy, autosomal dominant non-syndromic mental retardation, autosomal dominant optic atrophy plus syndrome, autosomal dominant partial epilepsy with auditory features, autosomal dominant spinal muscular atrophy, autosomal recessive axonal neuropathy with neuromyotonia, myotonia, autosomal recessive central core myopathy, autosomal recessive Charcot-Marie-Tooth disease with hoarseness, autosomal recessive intermediate Charcot-Marie-Tooth disease type A, autosomal recessive intermediate Charcot-Marie-Tooth disease type B, autosomal recessive juvenile Parkinson's disease, autosomal recessive neuronal ceroid lipofuscinosis 4A, adult neuronal ceroid lipofuscinosis, autosomal recessive primary microcephaly, autosomal recessive spinocerebellar ataxia 4, autosomal recessive spastic paraplegia type 49, autosomal recessive spinocerebellar ataxia 9, B4GALT1-CDG (CDG-IId), Banayan-Riley-Ruvalcaba syndrome, Barth syndrome, Battaglia-Neri syndrome, Becker muscular dystrophy, Behavioral variant of frontotemporal dementia, Behçet's disease, Bell's palsy, Benign essential blepharospasm, Benign familial neonatal epilepsy, Benign familial neonatal seizures, Benign hereditary chorea, Benign Rolandic epilepsy (BRE), Beta-propeller protein-related neurodegeneration, Bethlem myopathy, bilateral frontal polymicrogyria, bilateral frontoparietal polymicrogyria, bilateral generalized polymicrogyria, bilateral parasagittal parieto-occipital polymicrogyria, bilateral perisylvian polymicrogyria, Binswanger's disease, Biotinidase deficiency, Biotin-thiamine-responsive basal ganglia disease, Birk-Barel syndrome, Bixler ChristianGorlin syndrome, Blepharonasofacial dysplasia syndrome, Head-bobbing doll syndrome, Bowling Opitz syndrome, Bereson-Forssman-Lehmann syndrome, Bowen-Conradi syndrome, Brachioskeletogenital syndrome, Brachydactyly-mesomelia-intellectual disability-heart defects syndrome, Intracerebral dopamine-serotonin vesicle transport disorder, Brain-lung-thyroid syndrome, X-linked branchial arch syndrome, Brody myopathy, Brooks-Wiszniewski-Brown syndrome, Brown-Séquard syndrome, Vesicular dystrophy, C syndrome, Cabezas syndrome, CADASIL, Dorsiflexion, Camptodactyly arthropathy coxa vara pericarditis syndrome, CANOMAD syndrome, Kandt syndrome, Cap myopathy, Heart-face-skin syndrome, Carey-Fineman-Ziter syndrome, Carney complex, Cataract ataxia deafness, Cattel-Menzke syndrome, Caudal appendage deafness, Caudal regression sequence, Central core disease, Central nervous system germinoma, Central neurocytoma, Central pain syndrome, Pontine central myelinolysis, Cerebellar ataxia, Cerebellar degeneration, Cerebellar hypoplasia, Cerebellitis, Cerebelloparenchymal disorder 3, Cerebellum agenesis hydrocephaly, Cerebral autosomal recessive arteriopathy, Cerebrospinal fluid arteriovenous malformation, Cerebral malformation, Neuropathy, Ichthyosis, and Palmoplantar keratoderma syndrome, Cerebral folate deficiency, Cerebral gigantism jaw cysts, Cerebral palsy, Ataxic cerebral palsy, Athetoid cerebral palsy, Cerebral palsy spastic hemiplegiahemiplegic, cerebral palsy spastic monoplegic, cerebral palsy spastic quadriplegic, encephalosclerosis, craniofacial joint syndrome, cerebro-oculo-facio-skeletal syndrome, cerebro-oculo-nasal syndrome, cerebrospinal fluid leakage, cerebrotendinous xanthomatosis, neuronal ceroid lipofuscinosis type 1, cervical hypertrichosis peripheral neuropathy, Chanarin-Dorfman syndrome, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 1A, Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease type 3, Charcot-Marie-Tooth disease type 4, Chediak-Higashi syndrome, Chiari malformation, Chiari malformation type 1, Chiari malformation type 2, Chiari malformation type 4, childhood apraxia of speech, childhood-onset nemaline myopathy, neuroacanthocytosis, choroid plexus carcinoma, choroid plexus papilloma, Christianson syndrome, chromosome 17p13.1 deletion syndrome, chromosome 17q11.2 deletion syndrome, chromosome 19q13.11 deletion syndrome, chromosome 1p36 deletion syndrome, chromosome 3p- syndrome, chronic hiccups, chronic lymphocytic inflammation, chronic progressive external ophthalmoplegia, Chudley Rozdilsky syndrome, cisplatin-induced sensory neuropathy, cleft palate short stature vertebral anomalies, cluster headache, COACH syndrome, COASY protein-related neurodegeneration, Coats disease, Cobb syndrome, Cockayne syndrome type I, Cockayne syndrome type II, Cockayne syndrome type III, coenzyme Q10 deficiency, Coffin-Lowry syndrome, Coffin-Siris syndrome, COG1-CDG (CDG-IIg), COG4-CDG (CDG-IIj), COG5-CDG (CDG-IIi), COG7-CDG (CDG-IIe), COG8-CDG (CDG-IIh), Coen syndrome, cold-induced sweating syndrome, complex regional pain syndrome, congenital central hypoventilation syndrome, congenital cytomegalovirus infection, congenital muscular fiber disproportion, congenital extraocular muscle fibrosis, congenital generalized lipodystrophy type 4, congenital insensitivity to pain, congenital insensitivity to pain and anhidrosis, congenital intrauterine infection-like syndrome, congenital laryngeal paralysis, congenital mirror movement, congenital muscular dystrophy, congenital myastheniaSyndrome, congenital rubella, congenital toxoplasmosis, continuous spike-wave during slow sleep syndrome, spasm, decreased corneal sensation, Cornelia de Lange syndrome, agenesis of the corpus callosum, skin blindness, abnormal cortical formation, corticobasal degeneration, Costello syndrome, Crouzon syndrome, cranial nerve palsy, craniofrontonasal dysplasia, craniopharyngioma, myelomeningocele, telencephalic malformation, Creutzfeldt-Jakob disease, Chromosome syndrome, Curry-Jones syndrome, cylindrical spirals myopathy, Cyprus craniofacial myoskeletal syndrome, giant cell inclusion disease, D-2-hydroxyglutaric aciduria, Dandy-Walker cyst, Dandy-Walker-like malformation, Dandy-Walker malformation, Danon disease, dapsone-induced neuropathy, DDOST-CDG (CDG-Ir), DEAF1-related disorder, Dentatorubral-pallidoluysian atrophy, dermatomyositis, Developmental dysphasia familial, diabetic neuropathy, dihydrolipoyl dehydrogenase deficiency, dihydropteridine reductase deficiency, diphtheria, Distal myopathy with vocal cord weakness, DOOR syndrome, dopamine beta hydroxylase deficiency, dopamine transporter deficiency syndrome, dopamine-responsive dystonia, DPAGT1-CDG (CDG-Ij), DPM1-CDG (CDG-Ie), DPM2-CDG, DPM3-CDG (CDG-Io), drave Syndrome, Duane syndrome, Dokowicz syndrome, Duchenne muscular dystrophy, Dykes Markes Harper syndrome, autonomic nervous system dysfunction-like disorder, imbalance syndrome, congenital dyskeratosis, autosomal dominant congenital dyskeratosis, autosomal recessive congenital dyskeratosis, X-linked congenital dyskeratosis, myoclonic cerebellar ataxia, dystonia 2, DYT-PRKRA, DYT-THAP1, DYT-TOR1A, DYT-TUBB4A, early infantile epileptic encephalopathy, early infantile epileptic encephalopathy 25, early-onset anterior polar cataract, early-onset autosomal dominant Alzheimer's disease, early-onset Parkinson's disease-intellectual disability syndrome, eastern equine encephalitis, Turkish saddle cavitation syndrome, encephalitis lethargica, encephalocraniocutaneous lipomatosis, encephalopathy, eosinophilic fasciitis, eosinophilic granulomatosis, ependymoma, epidermolysa bullosa simplex with muscular dystrophy, juvenile absence epilepsy, epilepsy with occipital calcifications, epilepsy progressive myoclonic type 3, epilepsy with myoclonic-atonic seizures, epiphyseal dysplasia hearing loss dysmorphism, episodic ataxia, erythromelalgia, essential tremor, Fabry disease, facial-onset neuronopathy, facioscapulohumeral muscular dystrophy, Fallot complex, familial amyloidosis, familial bilateral striatal necrosis, familial caudaldysgenesis), familial congenital oculomotor nerve paralysis, familial dysautonomia, familial encephalopathy, familial exudative vitreoretinopathy, familial focal epilepsy, familial hemiplegic migraine, familial hemophagocytic syndrome, familial infantile convulsions · familial infantile paroxysmal choreoathetosis, familial porencephaly, familial transthyretin amyloidosis, familiar or sporadic hemiplegic migraine, Faber disease, fatal familial insomnia, fatal infantile encephalomyopathy, fatty acid hydroxylase-related neurodegeneration, FBXL4-related mitochondrial DNA depletion syndrome, intractable frequent partial seizure superadded acute encephalitis, Feingold-Bergelson-Richardson syndrome, Filippi syndrome, Fine-Lubinsky syndrome, fingerprint body myopathy, Fitzsimmons-Walsh-Meller syndrome, Fitzsimmons-Gilbert syndrome, Floating-Harbor syndrome, Flynn Aird syndrome, focal skin hypoplasia, focal motor weakness, focal segmental glomerulosclerosis, Fountain syndrome, FOXG1 syndrome, fragile X syndrome, fragile XE syndrome, Leber hereditary optic neuropathy, frontal metaphyseal dysplasia, frontotemporal dementia, frontotemporal lobardementia), Fryns syndrome, fucosidosis, Fukuyama type congenital muscular dystrophy, fumarase deficiency, galactosialidosis, Galloway-Mowat syndrome, gamma-aminobutyric acid aminotransferase deficiency, gangliocytoma, GAPO syndrome, Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Gemignani syndrome, Genitopatellar syndrome, Genoa syndrome, Gerstmann syndrome, Gerstmann-Straussler-Scheinker disease, giant axonal neuropathy, Gillespie syndrome, gliomatosis cerebri, glucose transporter 1 deficiency, congenital glutamine deficiency, glutaric acidemia type I, glutaric acidemia type II, glutaric acidemia type III, glycogen storage disease type 13, glycogen storage disease type 2, glycogen storage disease type 3, glycogen storage disease type 4, glycogen storage disease type 5, glycogen storage disease type 7, GM1 gangliosidosis type 1, GM1 gangliosidosis type 2, GM1 gangliosidosis type 3, GM3 synthase deficiency, GMS syndrome, Goldberg-Sprinz congenital megacolon syndrome, Gomez-Lopez-Hernandez syndrome, GOSR2-related progressive myoclonic epilepsy, Graham-Cox syndrome, polyangiitis granulomatosa, Griscelli syndrome type 1, Groenveld-de Cock-Bolgergraeff syndrome, GTP cyclohydrolase I deficiency, GTPCH1-deficient DRD, guanidinoacetate methyltransferase deficiency, Guillain-Barre syndrome, Gurrieri syndrome, cerebrotemporal retinal atrophy, Hair defect-photosensitivity-intellectual disability syndrome, Hallerman-Streiff syndrome, Hall-Riggs syndrome, Hamanishi Ueba Tsuji syndrome, Hansen's disease, Harding ataxia, harlequin syndrome, Harrod Doman Keele syndrome, Hartnup disease, Hashimoto encephalopathy, Hemangioblastoma, Hemicrania Continuacontinua), Hemimegalencephaly, Hennekam syndrome, genetic angiopathy, hereditary coproporphyria, genetic diffuse leukoencephalopathy, hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis, hereditary geniospasm, hereditary hemorrhagic telangiectasia, hereditary hemorrhagic telangiectasia type 2, hereditary hemorrhagic telangiectasia type 3, hereditary hemorrhagic telangiectasia type 4, hereditary startle disease, hereditary motor and sensory neuropathy type 5, hereditary neuropathy with liability to pressure palsies (HNPP), hereditary predisposition to pressure palsies (focal and symmetrical), hereditary proximal myopathy with early respiratory failure, hereditary sensorimotor neuropathy with hyperelastic skin, hereditary sensory and autonomic neuropathy type 1e, hereditary sensory and autonomic neuropathy type 2, hereditary sensory and autonomic neuropathy types 1 - 7 (HSAN I - VII), hereditary sensory and autonomic neuropathy type V, hereditary sensory neuropathy type 1, hereditary spastic paraplegia, hereditary vitreoretinopathy, Hernandez - Aguirre - Negrette syndrome, herpes simplex encephalitis, Ramsay Hunt syndrome, HIBCH deficiency, homocystinuria, Horizontal gaze palsy with progressive scoliosis, HoyeraalHreidarsson syndrome, HSD10 disease, HTLV-1 associated myelopathy / tropical spastic paraparesis, human HOXA1 syndrome, human immunodeficiency virus-induced neuropathy, Huntington disease, Huntington's disease, Hurler syndrome, Hurler-Scheie syndrome, anencephaly, hydrocephalus (e.g., due to congenital stenosis of the Sylvius aqueduct), hydrocephalus-cleft palate-contracture syndrome, hydroxykynureninuria, hyperbetalipoproteinemia, hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency, hyperkalemic periodic paralysis, hypermethioninemia, hyperphenylalaninemia, hyperprolinemia, hyperprolinemia type 2, hypertrophic neuropathy of Dejerine-Sottas, autosomal dominant hypocalcemia, hypokalemic periodic paralysis, Ito hypomelanosis, hypomyelination (e.g., associated with atrophy of the basal ganglia and / or cerebellum), hypoparathyroidism-intellectual disability-dysmorphism syndrome, hypospadias-intellectual disability, Goldblatt type syndrome, hypothalamic hamartoma, ichthyosis alopecia ectropion intellectual disability, idiopathic intracranial hypertension, idiopathic spinal hernia, inclusion body myositis, incontinentia pigmenti, infantile axonal neuropathy, infantile cerebelloretinal degeneration, infantile choroidocerebral calcification syndrome, infantile fibromatosis, infantile neuroaxonal dystrophy, infantile-onset spinocerebellar degeneration, nodding epilepsy-wide fingers with increased perimeter, infantile-onset ascendinghereditary spastic paralysis), infectious disease-induced acute encephalopathy 3, Buenos-Aires type intellectual deficit, athetosis intellectual disability, hypoplastic corpus callosum intellectual disability, intellectual disability-developmental delay-contractures syndrome, intellectual disability-dysmorphism-hypogonadism-diabetes mellitus syndrome, intellectual disability-severe speech delay-mild dysmorphism syndrome, intellectual disability-spasticity-ectrodactyly syndrome, Intermediate congenital nemaline myopathy, Internal carotid agenesis, Intraneural perineurioma, IRVAN syndrome, Isaac's syndrome, Isodicentric chromosome 15 syndrome, Johanson-Blizzard syndrome, Johnson neuroectodermal syndrome, Joubert syndrome, Joubert-Marsidi syndrome, juvenile amyotrophic lateral sclerosis, juvenile dermatomyositis, juvenile Huntington's disease, juvenile polymyositis, juvenile primary lateral sclerosis, Kabuki syndrome, Kanzaki disease, KapurToriello syndrome, Kaufman oculocerebrofacial syndrome, KBG syndrome, KCNQ2-related disorder, Kearns-Sayre syndrome, Kennedy disease, Keratosis follicularis dwarfism, cerebral atrophy, kernicterus, Keutel syndrome, King-Denborough syndrome, Cleidocranial dysplasia, Kleine-Levin syndrome, Cri du chat paralysis, Kosztolanyi syndrome, Kozlowski-Karajewska syndrome, Krabbe disease, tremors, Kuzniecky-Andermann syndrome, L-2-hydroxyglutaric aciduria, La Crosse encephalitis, Laband syndrome, Lafora disease, Laing distal myopathy, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, l-arginine:glycine amidinotransferase deficiency, Late-onset distal myopathy, Markesberry / Griggs type late-onset distal myopathy, lateral meningocele syndrome, Laurence-Moon syndrome, LCHAD deficiency, Leber hereditary optic neuropathy, Leigh syndrome, Lennox-Gastaut syndrome, Lenz Majewski hyperostotic dwarfism, Lenz microphthalmia syndrome, Lesch-Nyhan syndrome, leukodystrophy, leukoencephalopathy (e.g., involving the thalamus and brainstem and associated with high lactate), Levic Stefanovic Nikolic syndrome, Lewis-Sumner syndrome, Lhermitte-Duclos disease Li-Fraumeni syndrome, limb-girdle muscular dystrophy (e.g., types 1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, 2A, 2B, 2C, 2D, 2E, 2F, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2S, 2T), limbic encephalitis with LGI1 antibodies, localized systemic scleroderma, lipoic acid synthase deficiency, schizencephaly 1, schizencephaly 2, X-linked schizencephaly, focal hypertrophic neuropathy, locked-in syndrome, logopenic progressive aphasia, Lowe's oculocerebrorenal syndrome, Lowry Maclean syndrome, Lubarsch syndrome, Lyme disease, Mac Dermot Winter syndrome, macrocephaly-short stature-paraplegia syndrome, macrothrombocytopenia progressive deafness, Mar de Barquement syndrome, male pseudohermaphroditism intellectual disability syndrome, malignant hyperthermia, malignant hyperthermia arthrogryposis torticollis, malignant migrating partial seizures of infancy, MAN1B1-CDG, mandibulofacial dysostosis (e.g., with microcephaly), mannosidosis, Marchiafava-Bignami disease, Marden-Walker syndrome, Marfanoid habitus-autosomal recessive intellectual disabilitysyndrome), Marinesco-Sjögren syndrome, Martsolf syndrome, McDonough syndrome, McLeod neuroacanthocytosis syndrome, Meckel syndrome, MECP2 duplication syndrome, Medrano-Roldan syndrome, medulloblastoma, megalencephalic leukodystrophy (e.g., with subcortical cysts), megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, megaloblastic anemia, megalocornea-intellectual disability syndrome, Mehes syndrome, MEHMO syndrome, Meier-Gorlin syndrome, Majewski syndrome, Melnick-Needles syndrome, meningioma, meningitis, Menkes disease, lateral femoral cutaneous neuropathy, metaphyseal dysostosis-intellectual disability-conductive deafness syndrome, methionine adenosyltransferase deficiency, methylcobalamin deficiency cbl g type, methylmalonic acidemia with homocystinuria type cblC, mgat2-cdg (cdg-iia), micro syndrome, microbrachycephaly ptosis cleft lip, microcephalic osteodysplastic primordial dwarfism type 1, microcephalic osteodysplastic primordial dwarfism type 2, microcephalic primordial dwarfism (e.g., Montreal type, Toriello type), microcephaly, autosomal dominant microcephaly, microcephaly-brain defect-spasticity-hypernatremia, microcephaly cervical spine fusion anomalies, microcephaly deafness syndrome, microcephaly-glomerulonephritis-marfanoidhabitus), microcephaly microcornea syndrome, microcephaly-cardiomyopathy, Xp11.22-p11.23 microduplication syndrome, microphthalmia 10, microphthalmia 4, microphthalmia 8, microphthalmia with linear skin defects syndrome, microscopic polyangiitis, migraine (e.g., with brainstem aura), mild phenylketonuria, Miller-Dicker syndrome, Miller-Fisher syndrome, minicore myopathy with external ophthalmoplegia, mitochondrial complex I deficiency, mitochondrial complex II deficiency, mitochondrial DNA depletion syndrome, encephalomyopathic methylmalonic acidemia, mitochondrial DNA-related Leigh syndrome, mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes, mitochondrial membrane protein-associated neurodegeneration, mitochondrial myopathy and sideroblastic anemia, mitochondrial myopathy with diabetes, mitochondrial myopathy with lactic acidosis, mitochondrial neurogastrointestinal encephalopathysyndrome), mitochondrial trifunctional enzyme deficiency, mixed connective tissue disease, Miyoshi myopathy, Möbius syndrome, MOGS-CDG (CDG-IIb), Moersch-Woltman syndrome, molybdenum cofactor deficiency, monoamine oxidase A deficiency, monoclonal gammopathy of undetermined significance (MGUS), Morquio-Larsson-Sargent syndrome, Morvan fibrillary chorea, Mousa Al din Al Nassar syndrome, moyamoya disease, MPDU1-CDG (CDG-If), MPI-CDG (CDG-Ib), MPV17-related hepatocerebral mitochondrial DNA depletion syndrome, mucolipidosis type 4, mucopolysaccharidosis type III, mucopolysaccharidosis IIIA, mucopolysaccharidosis IIIB, mucopolysaccharidosis IIIC, mucopolysaccharidosis IIID, multifocal motor neuropathy, multiple congenital anomalies-hypotonia-seizures syndrome, multiple congenital anomalies-hypotonia-seizures syndrome type 2, multiple myeloma, multiple sulfatase deficiency, multiple system atrophy, multiple system atrophy, multiple system smooth muscle dysfunction syndrome, myoencephalopathy, muscular dystrophy with white matter spongiosis, megaconial type muscular dystrophy, myophosphorylase kinase deficiency, myotonic type Ehlers-Danlos syndrome, myasthenia gravis, myelitis, spinocerebellar disorder, spinal meningioma, MYH7-related scapuloperoneal myopathy, Mayer syndrome, myoclonic epilepsy with ragged red fibers, myoclonus cerebellar ataxia deafness, myoclonus-dystonia, recurrent myoglobinuria, myopathy with extrapyramidal signs, myosin storage myopathy, myotonia congenitacongenita), myotonic dystrophy type 1, myotonic dystrophy type 2, N syndrome, Nance-Horan syndrome, narcolepsy, NBIA / DYT / PARK-PLA2G6, immune-mediated necrotizing myopathy, neonatal adrenoleukodystrophy, neonatal meningitis, neonatal progeroid syndrome, Neu Laxova syndrome, neuroblastoma, neurocutaneous melanosis, neurofaciodigitorenal syndrome, neuroferritinopathy, neurofibromatosis type 1, neurofibromatosis type 2, neuroleptic malignant syndrome, neuromyelitis optica spectrum disorder, neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis 10, neuronal ceroid lipofuscinosis 2, neuronal ceroid lipofuscinosis 3, neuronal ceroid lipofuscinosis 5, neuronal ceroid lipofuscinosis 6, neuronal ceroid lipofuscinosis 7, neuronal ceroid lipofuscinosis 9, intranuclear inclusion body disease, neuropathic pain, neuropathy-ataxia-retinitis pigmentosa syndrome, distal hereditary motor Jerash type neuropathy, hereditary motor and sensory Okinawa type neurologic bladder neuropathy, hereditary motor and sensory Russe type neuropathy, neutral lipid storage disease with myopathy, nevoid basal cell carcinoma syndrome, new-onset refractory status epilepticus, Nicolau-Balus syndrome, Niemann-Pick disease type A, Niemann-Pick disease type B, Niemann-Pick disease type C1, Niemann-Pick disease type C2, non-sleep-wake disorder, non-dystrophic myotonia syndrome, Noonan syndrome, Norrie disease, Northern epilepsy, oculocutaneous syndrome, oculofaciocardiodentalsyndrome), oculopharyngeal muscular dystrophy, oculopharyngodistal myopathy, Okamoto syndrome, olfactory neuroblastoma, oligodendroglioma, anaplastic oligodendroglioma, Olive syndrome, olivopontocerebellar atrophy, lethal omphalocele cleft palate syndrome, OPHN1 syndrome, opsoclonus-myoclonus syndrome, optic atrophy 2, optic pathway glioma, optic neuritis, ornithine transcarbamylase deficiency, orofaciodigital syndrome 1, orofaciodigital syndrome 10, orofaciodigital syndrome 2, orofaciodigital syndrome 3, orofaciodigital syndrome 4, orofaciodigital syndrome 5, orofaciodigital syndrome 6, orthostatic intolerance due to NET deficiency, osteopenia and sparse hair, osteoporosis-pseudoglioma syndrome, oto-palato-digital syndrome type 1, oto-palato-digital syndrome type 2, Ouvrier Billson syndrome, pachygyria-intellectual disability-epilepsy syndrome, PACS1-related syndrome, painful orbital and systemic neurofibromas-marfanoid habitus syndrome, pallidopyramidal syndrome, Pallister W syndrome, Pallister-Killian mosaic syndrome, pantothenate kinase-associated neurodegeneration, Parkinson's disease, juvenile paralysis, Hunt paralysis, congenital paramyotonia, paraneoplastic / autoimmune (anti-Hu-associated) neuropathy, Parkinson's disease, Parkinson's disease type 3, Parkinson's disease type 9, paroxysmal exertion-induced dyskinesia, paroxysmal extremepain disorder), episodic unilateral headache, paroxysmal kinesigenic choreoathetosis, paroxysmal non - kinesigenic dyskinesia, Personage - Turner syndrome, Partington syndrome, PCDH19 - related female - limited epilepsy, pediatric autoimmune neuropsychiatric disorders associated with Streptococcus infections, PEHO syndrome, Pelizaeus - Merzbacher disease, periventricular heterotopia, periventricular leukomalacia, Perry syndrome, Peters plus syndrome, Pfeiffer - Meyer syndrome, Pfeiffer - Palm - Teller syndrome, Pfeiffer type cardiocranial syndrome, PGM3 - CDG, PHACE syndrome, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, phosphoserine aminotransferase deficiency, photosensitive epilepsy, Pitt - Hopkins syndrome, Pitt - Hopkins - like syndrome, plasmacytoma, pleomorphic xanthoastrocytoma, PMM2 - CDG (CDG - Ia), polyneuropathy organomegaly endocrinopathy or edema M - protein and skin abnormalities syndrome (POEMS), polio, POLR3 - related leukodystrophy, polyarteritis nodosa, Nasu... Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, Polyneuropathy-intellectual disability-acromicria-premature menopause syndrome, perinatal brain injury, pontocerebellar hypoplasia, pontocerebellar hypoplasia type 1, pontocerebellar hypoplasia type 2, pontocerebellar hypoplasia type 3, pontocerebellar hypoplasia type 4, pontocerebellar hypoplasia type 5, pontocerebellar hypoplasia type 6, postpoliomyelitis syndrome, porphyria, Friedreich's ataxia, posterior column ataxia with retinitis pigmentosa, postnatal progressive microcephaly, postherpetic neuralgia, postpartum epilepsy and postpartum brain atrophy, potassium-induced myotonia, Potocki-Lupski syndrome, PPM-X syndrome, Prader-Willi syndrome, primary amebic meningoencephalitis, central nervous system localized vasculitis, primary basilar invagination, systemic carnitine deficiency, primary central nervous system lymphoma, primary familial cerebral calcification, primary lateral sclerosis, primary central nervous system lymphoma, primary orthostatic tremor, primary progressive aphasia, Primrose syndrome, progressive bulbar palsy, Progressive encephalomyelitis with rigidity and myoclonus, chronic progressive external ophthalmoplegia, autosomal recessive type 1, progressive facial hemiatrophy, progressive non-fluent aphasia, progressive supranuclear palsy, prolidase deficiency, Proteus syndrome, Proud syndrome, pseudoaminopterin syndrome, pseudocholinesterase deficiency, pseudoneonatal adrenoleukodystrophy, pseudoprogeriasyndrome), Pseudotrisomy 13 syndrome, Pseudoxanthoma elasticum, Vulvar neuralgia, Pure autonomic failure, Pyridoxal 5'-phosphate-dependent epilepsy, Pyridoxine-dependent epilepsy, Pyruvate dehydrogenase phosphatase deficiency, Kearns-Sayre syndrome, Radiation-induced brachial plexopathy, Ramos Arroyo Clark syndrome, Ramsay Hunt syndrome I, Ramsay Hunt syndrome II, Acute-onset dystonia parkinsonism, Rasmussen encephalitis, Reardon Wilson Cavanagh syndrome, Reducing body myopathy, Refsum disease, Renal renal dysplasia-limb defects syndrome, Renier Gabreels Jasper syndrome, Restless legs syndrome, Retinal arterial macroaneurysm with supravalvular pulmonic stenosis, Retinal vasculopathy with cerebral leukodystrophy, Retrobulbar optic neuritis, Rett syndrome, Reversible cerebral vasoconstriction syndrome, RFT1-CDG (CDG-In), Rabdoid tumor, Acrocentric punctate chondrodysplasia type 1, Riboflavin transporter deficiency, Richards-Rundle syndrome, Richieri Costa da Silva syndrome, Spinal rigidity syndrome, Ring chromosome 10, Ring chromosome 14, Ring chromosome 20, Ripening muscle disease, RNAse T2-deficient leukodystrophy, Roussy Levy syndrome, RRM2B-related mitochondrial DNA depletion syndrome, Ruvalcaba syndrome, Salla disease, Sandhoff disease, Sandifer syndrome, Sarcoidosis induced neuropathy, Seckel Barber Miller syndrome, Say Meyer syndrome, Scapuloperoneal syndrome, SCARF syndrome, Sharp Young syndrome, Sheehan syndrome, Shimke immuno-osseous dysplasia, Sinder disease type 1, Schinzel Giedion syndrome, Schisis association (Schisisassociation), schizencephaly, schwannomatosis, Schwartz-Jampel syndrome, Scott-Bryan-Graham syndrome, Sjögren-Larsson syndrome, Seckel syndrome, semantic dementia, sensory ataxic neuropathy, sepiapterin reductase deficiency, septo-optic dysplasia spectrum, SeSAME syndrome, SETBP1 disorder, severe congenital nemaline myopathy, severe intellectual disability-progressive spastic diplegia syndrome, Gustavson type severe X-linked intellectual disability, Shapiro syndrome, short-chain acyl-CoA dehydrogenase deficiency, Spritzen umbilical hernia syndrome, Shprintzen-Goldberg craniosynostosis syndrome, sialidosis type I, sialidosis type II, sickle cell anemia, Simpson-Golabi-Behmel syndrome, single upper central incisor, Sjögren-Larsson syndrome, SLC35A1-CDG (CDG-IIf), SLC35A2-CDG, SLC35C1-CDG (CDG-IIc), slow-channel congenital myasthenic syndrome, Smith-Fineman-Myers syndrome, Smith-Lemli-Opitz syndrome, Smith-Magenis syndrome, Sneddon syndrome, Snyder-Robinson syndrome, Sonoda syndrome, spasmodic dysphonia, spastic ataxia Charlevoix-Saguenaytype), spastic paralytic cerebral palsy, spastic diplegic infantile type, hereditary spastic paraplegia 1, hereditary spastic paraplegia 10, hereditary spastic paraplegia 11, hereditary spastic paraplegia 12, hereditary spastic paraplegia 13, hereditary spastic paraplegia 14, hereditary spastic paraplegia 15, hereditary spastic paraplegia 16, hereditary spastic paraplegia 17, hereditary spastic paraplegia 18, hereditary spastic paraplegia 19, hereditary spastic paraplegia 2, hereditary spastic paraplegia 23, hereditary spastic paraplegia 24, hereditary spastic paraplegia 25, hereditary spastic paraplegia 26, hereditary spastic paraplegia 29, hereditary spastic paraplegia 3, hereditary spastic paraplegia 31, hereditary spastic paraplegia 32, hereditary spastic paraplegia 39, hereditary spastic paraplegia 4, hereditary spastic paraplegia 51, hereditary spastic paraplegia 5a, hereditary spastic paraplegia 6, hereditary spastic paraplegia 7, hereditary spastic paraplegia 8, hereditary spastic paraplegia 9, hereditary spastic paraplegia - facial cutaneous lesions, hereditary spastic paraplegia - epilepsy - intellectual disability syndrome, hereditary spastic paraplegia - glaucoma - intellectual disability syndrome, spastic tetraplegia - retinitis pigmentosa - intellectual disability syndrome, spastic tetraplegia - thin corpus callosum - progressive postnatal microcephaly syndrome, occult spinal dysraphism, spinal atrophy - ophthalmoplegia - pyramidal syndrome, spinal meningioma, spinal muscular atrophy 1, spinal muscular atrophy 2, spinal muscular atrophy 3, spinal muscular atrophy - progressive myoclonic epilepsy syndromesyndrome), spinal shock, spinocerebellar degeneration, spinocerebellar degeneration type 1, spinocerebellar degeneration type 10, spinocerebellar degeneration type 11, spinocerebellar degeneration type 12, spinocerebellar degeneration type 13, spinocerebellar degeneration type 14, spinocerebellar degeneration type 15, spinocerebellar degeneration type 17, spinocerebellar degeneration type 18, spinocerebellar degeneration type 19 and type 22, spinocerebellar degeneration type 2, spinocerebellar degeneration type 20, spinocerebellar degeneration type 21, spinocerebellar degeneration type 23, spinocerebellar degeneration type 25, spinocerebellar degeneration type 26, spinocerebellar degeneration type 27, spinocerebellar degeneration type 28, spinocerebellar degeneration type 29, spinocerebellar degeneration type 3, spinocerebellar degeneration type 30, spinocerebellar degeneration type 31, spinocerebellar degeneration type 34, spinocerebellar degeneration type 4, spinocerebellar degeneration type 5, spinocerebellar degeneration type 7, spinocerebellar degeneration type 8, spinocerebellar degeneration type 9, autosomal recessive spinocerebellar degeneration type 3, autosomal recessive spinocerebellar degeneration type 4, autosomal recessive spinocerebellar degeneration type 5, autosomal recessive spinocerebellar degeneration type 6, autosomal recessive spinocerebellar degeneration type 7, autosomal recessive spinocerebellar degeneration type 8, spinocerebellar degeneration type 6, spinocerebellar degeneration associated with axonal neuropathy type 1, spinocerebellar degeneration associated with dysmorphism, X-linked spinocerebellar degeneration type 2, X-linked spinocerebellar degeneration type 3, X-linked spinocerebellar degeneration type 4, spinocerebellar degeneration and corneal dystrophy, split hand muscular atrophy and split spinal cord urinary anomalies, split spinal cord malformation, congenital vertebral end malformation, SRD5A3-CDG (CDG-Iq), SSR4-CDG, STAC3 disorder, status epilepticus, Steinfeld syndrome, stiff person syndrome, Stocco dos Santos syndrome, juvenile-onset striatonigral degeneration, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical band heterotopia, subependymal giant cell astrocytoma, subependymal tumor, succinic semialdehyde dehydrogenase deficiency, Susac syndrome, Symmetrical thalamic calcifications, X-linked intellectual disability syndrome type 7, Tangier disease, TANGO2-related metabolic encephalopathy and arrhythmia, Talbot cyst, Tay-Sachs disease, TelHashomer's thumb sign syndrome, Ter Haar Sugar Yeger syndrome, Temple syndrome, Temple-Baraitser syndrome, temporal lobe epilepsy, Temtamy syndrome, spinal cord tethering syndrome, thoracic dysplasia hydrocephalus syndrome, thoracic outlet syndrome, thyrotoxic periodic paralysis, TMEM165-CDG (CDG-IIk), Toriello-Carey syndrome, Tourette syndrome, toxic neuritis (e.g., alcoholic neuropathy, chemotherapy-induced peripheral neuropathy), Tranebjaerg Svejgaard syndrome, transverse myelitis, trichinosis, trichorhinophalangeal syndrome type 2, trigeminal neuralgia, triosephosphate isomerase deficiency, triple A syndrome, Troyer syndrome, tuberous sclerosis complex, tubular aggregate myopathy, tumefactive multiple sclerosis, typical congenital nemaline myopathy, tyrosine hydroxylase deficiency, tyrosinemia type 1, Ullrich congenital muscular dystrophy, Unverricht-Lundborg disease, Van Benthem-Driessen-Hanveld syndrome, Van den Bosch syndrome, variant Creutzfeldt-Jakob disease, variegate porphyria, vasculitic neuropathy, vein of Galen aneurysm, Vici syndrome, Viljoen Kallis Voges syndrome, vincristine-induced neuropathy, snow blindness syndrome, vitamin B6-induced neuropathy, VLCAD deficiency, Vogt-Koyanagi-Harada disease, von Hippel-Lindau disease, Walker-Warburg syndrome, Weber syndrome, Welander distal myopathy, Wernicke-Korsakoff syndrome, West syndrome, Whipple's disease, white matter hypoplasia-corpus callosum agenesis-intellectual disabilitysyndrome), Wiedemann Oldigs Oppermann syndrome, Williams syndrome, Wilson disease, Wilson-Turner syndrome, Wolf-Hirschhorn syndrome, Wolman disease, Woodhouse-Sakati syndrome, Oster-Drought syndrome, Wrinkly skin syndrome, Wyburn-Mason syndrome, xeroderma pigmentosum, Sia-Gibbs syndrome, XK aprosencephaly, X-linked adrenoleukodystrophy, X-linked Charcot-Marie-Tooth disease type 1, X-linked Charcot-Marie-Tooth disease type 1A, X-linked Charcot-Marie-Tooth disease type 2, X-linked Charcot-Marie-Tooth disease type 3, X-linked Charcot-Marie-Tooth disease type 4, X-linked Charcot-Marie-Tooth disease type 5, X-linked Charcot-Marie-Tooth disease type 6, X-linked complicated corpus callosum agenesis, X-linked complicated spastic paraplegia type 1, X-linked creatine deficiency, X-linked dystonia-parkinsonism (Lubag) syndrome, X-linked hereditary sensory and autonomic neuropathy with deafness, X-linked intellectual disability-complicated corpus callosum agenesis -spastic quadriplegia, X-linked intellectual disability-short stature-obesity syndrome (Najm type), X-linked intellectual disability (Schimke type), Siderius X-linked intellectual disability, Turner X-linked intellectual disability, X-linked intellectual disability-malformation-cerebral atrophy syndrome, X-linked intellectual disability-torticollis syndrome, X-linked lissencephaly with genital anomalies, X-linked myopathy with excessive autophagy, X-linked myotubular myopathy, X-linked nonspecific intellectual disability, X-linked periventricular heterotopic gray matter, X-linked skeletal dysplasia-intellectual disability syndrome, Zechi Ceide syndrome It is a disease or disorder selected from the group consisting of Hou syndrome, Zellweger syndrome, and ZTTK syndrome. In some embodiments, the disease or disorder of the nervous system is a mental disorder. In some embodiments, the disease or disorder of the nervous system is a disease or disorder classified according to DSM-V (American Psychiatric Association, & American Psychiatric Association, 2013, Diagnostic and statistical manual of mental disorders: DSM-5. Arlington, VA). In some embodiments, the disease or disorder of the nervous system is a disease or disorder of the central nervous system. In some embodiments, the disease or disorder of the nervous system is an inflammatory disease or disorder of the nervous system. In some embodiments, the disease or disorder of the nervous system described herein is a disease or disorder selected from the group consisting of dementia, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, ataxia telangiectasia, multiple system atrophy, progressive supranuclear palsy, Krabbe disease, agenesis of the corpus callosum associated with peripheral neuropathy, Duchenne muscular dystrophy, Guillain-Barré syndrome, Charcot-Marie-Tooth disease type 1A, hereditary pressure susceptibility neuropathy, diabetic neuropathy, toxic neuropathy, age-related peripheral neuropathy, epilepsy, sleep disorder, encephalopathy, and neuropathic pain. In some embodiments, the disease or disorder of the nervous system is a neurodegenerative disease or disorder. 【0059】 In some embodiments, the disease or disorder of the nervous system described herein is a toxin and / or drug-induced neuropathy. In some embodiments, the drug-induced neuropathy described herein is induced, partially induced, or suspected of being induced by at least one agent selected from the group consisting of chemotherapeutic agents, TNFα inhibitors, antiretroviral agents, heart drugs, statins, and antibiotics. 【0060】 In some embodiments, the drug-induced neuropathy described herein is induced, partially induced, or suspected of being induced by at least one agent selected from the group consisting of thalidomide, disulfiram, pyridoxine, cortisol, phenytoin, lithium, chloroquine, hydroxychloroquine, cisplatin, oxaliplatin, taxane, vinca alkaloid, bortezomib, suramin, misonidazole, infliximab, etanercept, zalcitabine, didanosine, stavudine, amiodarone, perhexiline, metronidazole, dapsone, podophyllin, fluoroquinolone, isoniazid, and nitrofurantoin. 【0061】 In certain embodiments, the nervous system disease or disorder described herein is a disease or disorder of the peripheral nervous system. 【0062】 In some embodiments, the toxin-induced neuropathy described herein is induced, partially induced, or suspected of being induced by at least one agent selected from the group consisting of organic solvents, heavy metals, and organophosphoric acid esters. 【0063】 In some embodiments, the toxin and / or drug-induced neuropathy described herein is induced, partially induced, or suspected of being induced by alcohol and / or tobacco smoke. 【0064】 In some embodiments, the toxin and / or drug-induced neuropathy described herein is characterized by at least one selected from the group consisting of dorsal root ganglion toxicity, microtubule axonal transport dysfunction, voltage-dependence abnormality, sodium channel abnormality, and demyelination. 【0065】 The inventors have found that AAT can reduce neuropathic pathways (Figs. 2-4, Tables 1-10). This reduction of neuropathic pathways is observed in resting cells (Fig. 4B) and stimulated cells (Fig. 4C) and is thus useful for preventing and / or treating nervous system diseases or disorders and their symptoms. 【0066】 Thus, the effect of the combination of AAT and IgG antibodies in providing immunomodulatory, anti-inflammatory, and neuroprotective / regenerative effects in diseases and disorders of the nervous system is beyond the expectation of those skilled in the art. 【0067】 Accordingly, the present invention is based at least in part on the finding that combining AAT activity with IgG antibody activity is useful for treating the nervous system diseases or disorders described herein. 【0068】 In one embodiment, the present invention relates to a pharmaceutical composition for use in the treatment of a nervous system disease or disorder, comprising: i) a) an alpha1-antitrypsin (AAT) protein having protease inhibitory activity, variants, isoforms and / or fragments thereof, and / or b) a nucleic acid encoding an AAT having protease inhibitory activity, variants, isoforms and / or fragments thereof; iii) a plurality of IgG antibodies, isoforms thereof, fragments thereof, and / or IgG variants; and ii) at least one pharmaceutically acceptable carrier. 【0069】 In some embodiments, the pharmaceutically acceptable carrier described herein is a pharmaceutically acceptable diluent or carrier. 【0070】 "Pharmaceutically acceptable diluent or carrier" generally means a carrier or diluent that is safe, non-toxic, and useful for preparing a desired pharmaceutical composition, and includes carriers or diluents acceptable for human pharmaceutical use. 【0071】 Such pharmaceutically acceptable carriers can be sterile liquids (e.g., including water and oils (oils of petroleum origin, animal origin, plant origin or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.))). When the pharmaceutical composition is administered intravenously, water is a preferred carrier. Physiological saline and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injections. 【0072】 Examples of pharmaceutically acceptable diluents or carriers include starch, glucose, lactose, sucrose, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. 【0073】 The pharmaceutical composition may further contain one or more pharmaceutically acceptable salts such as mineral acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, and salts of organic acids such as acetate, propionate, malonate, benzoate, and the like. Further, auxiliary substances such as wetting agents or emulsifiers, pH buffering substances, gels or gelling materials, flavoring agents, coloring agents, microspheres, polymers, suspending agents, etc. may also be present herein. Further, especially when the dosage form is in a reconstitutable form, one or more other conventional pharmaceutical components such as preservatives, wetting agents, suspending agents, surfactants, antioxidants, anti-caking agents, fillers, chelating agents, coating agents, chemical stabilizers, etc. may also be present. Suitable exemplary components include microcrystalline cellulose, carboxymethyl cellulose sodium, polysorbate 80, phenylethyl alcohol, chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, parabens, ethyl vanillin, glycerol, phenol, parachlorophenol, gelatin, albumin, and combinations thereof. For a thorough discussion of pharmaceutically acceptable excipients, see REMINGTON’S PHARMACEUTICAL SCIENCES (Mack Pub. Co., N.J. 1991), which is incorporated herein by reference. 【0074】 In some embodiments, the pharmaceutically acceptable carriers described herein are agents (e.g., molecules or cells) that improve the drug delivery properties of the agents for use in the present invention. In some embodiments, the drug delivery properties described herein include at least one property selected from the group consisting of penetration ability (e.g., cell membrane and / or blood-brain barrier), site-specific delivery (e.g., brain-specific delivery), controlled release delivery, and stability (e.g., reduction of enzymatic degradation). In some embodiments, the pharmaceutical carriers described herein are agents selected from the group consisting of delivery cells, liposomes, nanoparticles, fusion proteins, niosomes, nanospheres, micelles, nanocapsules, nanoshells, lipid particles, and dendrimers. 【0075】 In one embodiment, the present invention is a method of treatment comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of an AAT protein and / or a nucleic acid encoding AAT, wherein the subject is suffering from a disease or disorder of the nervous system and the subject has received a therapy comprising administration of a plurality of IgG antibodies, isoforms thereof, fragments thereof, and / or IgG variants. 【0076】 An “effective amount” of an agent, e.g., a therapeutic agent, refers to an amount effective at dosages and for periods of time necessary to achieve the desired therapeutic or prophylactic result. Further, an effective amount may depend upon individual characteristics of the patient including medical history, age, weight, family history, genetic constitution, stage of an autoimmune disease related to the thyroid, if any, type of prior or concurrent treatment, and other individual characteristics of the subject being treated. 【0077】 In some cases, an effective amount of the composition / compound / product described herein can be any amount that reduces the severity or occurrence of symptoms of the disease, disorder, and / or condition being treated without causing significant toxicity to the subject. In some cases, an effective amount of the composition / compound / product described herein can be any amount that reduces the number of diseased cells, autoantibodies, and / or other disease markers (e.g., cytokines) in the subject without causing significant toxicity to the subject. 【0078】 As used herein, the terms "subject" / "subject in need thereof" or "patient" / "patient in need thereof" are well recognized in the art and are used interchangeably herein to refer to mammals including dogs, cats, rats, mice, monkeys, cows, horses, goats, sheep, pigs, camels, and most preferably humans. In some cases, the subject is a subject in need of treatment or a subject having a disease or disorder. In some embodiments, the subject to be treated is a subject over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 12 years old, preferably over 1 year old. According to certain embodiments, the subject is selected from the group consisting of prepubertal children, prepubertal adolescents, adolescents, and adults. In some embodiments, the subject to be treated is female. 【0079】 In one embodiment, the present invention is a method of treatment comprising administering to a subject a pharmaceutical composition comprising an effective amount of a plurality of IgG antibodies, isotypes, fragments, and / or IgG variants thereof, wherein the subject is suffering from a disease or disorder of the nervous system and the subject has received a therapy comprising administration of AAT protein and / or a nucleic acid encoding AAT. 【0080】 In certain embodiments, the present invention relates to a kit for use of the present invention, wherein the disease or disorder of the nervous system is chronic inflammatory demyelinating polyneuropathy. 【0081】 In certain embodiments, the present invention relates to a pharmaceutical composition for use of the present invention, wherein the disease or disorder of the nervous system is chronic inflammatory demyelinating polyneuropathy. 【0082】 In one embodiment, the present invention relates to a method of treatment of the present invention, wherein the disease or disorder of the nervous system is chronic inflammatory demyelinating polyneuropathy. 【0083】 In certain embodiments, the present invention relates to a medicament for use of the present invention, wherein the subject to be treated has at least one symptom of chronic inflammatory demyelinating polyneuropathy or a medical history of at least one symptom of chronic inflammatory demyelinating polyneuropathy. 【0084】 In certain embodiments, the present invention relates to a kit for use of the present invention, wherein the subject to be treated has at least one symptom of chronic inflammatory demyelinating polyneuropathy or a medical history of at least one symptom of chronic inflammatory demyelinating polyneuropathy. 【0085】 In certain embodiments, the present invention relates to a pharmaceutical composition for use of the present invention, wherein the subject to be treated has at least one symptom of chronic inflammatory demyelinating polyneuropathy or a medical history of at least one symptom of chronic inflammatory demyelinating polyneuropathy. 【0086】 In certain embodiments, the present invention relates to a method of treatment of the present invention, wherein the subject to be treated has at least one symptom of chronic inflammatory demyelinating polyneuropathy or a medical history of at least one symptom of chronic inflammatory demyelinating polyneuropathy. 【0087】 As used herein, the term "symptom of chronic inflammatory demyelinating polyneuropathy" refers to at least one symptom selected from the group consisting of decreased or absent deep tendon reflexes, sensory ataxia, weakness, paralysis, paresthesia, pain, gait difficulty, proximal muscle weakness of the extremities, and distal muscle weakness of the extremities. 【0088】 In certain embodiments, the present invention relates to a kit for use of the present invention, wherein the plurality of IgG antibodies, their isotypes, their fragments, and / or IgG variants are recombinant IgG antibodies, their isotypes, their fragments, and / or IgG variants. 【0089】 In certain embodiments, the present invention relates to a pharmaceutical composition for use of the present invention, wherein the plurality of IgG antibodies, their isotypes, their fragments, and / or IgG variants are recombinant IgG antibodies, their isotypes, their fragments, and / or IgG variants. 【0090】 In certain embodiments, the present invention relates to a method of treatment of the invention, wherein the plurality of IgG antibodies, their isotypes, their fragments, and / or IgG variants are plasma-derived IgG antibodies, their isotypes, their fragments, and / or IgG variants. 【0091】 In certain embodiments, the present invention relates to a kit for use of the invention, wherein the plurality of IgG antibodies, their isotypes, their fragments, and / or IgG variants are recombinant IgG antibodies, their isotypes, their fragments, and / or IgG variants. 【0092】 In certain embodiments, the present invention relates to a pharmaceutical composition for use of the invention, wherein the plurality of IgG antibodies, their isotypes, their fragments, and / or IgG variants are recombinant IgG antibodies, their isotypes, their fragments, and / or IgG variants. 【0093】 In certain embodiments, the present invention relates to a method of treatment of the invention, wherein the plurality of IgG antibodies, their isotypes, their fragments, and / or IgG variants are recombinant IgG antibodies, their isotypes, their fragments, and / or IgG variants. 【0094】 In certain embodiments, the present invention relates to a kit for use of the invention, wherein the IgG antibody, its isotype, its fragment, and / or IgG variant is formulated for intravenous administration. 【0095】 In certain embodiments, the present invention relates to a pharmaceutical composition for use of the invention, wherein the IgG antibody, its isotype, its fragment, and / or IgG variant is formulated for intravenous administration. 【0096】 In certain embodiments, the present invention relates to a method of treatment of the invention, wherein the IgG antibody, its isotype, its fragment, and / or IgG variant is formulated for intravenous administration. 【0097】 In certain embodiments, the present invention relates to a kit for use of the present invention, in which an IgG antibody, its isotype, its fragment, and / or an IgG variant are formulated for subcutaneous administration. 【0098】 In certain embodiments, the present invention relates to a pharmaceutical composition for use of the present invention, in which an IgG antibody, its isotype, its fragment, and / or an IgG variant are formulated for subcutaneous administration. 【0099】 In certain embodiments, the present invention relates to a method of treatment of the present invention, in which an IgG antibody, its isotype, its fragment, and / or an IgG variant are formulated for subcutaneous administration. 【0100】 In certain embodiments, the present invention relates to a medicament for use of the present invention, in which the AAT protein is recombinant AAT. 【0101】 In certain embodiments, the present invention relates to a kit for use of the present invention, in which the AAT protein is recombinant AAT. 【0102】 In certain embodiments, the present invention relates to a pharmaceutical composition for use of the present invention, in which the AAT protein is recombinant AAT. 【0103】 In certain embodiments, the present invention relates to a method of treatment of the present invention, in which the AAT protein is recombinant AAT. 【0104】 In certain embodiments, the present invention relates to a medicament for use of the present invention, in which the AAT protein is plasma-derived AAT. 【0105】 In certain embodiments, the present invention relates to a kit for use of the present invention, in which the AAT protein is plasma-derived AAT. 【0106】 In certain embodiments, the present invention relates to a pharmaceutical composition for use of the present invention, in which the AAT protein is plasma-derived AAT. 【0107】 In certain embodiments, the invention relates to a method of treatment of the invention wherein the AAT protein is plasma-derived AAT. 【0108】 In certain embodiments, the invention relates to a pharmaceutical for use of the invention, wherein a) an alpha1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof having inhibitory activity, and / or b) a nucleic acid encoding AAT, variants, isoforms and / or fragments thereof having ADAM17 inhibitory activity, are formulated for intravenous administration. 【0109】 In certain embodiments, the invention relates to a kit of parts for use of the invention, wherein a) an alpha1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof having inhibitory activity, and / or b) a nucleic acid encoding AAT, variants, isoforms and / or fragments thereof having ADAM17 inhibitory activity, are formulated for intravenous administration. 【0110】 In certain embodiments, the invention relates to a pharmaceutical composition for use of the invention, wherein a) an alpha1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof having inhibitory activity, and / or b) a nucleic acid encoding AAT, variants, isoforms and / or fragments thereof having ADAM17 inhibitory activity, are formulated for intravenous administration. 【0111】 In certain embodiments, the invention relates to a method of treatment of the invention, wherein a) an alpha1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof having inhibitory activity, and / or b) a nucleic acid encoding AAT, variants, isoforms and / or fragments thereof having ADAM17 inhibitory activity, are formulated for intravenous administration. 【0112】 In certain embodiments, the present invention relates to a pharmaceutical for use in the present invention, wherein a) an alpha1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having inhibitory activity, and / or b) a nucleic acid encoding AAT having ADAM17 inhibitory activity, its variants, isoforms and / or fragments are formulated for subcutaneous administration. 【0113】 In certain embodiments, the present invention relates to a kit of parts for use in the present invention, wherein a) an alpha1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having inhibitory activity, and / or b) a nucleic acid encoding AAT having ADAM17 inhibitory activity, its variants, isoforms and / or fragments are formulated for subcutaneous administration. 【0114】 In certain embodiments, the present invention relates to a pharmaceutical composition for use in the present invention, wherein a) an alpha1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having inhibitory activity, and / or b) a nucleic acid encoding AAT having ADAM17 inhibitory activity, its variants, isoforms and / or fragments are formulated for subcutaneous administration. 【0115】 In certain embodiments, the present invention relates to a method of treatment of the present invention, wherein a) an alpha1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having inhibitory activity, and / or b) a nucleic acid encoding AAT having ADAM17 inhibitory activity, its variants, isoforms and / or fragments are formulated for subcutaneous administration. 【0116】 The present invention also contemplates a gene delivery vector encoding AAT (or an isoform, fragment or variant thereof), and a pharmaceutical composition comprising the same. The gene delivery vector can be used for any of the therapeutic uses described herein. Preferably, the gene delivery vector is in the form of a plasmid or vector comprising one or more nucleic acids encoding the AAT protein, variants, isoforms, and / or fragments of the present invention. Examples of gene delivery vectors include, for example, viral vectors, non-viral vectors, particulate carriers, and liposomes. Gene delivery is preferably performed in vitro or ex vivo. 【0117】 The kits, pharmaceutical compositions and / or medicaments of the present invention can be administered to a subject by different routes including oral, parenteral, sublingual, transdermal, rectal, transmucosal, topical, inhalation, buccal, intrapleural, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intranasal, intrathecal, and intraarticular, or combinations thereof. For use in humans, the compositions can be administered as a pharmaceutically acceptable formulation in accordance with normal human practices. One of ordinary skill in the art will readily determine the most suitable dosing schedule and route of administration for a particular patient. The kits, pharmaceutical compositions and / or products of the present invention can be administered by conventional syringes, needleless injection devices, "microprojectile bombardment gone gun", or other physical methods such as electroporation ("EP"), "hydrodynamic methods" or ultrasound. The compositions can also be administered by intravenous injection, intravenous infusion, infusion using a dosing pump, inhaled nasal spray, eye drops, skin patches, sustained release formulations, ex vivo gene therapy or ex vivo cell therapy, preferably by intravenous injection. 【0118】 The pharmaceutical composition of the present invention can also be delivered to a patient by several techniques including DNA injection (also called DNA vaccination) of a nucleic acid encoding the AAT protein, its variants, isoforms and / or fragments of the present invention, by in vivo electroporation, liposome-mediated, nanoparticle-facilitated, using recombinant vectors such as recombinant lentivirus, recombinant adenovirus, and recombinant adeno-associated virus described herein, or without using them. 【0119】 All definitions and combinations provided herein apply to these embodiments where applicable and unless otherwise indicated. 【0120】 Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, but suitable methods and / or materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided only for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the materials, methods, and examples are illustrative only and not intended to be limiting. 【0121】 In case of conflict, the patent specification, including definitions, will control. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this specification belongs. When used herein, the following definitions are provided to facilitate understanding of the present invention. 【0122】 The term "about" means, with respect to a given amount, including a deviation of ±20 percent, preferably 10 percent, preferably 5 percent, more preferably 2 percent, and most preferably 1 percent. 【0123】 As used in this specification and the claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. 【0124】 As used herein, "at least one" means "one or more", "two or more", "three or more", etc. 【0125】 "Or" should be understood to mean any one of the alternatives, both, or any combination thereof. 【0126】 "And / or" should be understood to mean either or both of the alternatives. 【0127】 Throughout this specification, unless the context requires otherwise, the words "comprise", "comprises", and "comprising" are understood to imply the inclusion of the stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements. 【0128】 The terms "include" and "comprise" are used synonymously. "Preferably" means one of a series of alternatives that does not exclude other alternatives. "E.g." means one example not limited to the example(s) mentioned. "Consisting of" means that what follows the phrase "consisting of" includes and is limited to only what is specified. 【0129】 Throughout this specification, references to "one embodiment", "an embodiment", "a particular embodiment", "related embodiments", "a particular embodiment", "additional embodiments", "some embodiments", "specific embodiments", or "further embodiments", or combinations thereof, mean that the particular features, structures, or characteristics described in connection with the embodiment are included in at least one embodiment of the present invention. Thus, appearances of the foregoing phrases in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. It is also understood that a clear description of a feature in one embodiment may serve as a basis for excluding the feature in a particular embodiment. 【0130】 Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and / or materials are described below. In case of conflict, the present patent specification, including definitions, will apply. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. 【0131】 The general methods and techniques described herein can be carried out according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification unless otherwise indicated. See, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989) and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992), as well as Harlow and Lane Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1990). 【0132】 Embodiments of the present invention are illustrated and described in detail in the drawings and the foregoing description, which should be considered illustrative or exemplary and not limiting. It is understood that changes and modifications can be made by those skilled in the art within the scope and spirit of the following claims. In particular, the present invention encompasses further embodiments having any combination of features from the different embodiments described above and below. 【Brief Description of the Drawings】 【0133】 【Figure 1】 IFNγ-mediated microglial activation 【Figure 2】 AAT reduces IFNγ-mediated microglial activation 【Figure 3】 Verification of the anti-inflammatory effect of AAT on the experiments used for RNAseq 【Figure 4-1】 Verification of microglial activation and anti-inflammatory effect of AAT by GSEA analysis 【Figure 4-2】 Verification of microglial activation and anti-inflammatory effect of AAT by GSEA analysis 【Figure 5】 AAT (Sigma Aldrich, batch A6150) inhibits TACE activity in a cell-free assay, shown as relative fluorescence units (A) or as a percentage of control activity having an IC50 (C) of 15.3 μM (B). 【Figure 6】 Results of sciatic nerve electrophysiology (EMG) (A) Amplitude (B) Conduction velocity 【Figure 7】 Results of grip strength test (A) Absolute value, (B) % at 6 weeks 【Figure 8】 Results of rotarod test (A) Absolute value, (B) % at 6 weeks 【Figure 9】 DNAJB9 and PLA2G4B gene expression in response to AAT treatment 【Figure 10】 Axon number 【Figure 11】 Axon diameter 【Figure 12】 g ratio 【Figure 13】 Individual histological images of semi-thin sections of the sciatic nerve. Scale bar 10 μm A) Group 1: WT control, B) CMT1A + vehicle, C) CMT1A + AAT 【Figure 14】 Plasma IL-6 concentration 【Figure 15】 Plasma TNFα concentration 【Figure 16】 Study scheme of CMT1A mouse model and AAT administration 【Figure 17】 Cell morphology and cell number after treatment: Morphological analysis and cell number of SH-SY5Y after 6-OHDA administration and AAT treatment. Bright field photographs (20x) and cell number (D0 vs D4 of culture) show the SH-SY5Y cell phenotype and proliferation and the effect of treatment on the positive action of AAT. A) Example of image B) Quantification 【Figure 18】 Cell viability: The graph represents cell viability measured through absorbance (450 nm) for control and samples 【Figure 19】 Quantification of IL-6 in cell supernatant 【Figure 20】 Study scheme 【Figure 21】Neuromuscular tests: A Rotarod latency, B Grip strength, C von Frey test 【Figure 22】 Electrophysiology of the sciatic nerve: A Compound muscle action potential, B Nerve conduction velocity 【Figure 23】 A) Graphical representation of plasma TMPRSS5 B) Graphical representation of plasma NfL concentration 【Figure 24】 Graphical representation of plasma TNFα concentration 【Figure 25】 Rotarod latency until fall of CMT mice treated with AAT (180 mg / kg sc) 【Figure 26】 Grip strength (Newton) of CMT mice treated with AAT (180 mg / kg sc) 【Figure 27】 CMAP (mV) of CMT mice treated with AAT (180 mg / kg sc) 【Figure 28】 NCV (m / s) of CMT mice treated with AAT (180 mg / kg sc) 【Figure 29】 Plasma IL-6 concentration 【Figure 30】 Plasma TNFα concentration 【Figure 31】 Effect of peptide 8 on ADAM17 activity. (***, ****: P < 0.001, P < 0.0001, one-way ANOVA (multiple comparisons), ns = not significant compared to DMSO 【Figure 32】 Effect of AAT on gene expression of the NF-κB pathway after TNFα-dependent activation of Schwann cells 【Figure 33】 Effect of AAT on gene expression related to the oxidative stress response after TNFα-dependent activation of Schwann cells 【Figure 34】 Effect of AAT on gene expression related to the NRF2-related oxidative stress response after TNFα-dependent activation of Schwann cells 【Figure 35】 Effect of AAT and its derivative peptides on TNF-induced Schwann cells 【Figure 36】 Axon number / 100μm2 【Figure 37】 Axon diameter 【Figure 38】 g-ratio 【Figure 39-1】 A) Axon number / 100 μm2 B) Axon diameter and C) g-ratio 【Figure 39-2】 A) Axon number / 100 μm2 B) Axon diameter and C) g-ratio 【Figure 40】 Plasma NfL concentration 【Figure 41】 Effect of AAT and its derivative peptides in IFNγ-induced microglia 【Figure 42】 Synthesis of peptides #8 and #9 (Synthesis: Syro-1 automatic peptide synthesizer, double coupling conditions: DIC (4 equivalents) / Oxyma (4 equivalents), 40 minutes, HATU (4 equivalents) / DIPEA (8 equivalents), 30 minutes, deprotection: 40% piperidine in DMF, 3 minutes and 20% piperidine in DMF, 12 minutes) 【Figure 43】 Synthesis of peptide mimetic #14 (Synthesis: manual synthesis, coupling conditions: DIC (3 equivalents) / Oxyma (3 equivalents), 2 hours, deprotection: 20% piperidine in DMF, 5 minutes. 20% piperidine in DMF, 20 minutes) 【Example】 【0134】 Those skilled in the art will understand that the invention described herein can be subject to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from its spirit or essential characteristics. The invention also includes all of the steps, features, compositions, and compounds individually or collectively referred to or shown herein, as well as any combination or any two or more of these steps or features. Accordingly, this disclosure is to be considered in all of its exemplary embodiments as non-limiting, and the scope of the invention is indicated by the appended claims, and all changes that come within the meaning and range of equivalents are intended to be embraced therein. Various references have been cited throughout this specification, each of which is incorporated herein by reference in its entirety. The foregoing description will be more fully understood with reference to the following examples. 【0135】 Example 1 A) Human microglial cell HMC3-MHCII Luc The cells were seeded on day 0, activated with IFNγ from day 1 to day 2, and the luciferase activity and cell viability were measured on day 4. 【0136】 B) Activation was measured by the activity of MHCII-promoter luciferase and normalized to cell viability. The luciferase activity for all conditions was expressed as a fold of the untreated control. The potential effects of the highest concentration of the buffer used for drug presentation (IFNγ, AAT) were excluded. All conditions were performed in triplicate, and the error bars represent the standard deviation (Figure 1). 【0137】 Example 2 A) Human microglia HMC3-MHCII Luc and HMC3-MHCII Luc , Ubi AAT The cells were seeded on day 0, IFNγ was presented from day 1 to day 2, and the luciferase activity and cell viability were measured on day 4. 【0138】 B) AAT was applied to HMC3-MHCII Luc cells from day 0 to day 4. Activation was measured by the activity of MHCII-promoter luciferase and normalized to cell viability. The luciferase activity for all conditions was expressed as a percentage of the IFNγ control. All conditions were performed in triplicate, and the error bars represent the standard deviation. (Figure 2) 【0139】 Example 3 A) Human microglia HMC3-MHCII Luc The cells were seeded on day 0, IFNγ was presented from day 1 to day 2, and the luciferase activity and cell viability were measured on day 4. 【0140】 B) AAT was applied to HMC3-MHCII LucIt was applied to cells. Activation was measured by the activity of MHCII-promoter luciferase and represented as a percentage of the IFNγ control for all conditions. All conditions were performed in triplicate, and error bars represent standard deviation. 【0141】 C) Bulk RNA extraction was performed on the same HMC3-MHCII Luc cultures. Prior to sequencing, quality control (QC) was applied to the RNA. QC for sequencing was performed prior to mapping to the human genome. Mapped reads were counted, and differential gene expression between conditions was measured (see Tables 1-10). (Figure 3) 【0142】 Example 4 RNAseq data from plasma-derived AAT and recombinant AAT were pooled, normalized, and analyzed by Gene Set Enrichment Analysis (GSEA) (https: / / www.gsea-msigdb.org / gsea / index.jsp; Subramanian, A., et al. Proc. Natl. Acad. Sci. USA, 102(43):15545-15550, 2005.). Upregulated gene families (gray bars) and downregulated ones (black bars) are shown according to the normalized enrichment score. 【0143】 A) The inflammatory profile induced by IFNγ was confirmed by the upregulation of several processes related to inflammation (bold italic). 【0144】 B-C) Treatment with AAT in the absence (B) or presence (C) of IFNγ was able to significantly downregulate some of these pathways (bold italic). Importantly, both IFNγ and the inflammatory response were attenuated by AAT. However, the downregulation of inflammatory response genes in (C) was of borderline significance. 【0145】 Regarding other gene families, KRAS signaling is important because it is involved in the carcinogenic process and immune regulation (Dias Carvalho, P., et al., 2018, Cancer Res, 78:7-14). Similarly, the p53 pathway is noted as a mediator of the response to stress. (Figure 4) 【0146】 Example 5 AAT treatment equalizes the expression of inflammatory genes. 【0147】 Table of genes related to antigen presentation (Table 1), cytokine signaling (Table 2), interferon signaling (Table 3) and complement activation (Table 4). Inflammatory top genes (FC>2, p-value<0.05, left column) were defined by differential expression between untreated cells and IFNγ-treated cells (inflammation, middle column). Top genes significantly and oppositely regulated by AAT treatment are highlighted (right column, bold underline). 【0148】 A significant number (about 35%) of inflammatory top genes were found to be affected by AAT treatment (6 out of 23 genes related to antigen presentation, 14 out of 33 genes related to cytokine signaling, 1 out of 7 genes related to complement activation, 5 out of 13 genes related to interferon signaling), indicating its anti-inflammatory ability. For example, HLA-DRA gene promoter used as a promoter for luciferase expression in the HMC3-MHCII Luc strain was consistently upregulated and downregulated, respectively, in inflammation and using AAT treatment (bold italic). Notably, the FC shown in the AAT-treated inflammatory state should not be directly compared to that found in inflammation. Because for the former, FC = 2 already indicates 50% equalization for inflammation-inducing / suppressing genes. 【0149】 The second inflammatory gene that is significantly and oppositely regulated by AAT treatment in the inflammatory or quiescent state (regulated in AAT) (p-value < 0.05, FC < 2) is shown at the bottom of the table. (Figure 5) 【0150】 【Table 1】 【0151】 【Table 2-1】 【0152】 【Table 2-2】 【0153】 【Table 3】 【0154】 【Table 4】 【0155】 Example 6 - AAT treatment enhances the expression of characteristic genes related to M2 anti-inflammatory microglia M2 microglia gene expression is promoted after M2 induction (FC study; Satoh 2017). AAT treatment in resting microglia (FC AAT) and activated microglia (FC inflammation + AAT) was able to enhance the expression of M2 genes as well, although to a lower extent. Approximately 60% of the modified genes were common among AAT treatment conditions (Table 5, bold). 【0156】 【Table 5-1】 【0157】 【Table 5-2】 【0158】 Example 7 - AAT treatment affects the expression of neurodegenerative disease risk genes Risk genes associated with PD (21 genes), AD (15 genes), MS (53 genes), MCT (50 genes), PN (88 genes) and GBS (30 genes, FC) were extracted from public libraries (Timmerman, V., AV Strickland, and S. Zuchner. 2014., Genes (Basel), 5:13-32; Parnell, GP, and DR Booth. 2017. Front Immunol, 8:425; Nikolac Perkovic, M., and N. Pivac. 2019. Adv Exp Med Biol, 1192:27-52; Blauwendraat, C., MANalls, and ABSingleton. 2020. Lancet Neurol, 19:170-78.) and their expression in AAT-treated resting microglia (FC AAT) and activated microglia (FC inflammation+AAT) was assessed. Commonly altered genes among AAT-treated conditions are highlighted (bold underlined). Notably, the expression of several risk genes in all the above diseases was altered by AAT. 【0159】 [Table 6] 【0160】 [Table 7] 【0161】 [Table 8] 【0162】 [Table 9] 【0163】 【Table 10】 【0164】 Example 8 Further experiments include CSF-1 treatment for optimization of the transition from (Mφ) to M1 macrophages, dose-dependence of IFNγ for M1 macrophage activation, AAT treatment for resting and IFNγ-activated macrophages, and RNA extraction and RNAseq and analysis. Thereby, the cells are human primary resting (Mφ) macrophages or M1 differentiated macrophages. The treatment includes a 24-hour pretreatment with AAT, followed by 24-hour cell activation (or inactivation) with CSF-1 or IFN in the presence of AAT. The cells are further treated with AAT for 48 hours, and finally, the culture supernatant is used to test for pro-inflammatory cytokine release (IL-6, TNFα, IL-1β, IL-8, multiplexed readout) or to test for luciferase activity (MHCII Luc strain), and at the same time RNA is extracted for microarray analysis. Cultures with consistent readouts for cytokine release or luciferase assay are used as samples for RNA extraction and microarray analysis. 【0165】 Experimental conditions: Each condition is performed in triplicate. - Untreated (no AAT, no CSF-1) resting macrophage control - IFNγ: Activated macrophage control - AAT (plasma-derived, Sigma or recombinant, Lonza): AAT effect on resting macrophages - IFNγ and AAT (plasma-derived, Sigma or Lonza): AAT anti-inflammatory effect on activated macrophages 【0166】 Output: - Resting state macrophage gene expression - Genes differentially regulated in a pro - inflammatory manner (fold change relative to untreated, significant p - value, up / down - regulation fold - change threshold) - Changes in AAT - promoting gene expression in resting and activated macrophages - Differences between recombinant AAT gene regulation and plasma - derived AAT gene regulation 【0167】 Methods Human microglial cell line culture HMC3 - MHCII encoding Renilla luciferase under the major histocompatibility complex II promoter (HLA - DRA) Luc The cell line has been described as a valuable tool for studying human microglial activation and was obtained from Professor Karl - Heinz Krause at the University of Geneva. It was transduced with a lentiviral vector to obtain HMC3 - MHCII Luc and Ubi AAT cell lines (see Figure 3). Both HMC3 - MHCII Luc and HMC3 - MHCII Luc and Ubi AAT cell lines were cultured on TC - treated cell culture dishes (CELLSTAR®, Greiner, 7.664160) in DMEM high glucose + glutamine (Gibco, 41965039) supplemented with 10% (v / v) fetal bovine serum (FBS, Gibco, 10270106) and 100 μg / ml penicillin / streptomycin (Pen / Strep, ThermoFisher, 15070063). The cultures were maintained at 37 °C in a 5% CO2 atmosphere. Sub - culturing was performed by quickly rinsing the cells in 1X PBS, trypsinizing them at room temperature for 3 minutes (Tryple Express, ThermoFisher, 12604021), followed by centrifugation (5 minutes, 1000 RPM), and resuspending them in the above - mentioned supplemented DMEM. The cells were counted and plated at the desired concentration. 【0168】 Human microglial cell line transduction The lentivirus encoding human AAT under the ubiquitin promoter and GFP under the human PGK promoter was obtained according to the protocol described in Marc Giry-Laterriere, Els Verhoeyen, and Patrick Salmon, 2011, Methods in molecular biology. Briefly, 4.5x10 6 HEK cells were plated in a φ100 mm dish and, 16 hours later, transfected with 15 μg of pCWXPG-UBI-SP::AAT, 10 μg of the packaging plasmid (psPAX2, a gift from Didier Trono [Addgene plasmid 12260]), and 5 μg of the envelope (pMD2G, a gift from Didier Trono [Addgene plasmid 12259]). Eight hours after transfection, the medium was changed. Forty-eight hours later, the virus supernatant was collected, filtered using a 45 μm PVDF filter, and stored at -80 °C. The virus titer was measured, and the HMC3-MHCII Luc , Ubi AAT cell lines in which approximately 100% and 50% of the cells express AAT were selected for the experimental conditions. 【0169】 IFNγ-Mediated Human Microglia Activation HMC3-MHCII Luc cell lines were seeded in 96-well plates at a density of approximately 2500 cells / well. Twenty-four hours later, their activation was induced by presenting IFNγ (Sigma, SRP3058) at various concentrations (0.1, 1, 10, or 100 ng / ml) for 24 hours. Next, IFNγ was removed, and the cells were cultured for 48 hours before being evaluated for cell viability and activation (see Figure 2). 【0170】 Exogenous / Endogenous AAT Treatment of IFNγ-Activated Human Microglia HMC3-MHCII Luc and HMC3-MHCII Luc , Ubi AAT(Endogenous AAT) cell lines were seeded in 96-well plates at a density of approximately 2500 cells / well. HMC3-MHCII Luc Cell lines were seeded, and after 3 hours, plasma-derived AAT and recombinant AAT (AAT 1 and AAT 2 produced in CHO cells) were added at various concentrations (1, 10, or 25 μM). After 24 hours, microglial activation was induced by a 24-hour IFNγ presentation (10 ng / ml) still in the presence of exogenous or endogenous AAT. Then, IFNγ was removed, and both HMC3-MHCII Luc and HMC3-MHCII Luc were removed, and Ubi AAT cells were cultured for 48 hours in the presence of exogenous or endogenous AAT, and then the cell culture was evaluated for cell viability and activation (see Figures 3 and 4). 【0171】 Measurement of human microglial cell viability and activation HMC3-MHCII Luc and HMC3-MHCII Luc , Ubi AAT The viability (Cell Counting Kit-8, Sigma, 96992) and activation (Renilla-Glo® Luciferase Assay System, Promega, E2710) of cell cultures were measured according to the manufacturer's protocol. 【0172】 RNA collection, sequencing, and differential expression analysis RNA extraction was achieved using the RNeasy Mini Kit (Qiagen) according to the manufacturer's protocol. RNA samples from plasma-derived AAT and recombinant AAT Nr.2 were checked for quality (2100 Bioanalyzer, Agilent), and libraries were prepared using the Truseq RNA Library Kit (Illumina, RS-122-2001). The libraries were sequenced (HiSeq 4000, Illumina), the quality of the sequencing was controlled (FastQC), reads were counted against the human genome (STAR v.2.7.0f; UCSC hg38), (HTSeq v0.9.1), and differential expression analysis was performed using the R / Bioconductor package (edgeR 1.30.1.). 【0173】 RNA collection, sequencing, and differential expression analysis Human monocyte-derived M1 macrophages (GM-CSF, PromoCell, C-12916) were cultured on fibronectin-coated cell culture dishes in M1-macrophage generation medium XF, activated with CSF-1 (50 ng / ml, Sigma, SRP3058) according to the manufacturer's protocol, and the cultures were maintained at 37 °C in a 5% CO2 atmosphere. 【0174】 Cytokine multiplex assay Cell culture supernatants were collected and measured for IL-6, TNFα, IL-1β, and IL-8 using a bead-based Luminex assay according to the manufacturer's protocol. 【0175】 Cell-free TACE / ADAM17 activity TACE activity and its inhibition by human AAT (AAT) were performed in a black 96-well immunoplate (437111, ThermoFisher Scientific) using a recombinant human TACE / ADAM17 kit (930-ADB and ES003, R&D Systems). The enzymatic activity of TACE / ADAM17 was measured by mixing 0.005 μg of rhTACE with 10 μM of the Mca-PLAQAV-Dpa-RSSS-NH2 fluorogenic peptide substrate III in assay buffer (25 mM Tris, 2.5 μM ZnCl2, 0.005% Brij-35 (w / v), pH 9.0) to a final volume of 100 μl. AAT (Sigma Aldrich, batch A6150) was resuspended in water (vehicle), and the control TACE / ADAM17 activity was evaluated in the presence of the vehicle (the amount used for 100 μM of AAT). AAT was added at different concentrations (0, 6.25, 12.5, 25, 50, and 100 μM) to evaluate its dose-dependent inhibition of TACE / ADAM17. All conditions were performed in triplicate. The activity was measured as relative fluorescent units (RFU) in kinetic mode (9 time points over 5 minutes) using a SpectraMax iD3 Microplate Reader (low PMT gain, 1 second exposure, top read at 1 mm, wavelength: excitation 320 nm, emission 405 nm). A bar graph as a percentage of the control activity was obtained by averaging the values obtained over 5 minutes for each condition. 【0176】 Animal As a mouse model of CMT1A, the inventors used C3-PMP22 transgenic mice (B6.Cg-Tg(PMP22)C3Fbas / J, The Jackson Laboratory) that express three copies of the wild-type human peripheral myelin protein 22 (PMP22) gene (Verhamme, Camiel, et al. Journal of Neuropathology & Experimental Neurology 70.5 (2011): 386-398). The mice were housed in macrolon cages with filter hoods in continuously air-filtered rooms to avoid contamination. During the experiment, a pair of animals were caged at a constant temperature on a 12 / 12-hour light / dark cycle. The animals were fed ad libitum (regulated tap water and nutrition). The animal protocol was approved by the Animal Experimentation Committee of Languedoc Roussillon. This protocol and laboratory procedures comply with French laws implementing the European Directive (reference number: D3417223, APAFIS#23920-2020020320279696v3). Only animals in good health condition entered the examination procedure, and the health condition of the animals was monitored daily to ensure tracking of the study. 【0177】 in vivo research paradigm The animals were divided into three groups (wild-type control (subcutaneous 0.9% NaCl), CMT 1A-vehicle (subcutaneous 0.9% NaCl), CMT 1A-human alpha-1 antitrypsin (subcutaneous, twice a day, 50 mg / kg per injection)), with three mice each (3-week-old males weighing 18±2.5 g at the start of the test). After acclimatizing all of them on-site for 7 days, they were subjected to the following protocol. 【0178】 Starting at 4 weeks of age, the animals were subjected to blood sampling for determination of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) levels as described in Figure 16. 【0179】 The plasma levels of AAT were evaluated every 5 days from the first day of treatment to the last day of treatment. 【0180】 On the first and last days of treatment, the neuromuscular performance of the animals was tested by rotarod test, grip strength test, and sciatic nerve electrophysiology test. After the last treatment at week 8, these tests were repeated, the animals were sacrificed, and the left sciatic nerve was harvested for histological evaluation of the number and size of neurons. 【0181】 Example 9 TACE activity is evaluated in kinetic mode, with or without different AAT concentrations, according to the manufacturer's instructions (recombinant human TACE / ADAM17 kit, 930 - ADB, R&D Systems). All conditions are performed in triplicate and shown as mean ± SD (Figure 5). 【0182】 Example 10 The most common type of CMT is CMT1A, which is characterized by a duplication of the PMP22 gene that results in the accumulation of the pmp22 protein in Schwann cells and progressive demyelination. PMP22 is a four-transmembrane glycoprotein contained in the compact myelin of the peripheral nervous system. Duplication of PMP22 has been associated with the onset of Charcot-Marie-Tooth disease type 1A (CMT1A). C3-PMP22 transgenic mice (B6.Cg-Tg(PMP22)C3Fbas / J) express three copies of the wild-type human peripheral myelin protein 22 (PMP22) gene. The cause-and-effect relationship between the additional PMP22 gene and CMT1A remains poorly understood and remains unclear to this day. Nevertheless, several compelling hypotheses are available to link the genetic abnormality, which is the duplication of the PMP22 gene, to the manifestation of the disease state. Without being bound by theory, overexpression of PMP22 can have a negative effect on myelin sheath formation in the peripheral nervous system (PNS). These mice exhibit an age-dependent demyelinating neuropathy characterized primarily by distal weakness and loss of sensation. C3-PMP mice do not show obvious clinical signs at 3 weeks and develop progressive observable neuromuscular disorders 4 weeks later. The mice have a stable low nerve conduction velocity, similar to adults with human CMT1A. Myelination is delayed in these mice, and they contain a reduced number of myelinated axons at 3 weeks of age. This mouse model was used to study the effects of AAT in different paradigms. 【0183】 The obvious efficacy of AAT administration was observed 2 weeks later in CMT1A mice by increasing rotarod latency, grip strength, and nerve conduction performance compared to the untreated control group. Furthermore, there was no observable weight loss in the AAT-treated group compared to the vehicle group, suggesting the absence of systemic toxicity of the compound under these experimental conditions (Table 11). 【0184】 【Table 11】 【0185】 Sciatic nerve electrophysiology (EMG) provides a sensitive and quantitative approach for measuring compound muscle action potentials and nerve conduction velocity amplitudes in animals and was performed by stimulating the sciatic nerve. Similar compound muscle action potential (CMAP) amplitudes were observed between groups at baseline (6 weeks of age). As expected, a strong and significant decrease in CMAP amplitude was observed in the CMT1A + vehicle group compared to the 8-week-old wild-type control group. The results show an improvement in EMG parameters for CMT1A mice treated with AAT compared to controls (Figures 6 and Tables 12, 13, 14), suggesting a clear efficacy of AAT against axonal degeneration induced by CMT1A disorder. 【0186】 At baseline (6 weeks of age), lower nerve conduction velocities (NCV) were observed in both CMT1A groups compared to the wild-type control group. At baseline, the difference in NCV between groups was not statistically significant. As expected, a strong and significant decrease in NCV was observed in the CMT1A + vehicle group compared to the 8-week-old wild-type control group. The CMT1A + AAT treatment group showed an increase in NCV compared to the vehicle-treated group. Since nerve conduction velocity depends on myelin sheath integrity, these data also suggest a clear efficacy of AAT against Schwann cell demyelination induced by CMT disorder. 【0187】 [Table 12] 【0188】 [Table 13] 【0189】 [Table 14] 【0190】 The grip strength test measures neuromuscular strength by evaluating an animal's ability to grip a metal grid. At baseline (6 weeks of age), lower grip strength was observed in the CMT group compared to the wild-type control group. At baseline, the difference in grip strength between the groups was not statistically significant. As expected, a strongly significant decrease in grip strength was observed in the CMT1A + vehicle group compared to the 8-week-old wild-type control group. The results show an improvement in grip strength in CMT1A mice treated with AAT compared to the control group (Figure 7 and Tables 15, 16). 【0191】 【Table 15】 【0192】 【Table 16】 【0193】 The rotarod test measures neuromuscular coordination by evaluating an animal's ability to balance on a rotating cylinder. Similar rotarod latencies were observed between the groups at baseline (6 weeks of age). As expected, a strongly significant decrease in rotarod latency was observed in the CMT1A + vehicle group compared to the 8-week-old wild-type control group. The results show an improvement in rotarod latency in CMT1A mice treated with AAT compared to the control group (Figure 8 and Tables 17, 18). 【0194】 【Table 17】 【0195】 【Table 18】 【0196】 Example 11 The PMP22 protein is particularly important for protecting nerves from physical pressure and appears to help nerves recover their structure after being pinched or compressed (compressed). Compression can interrupt nerve signaling and generally cause a sensation in the limbs commonly referred to as "falling asleep." The ability of nerves to recover from normal daily compression, for example, when sitting for long periods, prevents the limbs from constantly losing sensation. In CMT1A patients, the myelination process is not properly completed, and the pathological symptoms associated with the disease most frequently appear after the teenage years. 【0197】 The PMP22 gene also plays a role in the processes of Schwann cell proliferation and the process by which cells mature to perform specific functions (differentiation). Before they become part of the myelin, newly produced PMP22 proteins are processed and packaged in specialized cell structures called the endoplasmic reticulum and Golgi apparatus. Completion of these processing and packaging steps is important for proper myelin function. The pathological mechanism of CMT1A is characterized by the absence of myelin sheaths due to an extra PMP22 gene, which causes abnormally high concentrations of peripheral myelin protein 22 (PMP22) in Schwann cells. GSEA analysis performed on human microglial cells showed upregulation of genes related to the unfolded protein response (UPR) pathway and cell survival (anti-apoptosis) by AAT treatment (Figure 4C, Figure 9). 【0198】 Example 12 ADAM17, also known as TACE, is a transmembrane protein containing an extracellular zinc-dependent protease domain. In the context of CMT1A, ADAM17 is known for its inhibitory effect on SC-mediated myelination via neuregulin 1 type III (NRG1-III). AAT can pass through the blood nerve barrier (BNB) and interact with ADAM17 to effectively inhibit its activity, thereby enabling SC to "manually" overcome the pain signals generated by the overloaded ER with PMP22 and promoting the formation of the myelin sheath around the axon. 【0199】 Example 13 Plasma AAT Levels AAT was not detected in the plasma of wild-type controls and CMT1A mice treated with vehicle at the time points analyzed (day 14, day 19, day 24, and day 29). AAT in the plasma of the CMT1A + AAT group was detected at an average of 6.07 μg / mL, 6.99 μg / mL, 8.14 μg / mL, and 5.22 μg / mL on day 14, day 19, day 24, and day 29, respectively. 【0200】 Example 14A Sciatic Nerve Histology As expected, at 8 weeks of age, compared with the wild-type control group, a decrease in the total number of axons per surface, axon diameter, and a significant increase in the g-ratio were observed in the CMT1A + vehicle group (Table 19, Figures 10 - 13). 【0201】 In the CMT1A+AAT treatment group, a slight increase in the total number of axons per surface area was observed compared to the vehicle group. Furthermore, in CMT1A animals treated with AAT, a significant increase in axon diameter and a decrease in the g-ratio (equal to the ratio of the inner diameter to the outer diameter of myelinated axons) were observed. Nevertheless, CMT1A+AAT animals also showed a statistically different number of axons, axon diameter, and g-ratio compared to the wild-type control group (Table 19, Figures 10-13). Collectively, these data suggest an evident but partial efficacy of AAT against the histopathology induced by CMT1A when administered subcutaneously at 50 mg / kg twice daily. 【0202】 【Table 19】 【0203】 Example 14B-IL-6 Similar plasma IL-6 concentrations were observed between groups at baseline (day 1) and day 8. 【0204】 As expected, a significant increase in plasma IL-6 concentration was observed in the CMT+vehicle group on days 14 and 29. The terms CMT and CMT1A are used interchangeably in the Examples section. 【0205】 The CMT+AAT treatment group also showed a significant increase in plasma IL-6 concentration compared to the baseline concentration. However, the plasma IL-6 concentration in animals treated with AAT was lower than that in animals treated with vehicle on day 29 (Table 20 and Figure 14), suggesting a direct or indirect effect of AAT on this inflammatory cytokine. 【0206】 【Table 20】 【0207】 Example 15-TNFα A significant increase in plasma TNFα concentration was observed in the CMT1A+vehicle group on days 14 and 29. 【0208】 The CMT1A + AAT treatment group also showed a significant increase in plasma TNFα concentration on days 14 and 29 compared to the baseline concentration (Table 21 and Figure 15), suggesting that AAT does not affect the level of this inflammatory cytokine in this CMT1A model. 【0209】 【Table 21】 【0210】 Example 16 The effect of AAT on SH-SY5Y treated with 6-OHDA was evaluated by quantification of cell morphology and cell proliferation, followed by cell viability. 【0211】 Cells and Treatments An in vitro Parkinson's disease model was created using SH-SY5Y cells commonly used to model neurodegenerative disorders (Que R, et al., 2021, Front. Immunol. 12). Cells were cultured in DMEMF12 / Glutamax supplemented with 10% FBS. 【0212】 Cells were treated for 24 hours with the neurotoxin 6-hydroxydopamine (6-OHDA, Sigma Aldrich 162957) alone at 50, 100 μM concentrations or in combination with AAT 25 μM (AAT plasma-derived, Sigma Aldrich batch A9024). Cells treated with AAT alone or in combination with 6-OHDA for 24 hours were then incubated for an additional 24 hours with fresh AAT. Control cells were treated with PBS. 【0213】 Cell Proliferation and Viability Assays On day 0, cells were plated in equal numbers in 24-well plates, and the next day, they were treated as described above. The final total cell count was performed on day 4 of culture (cell proliferation). Cell viability was evaluated using Cell Counting Kit-8 (CCK-8, Sigma Aldrich 96992). After treatment, the cells were incubated with 10 μl of CCK-8 solution in an incubator for 2 hours. Absorbance was measured at 450 nm using a SpectraMax iD3 microplate reader. The experiment was performed in triplicate. 【0214】 Human IL-6 Immunoassay Human Il-6 Immunoassay (R&D D6050) was performed on the cell supernatant. Briefly, 40,000 cells were plated in 24-well plates and treated the next day as described in the paragraph "Cells and Treatments". At the end of the treatment, the cells were washed with PBS and incubated with 2% FBS medium for 24 hours. Then, the cell culture supernatant was collected and centrifuged to remove particulates. The assay procedure was performed on replicates of standards and samples as described in the instructions regarding the manufacturing process. Absorbance was measured at 450 nm using a SpectraMax iD3 microplate reader. A standard curve was generated from seven IL-6 standard dilutions, and the IL-6 sample concentration was determined. 【0215】 6-OHDA induced cell death after 4 days of culture and reduced the number of cells, thereby inducing cell growth impairment at 50 μM to 100 μM for 24 hours (Figure 17). In contrast, the combined treatment with AAT significantly increased the counted cell number compared to 6-OHDA alone (Figure 17), indicating a clear effect of AAT on cell survival / growth. The t-test p-value was significant at p = 0.001 for control vs 6ohda; p = 0.003 for 6ohda vs AAT + 6ohda. Control vs AAT was not significant. Error bars are S.E.M. 【0216】 Next, the treated cells were challenged in a cell viability assay. SH-SY5Y treated with 6-OHDA alone showed a strong decrease in cell viability compared to control cells and cells treated with AAT alone (Figure 18). 【0217】 When 6-OHDA treatment was combined with AAT, cell number and cell viability were significantly enhanced compared to 6-OHDA treatment alone (Figure 18). Calculation of the P value using a t-test showed no significant difference between the control and AAT alone. All conditions were performed in triplicate. Based on these results, the inventors can conclude that AAT administration in a PD cell model (SH-SY5Y induced by 6-OHDA) has a favorable effect on cell proliferation and viability and probably protects cells from 6-OHDA-induced death. 【0218】 In addition, to investigate the role of AAT on pro-inflammatory cytokines, the inventors quantified IL-6 in the cell supernatant. The medium from cells induced by 6-OHDA had increased levels of IL-6 compared to control medium, and in contrast, the medium collected from cells treated with AAT showed lower concentrations of IL-6 (Figure 19). The t-test p value was significant for the control vs. 6-OHDA at p = 0.05 and not significant for the other comparisons. 【0219】 Example 17 C57BL / 6 mice were received at 8 weeks of age and housed under controlled conditions during the test period. Three groups of 4 animals each were assigned to the following subcutaneous treatments twice a day at 7:00 am and 7:00 pm for 2 weeks starting on day 20 to day 35 after the start of disease induction. · Wild type (WT) mice receiving vehicle, 0.9% NaCl (positive control) · CIDP mice receiving vehicle, 0.9% NaCl (negative control) · CIDP mice receiving human AAT (AAT), 50 mg / kg / injection 【0220】 Disease induction consisted of subcutaneous injection of mouse sciatic nerve homogenate in 10 mL / kg of phosphate-buffered saline (PBS) + Freund's adjuvant mixture. For each treatment, injections were performed at three different body sites. Control mice also received three subcutaneous injections of PBS + Freund's adjuvant at the same three different body sites. 【0221】 On the day before disease induction (day 1), the first day of treatment (day 20), and the last day of treatment (day 35), animals were subjected to blood sampling to determine nerve filament light chain (NfL), tumor necrosis factor alpha (TNFα), and TMPRSS5 levels as described in Figure 20. Additionally, plasma levels of AAT were evaluated on the last day of treatment. 【0222】 On the first day of treatment (day 20) and the last day of treatment (day 35), the neuromuscular and sensory abilities of the animals were tested using the rotarod test, grip strength test, and Von Frey filament test, as well as sciatic nerve electrophysiology tests. After the last treatment on day 35, these tests were repeated, and the animals were sacrificed, and the left sciatic nerve was harvested for histological evaluation of the number and size of neurons. 【0223】 Rotarod test Compared to the control group, a significant decrease in rotarod latency was observed in the CIDP group on day 20. On day 35, the CIDP + AAT treatment group showed an increase in rotarod latency compared to the vehicle treatment group (Table 22, Figure 21A). 【0224】 [Table 22] 【0225】 Grip strength test At baseline (day 20), lower grip strength was observed in the CIDP group compared to the wild-type control group. On day 35, the CIDP + AAT treatment group showed an increase in grip strength compared to the vehicle treatment group (Tables 23 and 21B). 【0226】 【Table 23】 【0227】 Von Frey test Lower paw withdrawal thresholds were observed in the CIDP group compared to the wild-type control group at baseline (day 20). On day 35, the CIDP + AAT treatment group showed an increase in paw withdrawal threshold compared to the vehicle treatment group (Table 24 and Figure 21C). The results from this test suggest that AAT shows a statistically significant and obvious effect (pain relief) on pain threshold in these CIDP mice when administered subcutaneously at 50 mg / kg twice a day. 【0228】 【Table 24】 【0229】 Compound muscle action potential On day 20, a highly significant decrease in CMAP amplitude was observed in both CIDP groups compared to the wild-type control group. 【0230】 On day 35, the CIDP + AAT treatment group showed an increase in CMAP amplitude compared to the CIDP + vehicle treatment group (Table 25 and Figure 22A). 【0231】 【Table 25】 【0232】 Nerve conduction velocity On day 20, a strong decrease in NCV was observed in both CIDP groups compared to the wild-type control group. The CIDP + AAT treatment group showed an increase in NCV compared to the vehicle treatment group (Table 26 and Figure 22B). 【0233】 【Table 26】 【0234】 Neuromuscular disorders and decreased nerve conduction amplitude and velocity were observed in a preclinical CIDP mouse model treated with vehicle 20 days after the onset of disease induction, compared to wild-type control groups. 【0235】 Increased rotarod latency, grip strength, hindlimb withdrawal threshold, and nerve conduction velocity and amplitude were observed in AAT-treated CIDP mice compared to the vehicle-treated group. 【0236】 These data suggest that AAT shows a clear trend of effect against CIDP when administered subcutaneously at 50 mg / kg twice daily in CIDP mice. 【0237】 Raw data 【0238】 【Table 27A】 【0239】 【Table 27B】 【0240】 【Table 28A】 【0241】 【Table 28B】 【0242】 【Table 29A】 【0243】 【Table 29B】 【0244】 【Table 30】 【0245】 【Table 31A】 【0246】 Histology On day 35, a significant decrease in the total number of axons and axon diameter and a significant increase in the g-ratio were observed in the CIDP + vehicle group compared with the sham control group (Table 31B and Figures 37 - 39). A slight but non-significant increase in the total number of axons per surface area was observed in the CIDP + AAT treatment group compared with the vehicle treatment group. On day 35, a significant increase in axon diameter and a decrease in the g-ratio were also observed in the CIDP + AAT treatment group compared with the CIDP + vehicle treatment group. 【0247】 【Table 31B】 【0248】 Example 18: Quantification of plasma NfL Similar plasma NfL concentrations were observed among the three groups at baseline (day 1, before model induction). 【0249】 Before compound treatment on day 20, a significant increase in plasma NfL concentration was observed in the CIDP + vehicle group and the CIDP + AAT group compared with the sham control group (Table 32, Table 33 and Figure 23B). 【0250】 Importantly, a significant decrease in plasma NfL concentration was observed in the CIDP + AAT treatment group compared with the CIDP + vehicle treatment group on day 35 (Table 32, Table 33 and Figure 23B), confirming the apparent efficacy of the compound against the peripheral axonal damage induced by this inflammatory neuropathy under these experimental conditions. 【0251】 Example 19: Quantification of plasma TNFα Similar plasma TNFα concentrations were observed among the three groups at baseline (day 1, before model induction). A significant increase in plasma TNFα concentration was observed in the CIDP + vehicle group and the CIDP + AAT group compared to the sham control group before compound treatment on day 20 (Tables 34, 35, and Figure 24). 【0252】 Importantly, a significant decrease in plasma TNFα concentration was observed in the CIDP + AAT treatment group compared to the CIDP + vehicle treatment group on day 35 (Tables 34, 35, and Figure 24), confirming the apparent efficacy of the compound against cytokine activation induced by autoimmune chronic inflammatory demyelinating polyneuropathy under these experimental conditions. 【0253】 In conclusion, neuromuscular impairment and decreased nerve conduction amplitude and velocity were observed in the pre - clinical CIDP mouse model treated with vehicle 20 days after the start of disease induction compared to the wild - type control group. 【0254】 Increases in rotarod latency, grip strength, and nerve conduction velocity were observed in the CIDP + AAT treatment group compared to the CIDP + vehicle treatment group. No statistical significant difference was observed in the plasma TMPRSS5 concentration in the CIDP + AAT treatment group compared to the vehicle group. However, on day 35, a significant increase in compound muscle action potential amplitude, a decrease in neuropathic pain, and decreases in plasma TNFα and NfL concentrations were observed in the CIDP + AAT treatment group compared to the CIDP + vehicle treatment group. Finally, histopathological analysis of the sciatic nerve showed a significant increase in axon diameter and myelin sheath diameter (decrease in g - ratio) in CIDP + AAT compared to the vehicle - treated group, confirming the apparent efficacy of the compound from a histological perspective. 【0255】 Collectively, these data suggest that AAT, when administered subcutaneously at 50 mg / kg twice daily in a preclinical CIDP mouse model, exhibits significant efficacy against autoimmune chronic inflammatory demyelinating polyneuropathy targeting the peripheral nervous system, increases neuromuscular and electrophysiological performance, and decreases neuropathic pain and plasma neuropathic biomarkers. 【0256】 【Table 32A】 【0257】 【Table 32B】 【0258】 【Table 33】 【0259】 【Table 34A】 【0260】 【Table 34B】 【0261】 【Table 35】 【0262】 Example 20 The compound muscle action potential (CMAP) significantly increases two weeks after AAT therapy. 【0263】 CMT mouse model: Non-humanized CMT1A mice B6.Cg-Tg(PMP22)C3Fbas / J (three copies of the PMP22 gene), three groups of eight animals each. 【0264】 Dose: 180 mg / kg / day of non - clinical grade AAT (Sigma) Administration: Subcutaneous (SC) (two - times - a - day injection of 90 mg / kg) 【0265】 The main disease progression parameters are significantly improved after 2 - week AAT treatment (180 mg / kg / day) (see Figures 25 - 30). 【0266】 【Table 36】 【0267】 【Table 37】 【0268】 【Table 38】 【0269】 【Table 39】 【0270】 Example 21 - Efficacy of AAT in a Mouse Model of Charcot - Marie - Tooth Disease Charcot - Marie - Tooth disease (CMT) is a hereditary motor and sensory neuropathy of the peripheral nervous system characterized by progressive loss of muscle tissue and tactile dysfunction in different parts of the body. This currently incurable disease is the most common hereditary neuropathy, affecting approximately 1 in 2,500 people. The most common type of CMT is CMT1A, which is characterized by duplication of the PMP22 gene, resulting in accumulation of the pmp22 protein and progressive demyelination in Schwann cells. PMP22 is a four - transmembrane glycoprotein contained in the compact myelin of the peripheral nervous system. Duplication of PMP22 has been associated with the onset of Charcot - Marie - Tooth disease type 1A (CMT1A). 【0271】 C3-PMP22 transgenic mice (B6.Cg-Tg(PMP22)C3Fbas / J) express three copies of the wild-type human peripheral myelin protein 22 (PMP22) gene. These mice exhibit an age-dependent demyelinating neuropathy characterized mainly by distal weakness and sensory loss. C3-PMP mice do not show obvious clinical signs at 3 weeks of age and develop mild neuromuscular disorders by an age-dependent method. They have a stable low nerve conduction velocity similar to that of adults with human CMT1A. Myelination is delayed in these mice, and they contain a reduced number of myelinated axons at 3 weeks of age. 【0272】 In CMT1A, the major element of the disease is abnormal development of myelination (hypomyelination). Myelin is produced by SCs in the peripheral nervous system and is important for the proper transmission of electrical impulses in nerves. The primary hypomyelination seen in CMT1A patients results in abnormal SC organization around axons and uniformly slowed nerve conduction velocities. 【0273】 The transmembrane protein ADAM17 (also known as TACE, tumor necrosis factor-α converting enzyme) has been shown to block axonal myelination in SCs by inhibiting the neuregulin 1 type III signal (NRG1-III) (La Marca et al., 2011; Pisciotta et al., 2021). AAT may be a promising treatment for CMT by modulating NRG1-III signaling through its pharmacological inhibition of ADAM17. Inhibition of ADAM17 by AAT can promote SC myelination in the peripheral nervous system and thus reduce the progression of CMT disease. 【0274】 In addition to its inhibitory function on ADAM17, another mechanism of AAT in the treatment of CMT is its anti-inflammatory activity. AAT exhibits broad anti-inflammatory and immunomodulatory activities. An increase in AAT serum concentration beyond normal levels by administration of exogenous AAT is expected to be therapeutic in CMT. 【0275】 The B6.Cg-Tg(PMP22)C3Fbas / J transgenic mice express three copies of the wild-type human peripheral myelin protein 22 (PMP22) gene. They exhibit an age-dependent demyelinating neuropathy characterized primarily by distal weakness and sensory loss. These mice do not show obvious clinical signs at 3 weeks of age, develop mild neuromuscular impairment by an age-dependent approach, which is well established by 8 weeks of age. They have a stable low nerve conduction velocity similar to that of adults with human CMT1A. Myelination is delayed in these mice, and they contain a reduced number of myelinated axons. 【0276】 Materials and Methods Animals were received at 6 weeks of age and housed under controlled conditions during the study period. This study included two groups of 8 transgenic mice (CMT mice) each and one group of 8 age-matched wild-type (WT) C57Bl6 mice serving as a positive control. Animals were assigned to the following subcutaneous treatments twice a day at 7:00 am and 7:00 pm for 2 weeks starting at 8 weeks of age and up to 10 weeks of age. · Wild-type (WT, disease-free) mice receiving vehicle 0.9% NaCl (positive control) · CMT1A mice receiving vehicle 0.9% NaCl (negative control) · CMT1A mice receiving AAT at 90 mg / kg per injection (180 mg / kg daily dose) 【0277】 The efficacy parameters included the following: · Neuromuscular performance (rotarod latency to fall and grip strength test) · Sciatic nerve electrophysiology (CMAP amplitude and NCV) · Cytokines (IL-6 and TNFα), and NfL analysis · Sciatic nerve histology (axon number and axon diameter) 【0278】 On the first day of treatment (day 1), the neuromuscles and performance of the animals were tested by rotarod test, grip strength test, and sciatic nerve electrophysiology test, which measured compound muscle action potential (CMAP) and nerve conduction velocity (NCV). After the last treatment on day 15, these tests were repeated. Then, the animals were left untreated for an additional 2 weeks to evaluate the duration of the treatment effect. After a 2-week untreated period until 12 weeks of age (day 30), the behavioral and electrophysiological tests were repeated. 【0279】 As information to support the mode of action of AAT in CMT, the plasma concentrations of interleukin 6 (IL-6) and TNFα were measured on day 1 (8 weeks), day 15 (10 weeks), and day 30 (12 weeks). At the same time points, the plasma levels of NfL, a biomarker of nerve injury, were determined. 【0280】 Results At 8 weeks of age (baseline), CMT mice show obvious clinical signs / symptoms of the disease compared to normal wild-type mice. Neuromuscular impairment (decrease in latency to fall) can be seen in Figure 25 and Table 40A. 【0281】 [Table 40A] 【0282】 The decrease in grip strength in CMT mice compared to wild-type mice can be seen in Figure 26 and Table 40B. 【0283】 [Table 40B] 【0284】 The decrease in nerve CMAP amplitude is shown in Figure 27 and Table 40C 【0285】 [Table 40C] 【0286】 The decrease in sciatic nerve velocity is shown in Figure 28 and Table 40D. 【0287】 [Table 40D] 【0288】 Plasma cytokine levels of IL-6 and TNFα (Tables 40E, 40F, Figures 29 and 30), and the biomarker of nerve injury NfL (Table 40G and Figure 40) are increased in CMT mice. 【0289】 [Table 40E] 【0290】 [Table 40F] 【0291】 [Table 40G] 【0292】 [Table 40H] 【0293】 All of these clinical signs / symptoms present in CMT mice were well established as expected at 8 weeks of age. Furthermore, the signs progressed over time and became more severe at 10 weeks of age, and their severity still increased at 12 weeks of age in control CMT mice. 【0294】 Treatment with AAT was started at 8 weeks of age and continued for 2 weeks until 10 weeks of age. The results show that AAT increased neuromuscular and electrophysiological performance when administered subcutaneously at 90 mg / kg twice a day in CMT mice. CMT mice treated with AAT showed a significant increase in the rotarod latency to fall ( ****: P < 0.0001 compared to WT + vehicle, : P < 0.001 compared to CMT + vehicle, two-way ANOVA and Bonferroni test, ns: not significant, P > 0.05 (Figure 25), significant increase in grip strength ( **** : P < 0.0001 compared to WT + vehicle, #, #: P < 0.05, P < 0.0001 compared to CMT + vehicle, two-way ANOVA and Bonferroni test, ns: not significant, P > 0.05 (Figure 26), significant increase in compound muscle action potential amplitude ( **** : P < 0.0001 compared to WT + vehicle, #, : P < 0.05, P < 0.001 compared to CMT + vehicle, two-way ANOVA and Bonferroni test, ns: not significant, P > 0.05 (Figure 27) and significant increase in nerve conduction velocity ( **** : P < 0.0001 compared to WT + vehicle, : P < 0.001 compared to CMT + vehicle, two-way ANOVA and Bonferroni test, ns: not significant, P > 0.05 when compared to CMT mice not treated with AAT (Figure 28). AAT decreased the plasma levels of the inflammatory cytokines IL-6 (P < 0.01) and TNFα (P < 0.0001), (Table 40E, Table 40F, Figure 29 and Figure 30), as well as the level of NfL (Table 40G and Figure 40). 【0295】 At 12 weeks of age after a 2-week untreated period, the effect of AAT decreased, suggesting that repeated administration of AAT is required to obtain a sustained effect. At this time point, the grip strength and CMAP of AAT-treated mice decreased compared to the end of the treatment period but remained significantly higher than those of untreated CMT animals (P < 0.05 for both parameters). The obvious effects remained significant for IL-6, TNFα and NfL plasma levels, and even after a 2-week treatment-free period, the axon number and the size of the myelin sheath were significantly larger in treated animals. The only parameters that did not differ significantly from the untreated group were the rotarod fall latency and NCV. 【0296】 Conclusion AAT therapy was evaluated in a mouse model relevant to CMT disease. At baseline, at 8 weeks of age, the disease was fully established and the animals showed obvious clinical signs and symptoms of CMT1A. AAT treatment was associated with improvement of neuropathy as shown by a significant increase in neuromuscular and electrophysiological performance, as well as an increase in axon number and axon diameter and a decrease in g-ratio, compared to untreated CMT animals. A decrease in plasma cytokines (TNFα and IL-6) and NfL biomarker was also observed in treated animals. It was demonstrated that AAT could reduce the progression of the disease. The effect of treatment with AAT was time-limited. Two weeks after treatment cessation, the symptoms worsened but did not reach the level of untreated CMT animals. 【0297】 Collectively, these data demonstrate the potential of AAT to improve the outcome of CMT1A patients by not only reducing the progression of the disease but also reversing its symptoms. 【0298】 Example 22 Inhibitory effects of AAT-related peptides and peptidomimetics on ADAM17 activity Biologically active immunomodulatory sites on the surface of AAT (not related to standard anti-protease activity) were identified by in silico methods and several peptides were derived from these immunomodulatory sites (Lior, Yotam, et al. European Journal of Medicinal Chemistry 228 (2022): 113969). The potential of two peptides (peptide 8 and peptide 9) and one peptidomimetic (peptide 14) to modulate ADAM17 activity was investigated. 【0299】 Peptide 8 (sequence: Ac-YRAHQGE-NH2, MW: 945.4) and peptide 9 (sequence: Ac-LFLYVIH-NH2, MW: 901.3) were synthesized using a Syro-1 automated peptide synthesizer and the Fmoc / tBu strategy (Figure 42). Peptide 14 (4-hydroxy-Bzl-His-Phg-NH2 [TFA salt], MW: 394.2) was synthesized manually using the Fmoc / tBu strategy (Figure 43). 【0300】 The activity of ADAM-17 and its inhibition by human peptide 8 were measured in a black 96-well immunoplate (437111, Thermo Fisher Scientific) using a recombinant human ADAM-17 kit (recombinant human TACE / ADAM17 protein, CF: 930-ADB-010 and Mca-PLAQAV-Dpa-RSSSR-NH2 fluorogenic peptide substrate: ES003, R&D Systems). The enzymatic activity of ADAM-17 was measured by mixing 0.005 μg of rhADAM-17 with 10 μM of Mca-PLAQAV-Dpa-RSSS-NH2 fluorogenic peptide substrate III in assay buffer (25 mM Tris, 2.5 μM ZnCl2, 0.005% Brij-35 (w / v), pH 9.0) to a final volume of 100 μl. Peptide 8 (Syngene) was dissolved in DMSO and diluted to the desired concentration in assay buffer. Control ADAM-17 activity was evaluated in the presence of assay buffer. Peptide 8 was added at different concentrations in two separate experiments (0, 10, and 50 μM in Experiment 1; 0, 100, 200, and 250 μM in Experiment 2), and its dose-dependent inhibition of ADAM-17 was evaluated. All conditions were performed in triplicate. Activity was measured as relative fluorescence units (RFU) in endpoint mode (5 minutes) using a SpectraMax iD3 microplate reader (automatic PMT gain, wavelength: excitation 320 nm, emission 405 nm). 【0301】 No significant inhibition of ADAM17 activity was observed at concentrations up to 50 μM (left graph in Figure 31), but significant concentration-dependent inhibition was observed at concentrations of 100 (36% inhibition) and 200 (65% inhibition) (right graph in Figure 31). 【0302】 Example 23 Regulatory effect of AAT on TNFα-induced Schwann cell activation Human Schwann cells (P10351, Innoprot) were seeded in 12-well plates at 120,000 cells / well in DMEM. Cells were pretreated with either buffer (control) or AAT (50 μM) for 24 hours and then stimulated with TNFα (10 ng / mL). The plates were then incubated at 37 °C for 24 hours. RNA was extracted and the expression of selected target genes was measured by qPCR. 【0303】 The rationale for gene selection is explained below. 【0304】 TNF can activate nuclear factor κB (NF-κB) by binding to TNFR1, which promotes cell survival signaling and cell death. NF-κB activation induces upregulation of the transcription of inflammasome regulators such as IL-1β, IL-18, TNFα, and IFN-γ, which mediate the inflammatory response. Furthermore, TNFR1 can directly induce oxidative stress by activating reactive oxygen species (ROS) and reactive nitrogen species (RNS) generating enzymes. 【0305】 The genes whose regulation was evaluated included the NF-κB early gene response NFKBIA, as well as the TNFα and TNFR1 genes. The expression of the gene encoding the IL-6 pro-inflammatory cytokine was also evaluated. 【0306】 Nuclear factor E2-related factor 2 (Nrf2) plays an important role in regulating the redox state of cells in various physiological and pathological processes. Under normal physiological conditions, Nrf2 is not biologically active and does not activate downstream genes. Through its interaction with the antioxidant response element (ARE) of cytoprotective genes, Nrf2 activates antioxidant enzymes such as SOD, CAT, HO-1, and NAD(P)H oxidase (G6PD). 【0307】 The TXN system plays an important role in maintaining the intracellular reducing environment. Thioredoxin (TXN) is a thiol oxidoreductase that is a major regulator of cellular redox signaling, protecting cells from oxidative stress. TXNIP directly interacts with TXN and inhibits its ability to remove reactive oxygen species (ROS). TXNIP has been demonstrated to be upregulated in diseases such as type 2 diabetes mellitus and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. 【0308】 As a potential early response gene, TXNIP is tightly regulated and strongly correlated with changes at the mRNA and protein levels, and has been shown to play an important function in Schwann cell dysfunction in diabetic peripheral neuropathy. 【0309】 As shown in FIGS. 32 to 34, NF-κb pathway transcripts were downregulated by AAT treatment after TNF induction. κAAT inhibited the expression of genes regulated by the TNF-induced oxidative stress response. Collectively, these results demonstrate the regulatory effect of AAT on TNFα-induced gene expression in human Schwann cells. 【0310】 Example 24 Microglia (HMC3) cells were seeded in 96-well plates at a density of approximately 2500 cells / well. Plasma-derived AAT (Sigma, 25 μM) or peptide 8, peptide 9, or peptide 14 (Syngene, 50 μM) was added, and microglial activation was induced with interferon gamma (IFNγ) (10 ng / mL) for 24 hours without pre-incubation. RNA was then extracted (RNAeasy mini kit, Qiagen), and the expression of interleukin-6 (IL6) and interleukin-1β (IL1B) genes was analyzed. qPCR was performed using Syber green POWER UP master mix with 10 ng / well of cDNA for all gene expression results. 【0311】 The results showed that AAT and its derivative peptides reduced IL6 expression by 30% - 40% and IL1B expression by 60% - 70% (Figure 41), suggesting that all three peptides mimic the function of AAT in the inflammatory response. 【0312】 Example 25 Effects of AAT and its derivative peptides on TNF-induced Schwann cells Schwann cells were seeded at a density of 75,000 cells per well. At the time of seeding, plasma-derived AAT (50 μM) or peptides 8, 9, 14 (Syngene, 50 μM) were added. The next day, the cells were treated with 10 ng / ml of TNF alpha with or without AAT and its derivative peptides for 24 hours. 【0313】 NAD(P)H oxidase (G6PD) expression is induced by TNF treatment in Schwann cells and is reduced by 40% - 30% in stimulated cells treated with AAT and its derivative peptides (Figure 35). G6PD plays an important role in the production of ROS. 【0314】 The present invention further relates to the following items. 1. A pharmaceutical for use in the treatment of chronic inflammatory demyelinating polyneuropathy, a) an alpha1-antitrypsin (AAT) protein having ADAM17 inhibitory activity, its variants, isoforms and / or fragments, and / or b) a nucleic acid encoding an AAT having ADAM17 inhibitory activity, its variants, isoforms and / or fragments comprising a pharmaceutical for use. 2. A kit for use in the treatment of a disease or disorder of the nervous system, i) a) an alpha1-antitrypsin (AAT) protein having ADAM17 inhibitory activity, its variants, isoforms and / or fragments, and / or b) a nucleic acid encoding an AAT having ADAM17 inhibitory activity, its variants, isoforms and / or fragments, and ii) a plurality of IgG antibodies, their IgG variants, isotypes and / or fragments, and a parts kit for use. 3. A pharmaceutical composition for use in the treatment of a disease or disorder of the nervous system, i) a) an alpha 1-antitrypsin (AAT) protein having ADAM17 inhibitory activity, its variants, isotypes and / or fragments, and / or b) a nucleic acid encoding an AAT having ADAM17 inhibitory activity, its variants, isotypes and / or fragments, and ii) a plurality of IgG antibodies, their IgG variants, isotypes and / or fragments, and iii) at least one pharmaceutically acceptable carrier and a pharmaceutical composition for use. 4. A method of treatment comprising administering to a subject a pharmaceutical composition comprising an effective amount of an AAT protein and / or a nucleic acid encoding AAT, wherein the subject suffers from a disease or disorder of the nervous system and the subject is receiving a therapy comprising administration of a plurality of IgG antibodies, their IgG variants, isotypes and / or fragments. 5. A method of treatment comprising administering to a subject a pharmaceutical composition comprising an effective amount of a plurality of IgG antibodies, their isotypes, fragments, and / or IgG variants, wherein the subject suffers from a disease or disorder of the nervous system and the subject is receiving a therapy comprising administration of an AAT protein and / or a nucleic acid encoding AAT. 6. The parts kit for use according to item 2, the pharmaceutical composition for use according to item 3, the method of treatment according to item 4 or 5, wherein the disease or disorder of the nervous system is chronic inflammatory demyelinating polyneuropathy. 7. The pharmaceutical product for use according to item 1, the parts kit for use according to item 6, the pharmaceutical composition for use according to item 6, the method of treatment according to item 6, wherein the subject to be treated has a history of at least one symptom of chronic inflammatory demyelinating polyneuropathy or at least one symptom of chronic inflammatory demyelinating polyneuropathy. 8. A parts kit for use according to any one of items 2, 6, or 7, a pharmaceutical composition for use according to any one of items 3, 6, or 7, or a treatment method according to any one of items 4 - 7, wherein the plurality of IgG antibodies, their isotypes, their fragments, and / or IgG variants are plasma-derived IgG antibodies, their isotypes, their fragments, and / or IgG variants. 9. A parts kit for use according to any one of items 2, 6, or 7, a pharmaceutical composition for use according to any one of items 3, 6, or 7, or a treatment method according to any one of items 4 - 7, wherein the plurality of IgG antibodies, their isotypes, their fragments, and / or IgG variants are recombinant IgG antibodies, their isotypes, their fragments, and / or IgG variants. 10. A parts kit for use according to any one of items 2, 6 - 9, a pharmaceutical composition for use according to any one of items 3, 6 - 9, or a treatment method according to any one of items 4 - 9, wherein the plasma-derived IgG antibodies, their isotypes, their fragments, and / or IgG variants are formulated for intravenous administration. 11. A parts kit for use according to any one of items 2, 6 - 9, a pharmaceutical composition for use according to any one of items 3, 6 - 9, or a treatment method according to any one of items 4 - 9, wherein the plasma-derived IgG antibodies, their isotypes, their fragments, and / or IgG variants are formulated for subcutaneous administration. 12. A pharmaceutical product for use according to any one of items 1 or 7, a parts kit for use according to any one of items 2, 6 - 11, a pharmaceutical composition for use according to any one of items 3, 6 - 11, or a treatment method according to any one of items 4 - 11, wherein the AAT protein is recombinant AAT. 13. A pharmaceutical product for use according to any one of items 1 or 7, a parts kit for use according to any one of items 2, 6 - 11, a pharmaceutical composition for use according to any one of items 3, 6 - 11, or a treatment method according to any one of items 4 - 11, wherein the AAT protein is plasma-derived AAT. 14. a) An alpha1-antitrypsin (AAT) protein having ADAM17 inhibitory activity, variants, isoforms and / or fragments thereof, and / or b) A nucleic acid encoding an AAT having ADAM17 inhibitory activity, variants, isoforms and / or fragments thereof A pharmaceutical for use according to any one of items 1, 7, 12 or 13, which is formulated for intravenous administration; a parts kit for use according to any one of items 2, 6 to 13; a pharmaceutical composition for use according to any one of items 3, 6 to 13; a treatment method according to any one of items 4 to 13. 15. a) An alpha1-antitrypsin (AAT) protein having ADAM17 inhibitory activity, variants, isoforms and / or fragments thereof, and / or b) A nucleic acid encoding an AAT having ADAM17 inhibitory activity, variants, isoforms and / or fragments thereof A pharmaceutical for use according to any one of items 1, 7, 12 or 13, which is formulated for subcutaneous administration; a parts kit for use according to any one of items 2, 6 to 13; a pharmaceutical composition for use according to any one of items 3, 6 to 13; a treatment method according to any one of items 4 to 13. 【0315】 SEQ ID NO: 1 MPSSVSWGILLLAGLCCLVPVSLAEDPQGDAAQKTDTSHHDQDHPTFNKITPNLAEFAFSLYRQLAHQSNSTNIFFSPVSIATAFAMLSLGTKADTHDEILEGLNFNLTEIPEAQIHEGFQELLRTLNQPDSQLQLTTGNGLFLSEGLKLVDKFLEDVKKLYHSEAFTVNFGDTEEAKKQINDYVEKGTQGKIVDLVKELDRDTVFALVNYIFFKGKWERPFEVKDTEEEDFHVDQVTTVKVPMMKRLGMFNIQHCKKLSSWVLLMKYLGNATAIFFLPDEGKLQHLENELTHDIITKFLENEDRRSASLHLPKLSITGTYDLKSVLGQLGITKVFSNGADLSGVTEEAPLKLSKAVHKAVLTIDEKGTEAAGAMFLEAIPMSIPPEVKFNKPFVFLMIEQNTKSPLFMGKVVNPTQK 【0316】 Sequence number 2: VFALVNYIFFKGKWERPFEVKDTEEEDFHVDQVTTVKVPMMKRLGMFNIQHCKKLSSWVLLMKYLGNATAIFFLPDEGKLQHLENELTHDIITKFLENEDRRSASLHLPKLSITGTYDLKSVLGQLGITKVFSNGADLSGVTEEAPLKLSKAVHKAVLTIDEKGTEAAGAMFLEAIPMSIPPEVKFNKPFVFLMIEQNTKSPLFMGKVVNPTQK

Claims

[Claim 1] A pharmaceutical product for use in the treatment of inflammatory diseases or disorders, a) Alpha-1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having ADAM17 inhibitory activity, or small molecules having ADAM17 inhibitory activity, and / or b) Nucleic acids encoding AAT, its variants, isoforms, and / or fragments having AAT, ADAM17 inhibitory activity. A pharmaceutical product intended for use, including [specific product / service]. [Claim 2] The pharmaceutical product for use according to claim 1, wherein the inflammatory disease or disorder is an autoimmune inflammatory disease. [Claim 3] The pharmaceutical product for use according to claim 1, wherein the inflammatory disease or disorder is an inflammatory disease or disorder of the nervous system, or the inflammatory disease or disorder is neuropathic pain. [Claim 4] The pharmaceutical product for use according to claim 1, wherein the inflammatory disease or disorder is chronic inflammatory demyelinating polyneuropathy. [Claim 5] The pharmaceutical product for use according to claim 1, wherein the inflammatory disease or disorder is complex regional pain syndrome. [Claim 6] The pharmaceutical product for use according to claim 1, wherein the inflammatory disease or disorder is inflammatory pain. [Claim 7] A parts kit for use in the treatment of diseases or disorders of the nervous system, or inflammatory diseases or disorders of the nervous system, i) a) Alpha-1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having ADAM17 inhibitory activity, or small molecules having ADAM17 inhibitory activity, and / or b) A nucleic acid encoding a variant, isoform, and / or fragment thereof having AAT, ADAM17 inhibitory activity, ii) Multiple IgG antibodies, their isoforms, their fragments, and / or IgG variants A parts kit for use, including the parts for use. [Claim 8] A pharmaceutical composition for use in the treatment of diseases or disorders of the nervous system, or inflammatory diseases or disorders of the nervous system, i) a) Alpha-1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having ADAM17 inhibitory activity, or small molecules having ADAM17 inhibitory activity, and / or b) A nucleic acid encoding a variant, isoform, and / or fragment thereof having AAT, ADAM17 inhibitory activity, ii) Multiple IgG antibodies, their IgG variants, isoforms and / or fragments, iii) at least one pharmaceutically acceptable carrier and A pharmaceutical composition for use, including the following. [Claim 9] The pharmaceutical product for use according to claim 4, wherein the person to be treated has at least one symptom of chronic inflammatory demyelinating polyneuropathy or a history of at least one symptom of chronic inflammatory demyelinating polyneuropathy. [Claim 10] The pharmaceutical product for use according to claim 1, wherein the AAT protein is recombinant AAT. [Claim 11] The pharmaceutical product for use according to claim 1, wherein the AAT protein is plasma-derived AAT. [Claim 12] a) Alpha-1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having ADAM17 inhibitory activity, or small molecules having ADAM17 inhibitory activity, and / or b) Nucleic acids encoding AAT, its variants, isoforms, and / or fragments having AAT, ADAM17 inhibitory activity. A pharmaceutical product for use according to claim 1, wherein the pharmaceutical product is formulated for intravenous administration. [Claim 13] a) Alpha-1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having ADAM17 inhibitory activity, or small molecules having ADAM17 inhibitory activity, and / or b) Nucleic acids encoding AAT, its variants, isoforms, and / or fragments having AAT, ADAM17 inhibitory activity. A pharmaceutical product for use according to claim 1, wherein the pharmaceutical product is formulated for subcutaneous administration.

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