Alpha1-antitrypsin for treatment of diseases or conditions of nervous system, such as chronic inflammatory demyelinating polyneuropathy

Abstract

The present invention relates to alpha 1-antitrypsin (AAT) proteins, variants, isoforms and / or fragments thereof and / or corresponding nucleic acid sequences thereof for use in the treatment of diseases or disorders of the nervous system, such as chronic inflammatory demyelinating polyneuropathy. The invention also relates to combinations with IgG antibodies, such as immunoglobulin therapy, for use in these diseases or disorders.

Description

[0001] The present invention relates to alpha 1-antitrypsin (AAT) proteins, variants, isoforms and / or fragments thereof and / or corresponding nucleic acid sequences for use in treating diseases or conditions of the nervous system such as chronic inflammatory demyelinating polyneuropathy. The present invention also relates to combinations with IgG antibodies such as immunoglobulin therapies for these diseases or conditions.

[0002] Diseases or disorders of the nervous system are diseases or disorders that can significantly affect the peripheral and / or central nervous system (PNS / CNS). In the last decade, neuroinflammation has become increasingly important in our understanding of neurological disorders. Inflammation itself can directly or indirectly cause disease, but there is no doubt that it does contribute to the pathogenesis of a whole range of peripheral nervous system (PNS) and central nervous system (CNS) diseases.

[0003] Peripheral neuropathies constitute a highly diverse group of disorders, a major component of which is damage to the myelin sheath, either following abnormal development of the myelin sheath (dysmyelination) in inherited forms (CMT1A-F and CMT1A-X) or directly in acquired forms such as chronic inflammatory demyelinating polyneuropathy.

[0004] Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease that targets the myelin sheath, particularly in peripheral nerves, and causes progressive weakness and loss of sensation. Swelling of the nerve roots is also a feature of the disease. Although it can occur at any age and in both sexes, CIDP is more common in young adults, and it is more common in males than in females.

[0005] If left untreated, CIDP is characterized by accumulating disability, which requires physical and occupational therapy, orthopedic devices, and long-term treatment. Early intervention can prevent permanent damage and disability. Current treatments for CIDP include administration of corticosteroids, such as prednisone, which may be prescribed alone or in combination with immunosuppressive drugs. Immunosuppressant drugs may also be given in the absence of steroids.

[0006] Myelin is produced by Schwann cells (SC) in the PNS and is essential for the proper transmission of electrical impulses in nerves. In the complex neuronal / glial cross-communication required for proper myelin regulation (Rao and Pearse 2016), several different signaling pathways are involved, including growth factors, integrins, and cell adhesion molecules, but more importantly, neuregulin 1 type III (NRG1-III), which signals through the ERBB2 / 3 receptors and their proteolytic degrading enzyme regulator, tumor necrosis factor-α-converting enzyme (TACE), also known as ADAM17. TACE / ADAM17 is a transmembrane protein that contains 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.). Contradictory evidence has been reported in the literature regarding the role of the human protease α1-antitrypsin (AAT), specifically, in 2013 AAT was shown not to interact with TACE (van't Wout EF et al., 2014, Hum Mol Genet.; 23(4):929-4), in contrast to an earlier report in 2010 claiming that AAT did interact with TACE and inhibited its activity in a dose-dependent manner (Bergin, DA et al., 2010, J Clin Invest 120(12):4236-4250.).

[0007] A common biological trait of many PNS and CNS neurodegenerative diseases is a sustained acute inflammatory response (also known as a "cytokine storm") caused by coordinated cytokine release in a feedforward loop. Therefore, inhibition of the inflammatory response has become a central goal of therapeutic strategies. However, the subtleties of the inflammatory mechanisms behind its multiple mediators are not yet fully understood.

[0008]

[0006] Therefore, there is a need for improved treatments 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 as defined in the claims.

[0010] Therefore, the present invention relates in particular to the following embodiments:

[0011] 1. A pharmaceutical product for treating an inflammatory disease or condition, the pharmaceutical product comprising:

[0012] a) α1-antitrypsin (AAT) protein, its variant, isoform and / or fragment, wherein the variant, isoform and / or fragment has ADAM17 inhibitory activity, or a small molecule having ADAM17 inhibitory activity; and / or

[0013] b) a nucleic acid encoding AAT, a variant, an isoform and / or a fragment thereof, wherein said variant, isoform and / or fragment has inhibitory activity.

[0014] 2. The pharmaceutical product for use according to embodiment 1, wherein the inflammatory disease or disorder is an autoimmune inflammatory disease.

[0015] 3. The pharmaceutical product 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 wherein the inflammatory disease or disorder is neuropathic pain caused by an inflammatory disease or disorder of the nervous system.

[0016] 4. The pharmaceutical product for use according to any one of embodiments 1 to 3, wherein the inflammatory disease is chronic inflammatory demyelinating polyneuropathy.

[0017] 5. The pharmaceutical product for use according to embodiment 1 or 2, wherein the inflammatory disease is complex regional pain syndrome.

[0018] 6. The pharmaceutical product for use according to any one of embodiments 1 to 3, wherein the inflammatory disease or disorder is inflammatory pain.

[0019] 7. A kit for treating a disease or condition of the nervous system, the kit comprising:

[0020] i) a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof, wherein the variants, isoforms and / or fragments have inhibitory activity, or small molecules having ADAM17 inhibitory activity; and / or

[0021] b) a nucleic acid encoding AAT, a variant, isoform and / or fragment thereof, wherein the variant, isoform and / or fragment has inhibitory activity; and

[0022] ii) various IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants thereof.

[0023] 8. A pharmaceutical composition for treating a disease or disorder of the nervous system, the composition comprising:

[0024] i) a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof, wherein the variants, isoforms and / or fragments have inhibitory activity, or small molecules having ADAM17 inhibitory activity; and / or

[0025] b) a nucleic acid encoding AAT, a variant, isoform and / or fragment thereof, wherein the variant, isoform and / or fragment has inhibitory activity; and

[0026] ii) a plurality of IgG antibodies, IgG variants, isotypes and / or fragments thereof; and

[0027] iii) at least one pharmaceutically acceptable carrier.

[0028] 9. A method of treatment comprising administering to a subject an effective amount of a pharmaceutical composition, wherein the subject suffers from a disease or disorder of the nervous system, and wherein the subject is undergoing a therapy comprising administration of a plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants, the pharmaceutical composition comprising

[0029] a) AAT protein, its variant, isoform and / or fragment, wherein the variant, isoform and / or fragment has inhibitory activity, or a small molecule having ADAM17 inhibitory activity; and / or

[0030] b) a nucleic acid encoding AAT, a variant, an isoform and / or a fragment thereof, wherein said variant, isoform and / or fragment has inhibitory activity.

[0031] 10. A method of treatment comprising administering to a subject an effective amount of a pharmaceutical compound comprising a plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants, wherein the subject suffers from a disease or disorder of the nervous system, and wherein the subject is undergoing a therapy comprising administering:

[0032] a) AAT protein, its variant, isoform and / or fragment, wherein the variant, isoform and / or fragment has inhibitory activity, or a small molecule having ADAM17 inhibitory activity; and / or

[0033] b) a nucleic acid encoding AAT, a variant, an isoform and / or a fragment thereof, wherein said variant, isoform and / or fragment has inhibitory activity.

[0034] 11. The kit of parts 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.

[0035] 12. The kit of parts 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.

[0036] 13. The kit of parts 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 disease or disorder of the nervous system is chronic inflammatory demyelinating polyneuropathy.

[0037] 14. The pharmaceutical product 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 at least one symptom of chronic inflammatory demyelinating polyneuropathy or a history of at least one symptom of chronic inflammatory demyelinating polyneuropathy.

[0038] 15. The kit of parts 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, isotypes thereof, fragments thereof and / or IgG variants are plasma-derived IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants.

[0039] 16. The kit of parts 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, isotypes thereof, fragments thereof and / or IgG variants are recombinant IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants.

[0040] 17. The kit for use 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, the method of treatment according to any one of embodiments 9 to 16, wherein the plasma-derived IgG antibody, its isotype, its fragment and / or IgG variant is formulated for intravenous administration.

[0041] 18. The kit of parts for use 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, the method of treatment according to any one of embodiments 9 to 16, wherein the plasma-derived IgG antibody, its isotype, its fragment and / or IgG variant is formulated for subcutaneous administration.

[0042] 19. A pharmaceutical product for use according to any one of embodiments 1 to 6, a kit of parts for use according to any one of embodiments 7 and 11 to 18, a pharmaceutical composition for use according to any one of embodiments 8 and 11 to 18, a method of treatment according to any one of embodiments 9 to 18, wherein the AAT protein is recombinant AAT.

[0043] 20. A pharmaceutical product for use according to any one of embodiments 1 to 6, a kit of parts for use according to any one of embodiments 7 and 11 to 18, a pharmaceutical composition for use according to any one of embodiments 8 and 11 to 18, a method of treatment according to any one of embodiments 9 to 18, wherein the AAT protein is plasma-derived AAT.

[0044] 21. A pharmaceutical product for use according to any one of embodiments 1 to 6, 19 or 20, a kit of parts 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, a method of treatment according to any one of embodiments 9 to 20, wherein

[0045] a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof, wherein the variants, isoforms and / or fragments have inhibitory activity, or small molecules having ADAM17 inhibitory activity; and / or

[0046] b) a nucleic acid encoding AAT, a variant, an isoform and / or a fragment thereof, wherein said variant, isoform and / or fragment has inhibitory activity,

[0047] Formulated for intravenous administration.

[0048] 22. A pharmaceutical product for use according to any one of embodiments 1 to 6, 19 or 20, a kit of parts 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, a method of treatment according to any one of embodiments 9 to 20, wherein

[0049] a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof, wherein the variants, isoforms and / or fragments have inhibitory activity, or small molecules having ADAM17 inhibitory activity; and / or

[0050] b) a nucleic acid encoding AAT, a variant, an isoform and / or a fragment thereof, wherein said variant, isoform and / or fragment has inhibitory activity,

[0051] Formulated for subcutaneous administration.

[0052] Therefore, in one embodiment, the present invention relates to a pharmaceutical product for treating an inflammatory disease or condition, the pharmaceutical product comprising: a) an α1-antitrypsin (AAT) protein, a variant, isoform and / or fragment thereof, wherein the variant, isoform and / or fragment has inhibitory activity, or a small molecule with ADAM17 inhibitory activity; and / or b) a nucleic acid encoding AAT, a variant, isoform and / or fragment thereof, wherein the variant, isoform and / or fragment has inhibitory activity.

[0053] As used herein, the term "inflammatory disease or condition" refers to a disease, condition or illness characterized by increased inflammation in a tissue, organ or system 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 immune cell infiltration, activation, proliferation and / or differentiation in the blood and / or tissue. Inflammatory markers are markers indicating inflammation in a subject. In certain aspects, the inflammatory markers described herein are markers selected from the following groups: 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-2 Inflammatory markers can also be indirectly detectable, for example, by detecting inhibitors (for example, binding factors and / or antagonists) of inflammatory markers. In some aspects, 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 aspects, inflammatory markers indicate immune cell infiltration, activation, proliferation and / or differentiation. The detection of inflammatory markers or the ratio of two or more inflammatory markers is detected outside the normal range. The normal range of inflammatory markers and whether the markers (ratios) must be below or above a threshold value indicating inflammation are known to those skilled in the art. In some aspects, the gene expression level, RNA transcription level, protein expression level, protein activity level and / or enzyme activity level of at least one inflammatory marker are detected. In some aspects, at least one inflammatory marker is quantitatively and / or qualitatively detected to determine an inflammatory disease or condition in a subject in need of treatment and / or prevention.

[0054] In some aspects, inflammatory diseases or conditions described herein are characterized by acute inflammation, i.e., the duration of inflammatory symptoms usually takes about several minutes (e.g., 2 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes) to several days (e.g., 2 days, 3 days, 5 days, 7 days, 10 days or 14 days). In some aspects, inflammatory diseases or conditions are characterized by chronic inflammation, i.e., the duration of inflammatory symptoms usually takes at least about several days (e.g., 2 days, 3 days, 5 days, 7 days, 10 days or 14 days) or inflammatory symptoms at least recur once (e.g., one or more times, twice or more times or three times or more times). In some aspects, inflammatory diseases or conditions are characterized by chronic low-grade inflammation. Chronic low-grade inflammation can occur in the absence of clinical symptoms. In certain embodiments, inflammatory diseases described herein are inflammatory diseases characterized by increased inflammation affecting Schwann cell (SC) phenotype or health. In certain embodiments, inflammatory diseases described herein are inflammatory diseases characterized by increased inflammatory microglia and / or increased microglial inflammatory phenotype.

[0055] The inventors have found that AAT can inhibit TACE / ADAM17 in a dose-dependent manner, which rescues SC from producing myelin without being bound by theory, and thus subsequently prevents or slows down and / or reverses the progression of inflammatory diseases. In addition, when stimulated with the proinflammatory cytokine TNFα (TNF-α), α1-antitrypsin (AAT) protein and its variants can weaken the reactive oxygen species (ROS) response of SC. This indicates that AAT and its derivatives play a novel therapeutic effect by directly acting on Schwann cells (SC) and rescuing these cells from their inflammatory state back to their natural wild-type state (e.g., rescuing the ability of SC to restore myelin formation around axons). Therefore, this anti-inflammatory effect on SC in PNS or microglia in CNS is surprisingly effective in the treatment of inflammatory diseases involving these cells.

[0056] Thus, the present invention is based, at least in part, on the anti-inflammatory effects of AAT and variants, isoforms and / or fragments thereof.

[0057] In certain embodiments, the invention relates to a pharmaceutical product for use in the present invention, wherein the inflammatory disease or disorder is an autoimmune inflammatory disease.

[0058] As used herein, the term "autoimmune inflammatory disease" refers to a group of diseases or conditions in which tissue damage is associated with a humoral and / or cell-mediated immune response to a body part, or in a broader sense, with an immune response to oneself. The pathological immune response can be systemic or organ-specific. In certain embodiments, the autoimmune disease described herein is a disease selected from the group consisting of multiple sclerosis, myasthenia gravis, pernicious anemia, arthritis, Sjögren's syndrome ( syndrome, systemic lupus erythematosus, complex regional pain syndrome, and type 1 diabetes mellitus.

[0059] In certain embodiments, the invention relates to a pharmaceutical product for use in the invention, wherein the inflammatory disease or disorder is an inflammatory disease or disorder of the nervous system. In certain embodiments, the invention relates to a pharmaceutical product for use in the invention, wherein the inflammatory disease or disorder is neuropathic pain.

[0060] In certain embodiments, the invention relates to kits of parts, pharmaceutical compositions and methods of treatment for use in the invention, wherein the disease or disorder of the nervous system is neuropathic pain.

[0061] In certain embodiments, the invention relates to a pharmaceutical product for use in the present invention, wherein the inflammatory disease or disorder is neuropathic pain caused by an inflammatory disease or disorder of the nervous system.

[0062] As used herein, the term "inflammatory disease or disorder of the nervous system" refers to a disease, disorder or condition characterized by increased inflammation in the nervous system compared to a healthy reference subject.

[0063] In certain embodiments, the present invention relates to a pharmaceutical product for use in 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 product for use in 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 product for use in 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.

[0064] As used herein, the term "neuropathic pain" refers to pain caused by an injury or disease affecting the somatosensory system, preferably pain caused by an inflammatory disease or condition. As used herein, the term "neuropathic pain caused by an inflammatory disease or condition of the nervous system" refers to pain induced by damaged nerves, where the damage is caused by an inflammatory disease or condition. In certain embodiments, pain is considered to be "caused by" a disease if the disease and pain described herein are present, and the disease is known to have pain as a symptom, preferably where the disease is the most likely cause of the subject's pain.

[0065] In certain embodiments, the invention relates to a pharmaceutical product for use in the present invention, wherein the inflammatory disease is Complex Regional Pain Syndrome.

[0066] In certain embodiments, the invention relates to kits of parts, pharmaceutical compositions and methods of treatment for use in the invention, wherein the disease or disorder of the nervous system is complex regional pain syndrome.

[0067] As used herein, the term "complex regional pain syndrome" refers to a syndrome characterized by excessive and prolonged pain and inflammation following an injury, usually to the arms or legs.

[0068] In certain embodiments, the invention relates to a pharmaceutical product for use in the present invention, wherein the inflammatory disease or disorder is inflammatory pain.

[0069] In certain embodiments, the invention relates to kits of parts, pharmaceutical compositions and methods of treatment for use in the invention, wherein the disease or disorder of the nervous system is inflammatory pain.

[0070] 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.

[0071] As described herein, the term "pain" refers to a term as used in the art. In certain embodiments, pain as described herein is chronic pain, such that it occurs longer than 2 weeks, longer than 4 weeks, longer than 6 weeks, longer than 8 weeks or longer than 12 weeks. In certain embodiments, pain as described herein is a subject suffering from chronic pain or a subject under pain relief therapy (such as pharmacological pain treatment) or a subject suffering from chronic pain under pain relief therapy. In certain embodiments, pain as described herein occurs in the absence of a causal history of injury or surgery. In certain embodiments, pain as described herein is self-reported pain. Numerical rating scale (NRS) is the most commonly used pain scale for scoring pain on a scale of 0 to 10. In certain embodiments, pain as described herein is pain rated 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 NRS.

[0072] In certain embodiments, the present invention relates to a pharmaceutical product for treating pain caused by a disease or disorder of the nervous system, the pharmaceutical product comprising: a) α1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments, wherein the variants, isoforms and / or fragments have inhibitory activity, or a small molecule with ADAM17 inhibitory activity; and / or b) a nucleic acid encoding AAT, its variants, isoforms and / or fragments, wherein the variants, isoforms and / or fragments have inhibitory activity.

[0073] Oxidative stress has been well documented to be involved in neuropathic pain. The inventors found that oxidative stress is downregulated by AAT and its peptide derivatives, specifically in the SC which reduces pain.

[0074] Thus, the present invention is based, at least in part, on the effects of AAT and variants, isoforms and / or fragments thereof on oxidative stress.

[0075] In certain embodiments, the present invention relates to a pharmaceutical product for treating chronic inflammatory demyelinating polyneuropathy, which comprises: a) α1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments, wherein the variants, isoforms and / or fragments have inhibitory activity, or a small molecule with ADAM17 inhibitory activity; and / or b) a nucleic acid encoding AAT, its variants, isoforms and / or fragments, wherein the variants, isoforms and / or fragments have inhibitory activity.

[0076] Therefore, the drug product described herein may include α1-antitrypsin (AAT) protein, AAT variants with ADAM17 inhibitory activity, AAT isoforms with ADAM17 inhibitory activity, or AAT fragments with ADAM17 inhibitory activity, or any combination thereof. Additionally or alternatively, a small molecule with ADAM17 inhibitory activity may be included.

[0077] The terms "peptide," "protein," "polypeptide," "polypeptide," and "peptidic" are used interchangeably herein to refer to a series of amino acid residues linked to each other by peptide bonds between the α-amino and carboxyl groups of adjacent residues.

[0078] As used herein, the term "α1-antitrypsin" or "AAT" refers to a protease inhibitor belonging to the superfamily of serine protease inhibitors. 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 isoforms of AAT, preferably produced by alternative splicing. The sequences of AAT from different species and sources can be found in protein databases and nucleic acid databases, such as UniProt, Genbank, DDBJ and EMBL. In a very preferred embodiment, the term "AAT" includes variants as disclosed in protein databases and nucleic acid databases. In a very preferred embodiment, the term "AAT" refers to a protein having an amino acid sequence as defined by SEQ ID NO: 1 or a nucleotide sequence encoding a protein having an amino acid sequence as defined by SEQ ID NO: 1. In some embodiments, AAT described herein is a protein, a peptide or a polypeptide. The AAT protein can be obtained by separation from blood (e.g., human blood), or can be recombinantly produced.

[0079] The term "variant" refers to a protein, peptide or polypeptide having an amino acid sequence that is different from the AAT native sequence peptide (preferably SEQ ID NO: 1) to some extent, which is an amino acid sequence that is different from the AAT native sequence (preferably SEQ ID NO: 1) by amino acid substitution (wherein one or more amino acids are substituted by another amino acid having the same characteristics and conformational effects). Preferably, the variant described herein is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% homologous to the amino acids of SEQ ID NO: 1. The amino acid sequence variant may have a substitution, deletion and / or insertion at certain positions within the amino acid sequence of the native amino acid sequence (e.g., in the N-terminal sequence or C-terminal sequence or within the amino acid sequence). The substitution may also be conservative, in which case conservative amino acid substitutions are defined herein as exchanges within one of the following five groups:

[0080] I. Small aliphatic, nonpolar or weakly polar residues: Ala, Ser, Thr, Pro, Gly

[0081] II. Polar, positively charged residues: His, Arg, Lys

[0082] III. Polar, negatively charged residues: and their amides: Asp, Asn, Glu, Gln

[0083] IV. Large, aromatic residues: Phe, Tyr, Trp

[0084] V. Large, aliphatic, nonpolar residues: Met, Leu, Ile, Val, Cys.

[0085] In some embodiments, the AAT variants described herein are AAT variants having protease inhibitory activity, preferably having disintegrin and metalloproteinase 17 (ADAM17) inhibitory activity. "Disintegrin and metalloproteinase 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 system, preferably under the conditions described in Example 22). "Disintegrin and metalloproteinase 17 (ADAM17) inhibitory activity" is at least about 30% reduction in ADAM17 activity at 200uM, preferably at least about 30% reduction in ADAM17 activity at 100uM and / or at least about 45% reduction in ADAM17 activity at 200uM, more preferably at least about 45% reduction in ADAM17 activity at 15uM. In these embodiments, the concentration in uM can be the concentration of the AAT variant. In certain embodiments, wherein 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 is a sequence having no more than 5, no more than 4, no more than 3 or no more than one amino acid substitution compared to Ac-VKFNKPFVFLNleIEQNTK-NH2, preferably wherein the amino acid substitution is a conservative amino acid substitution. The sequence related to Ac-VKFNKPFVFLNleIEQNTK-NH2 may also include one or more terminal insertions. In certain embodiments, preferably in embodiments in which the AAT variant described herein is Ac-VKFNKPFVFLNleIEQNTK-NH2 or a sequence related to Ac-VKFNKPFVFLNleIEQNTK-NH2, the AAT variant is not used to treat acute nociceptive pain, inflammatory pain and neuropathic pain. In certain embodiments, Ac-VKFNKPFVFLNleIEQNTK-NH2 or a sequence related to Ac-VKFNKPFVFLNleIEQNTK-NH2 described herein is used to treat chronic inflammatory demyelinating polyneuropathy or a symptom thereof.

[0086] As used herein, the "isoform" of the AAT protein, peptide or polypeptide of the present invention refers to a splice variant caused by alternative splicing of AAT mRNA. In some embodiments, the AAT isoform described herein is an AAT isoform having ADAM17 inhibitory activity, preferably having ADAM17 inhibitory activity, more preferably having a disintegrin and metalloproteinase 17 (ADAM17) inhibitory activity.

[0087] As used herein, a "fragment" of an AAT protein, peptide or polypeptide of the present invention refers to a sequence containing fewer amino acids in length than an AAT protein, peptide or polypeptide of the present invention, in particular, a sequence of fewer amino acids such as the sequence of AAT shown in SEQ ID NO: 1. The fragment is preferably a functional fragment, for example, a fragment having the same biological activity as the AAT protein shown in SEQ ID NO: 1. The functional fragment is preferably derived from the AAT protein shown in SEQ ID NO: 1. Any AAT fragment can be used as long as it exhibits the same properties as the natural AAT sequence from which it is derived, i.e., has biological activity. In some embodiments, the AAT fragment described herein is an AAT fragment having protease inhibitory activity, preferably ADAM17 inhibitory activity, more preferably having disintegrin and metalloproteinase 17 (ADAM17) inhibitory activity.

[0088] Preferably, the (functional) fragment shares about 5 consecutive amino acids, at least about 7 consecutive amino acids, at least about 15 consecutive amino acids, at least about 20 consecutive amino acids, at least about 25 consecutive amino acids, at least about 20 consecutive amino acids, at least about 30 consecutive amino acids, at least about 35 consecutive amino acids, at least about 40 consecutive amino acids, at least about 45 consecutive amino acids, at least about 50 consecutive amino acids, at least about 55 consecutive amino acids, at least about 60 consecutive amino acids, at least about 100 consecutive amino acids, at least about 150 consecutive amino acids, at least about 200 consecutive amino acids, at least about 300 consecutive amino acids or more of the natural human AAT amino acid sequence as shown in SEQ ID NO: 1. In some embodiments, the (functional) fragment described herein comprises an expression-optimized signal protein. In certain embodiments, the fragments described herein are derived from the C-terminus of AAT, so that the fragment shares about 5 consecutive amino acids, at least about 7 consecutive amino acids, at least about 15 consecutive amino acids, at least about 20 consecutive amino acids, at least about 25 consecutive amino acids, at least about 20 consecutive amino acids, at least about 30 consecutive amino acids, at least about 35 consecutive amino acids, at least about 40 consecutive amino acids, at least about 45 consecutive amino acids, at least about 50 consecutive amino acids, at least about 55 consecutive amino acids, at least about 60 consecutive amino acids, at least about 100 consecutive amino acids, at least about 150 consecutive amino acids or more consecutive amino acids of the natural human AAT amino acid sequence as shown in SEQ ID NO: 2. In very preferred embodiments, the fragment is derived from the C-terminus of AAT, so that the fragment shares about at least about 200 or more of the natural human AAT amino acid sequence as shown in SEQ ID NO: 2. In very preferred embodiments, the fragment has the sequence of SEQ ID NO: 2.

[0089] As used herein, " small molecule " with ADAM17 inhibitory activity refers to a molecule with a molecular weight of less than 1500kD, less than 1400kD, less than 1300kD, less than 1200kD, less than 1100kD, less than 1000kD, less than 900kD, less than 800kD, less than 700kD, less than 600kD, less than 500kD or less than 400kD. In certain embodiments, small molecule as described herein is a peptide with a molecular weight between 1500kD and 500kD, preferably between 1300kD and 600kD, more preferably between 1100kD and 700kD. The example of such peptides is given as peptide 9 and peptide 8 in Example 22. In certain embodiments, small molecule is a variant of peptide 9 and peptide 8, in which one or two amino acids are substituted, inserted or removed, preferably substituted by conservative amino acid substitutions. In certain embodiments, small molecules as described herein are molecules with a molecular weight between 1000kD and 50kD, preferably between 600kD and 100kD, more preferably between 400kD and 200kD. Examples of such small molecules (peptide mimetics 14) are provided in Example 22. Those skilled in the art know how to identify other small molecules for use in the present invention, such as by following the teachings of Lior, Yotam et al. (European Journal of Medicinal Chemistry (European Journal of Medicinal Chemistry) 228 (2022): 113969) and as described in Example 22, ADAM17 inhibitory activity is screened.

[0090] In some embodiments, the amino acid sequence of AAT, a variant, isoform or fragment thereof as described herein is at least 80% identical to the corresponding amino acid sequence in SEQ ID NO: 1. In some embodiments, the amino acid sequence of AAT, a variant, isoform or fragment thereof 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 in SEQ ID NO: 1.

[0091] 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.) polymers or a combination of deoxyribonucleotide and ribonucleotide (e.g., DNA / RNA) polymers in linear or circular conformation and single-stranded or double-stranded form. These terms should not be construed as limitations on polymer length, and may encompass known analogs of natural nucleotides, as well as nucleotides modified in the base, sugar and / or phosphate moieties (e.g., phosphorothioate backbones). Typically, analogs of a particular nucleotide have the same base pairing specificity; i.e., an analog of A will base pair with T.

[0092] As used herein, the term "treatment" (and grammatical variants such as "treat" or "treating") refers to clinical intervention that attempts to alter the natural course of the individual being treated, and can be used preventively or during clinical pathological processes. Desired therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, reducing the rate of disease progression, ameliorating or alleviating the disease state, and alleviating or improving prognosis. In some embodiments, the antibodies of the invention are used to delay the development of a disease or slow the progression of a disease.

[0093] CIDP is an acquired polyneuropathy within the peripheral nervous system with a presumed autoimmune-mediated pathogenesis. CIDP is characterized by symmetrical weakness of proximal and distal muscles that gradually worsens. The disease is usually, but not always, associated with impaired sensation, absent or reduced tendon reflexes, elevated 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, e.g., Mathey EK, et al. J Neurol Neurosurg Psychiatry 2015; 86: 973-985; H, et al. New England Journal of Medicine (N Engl J Med.) 2005; 352(13): 1343-1356), the former is much more common in young adults. CIDP is a rare disease with an estimated prevalence of about 1.6 to 8.9 cases per 100,000 adults and about 0.5 cases per 100,000 children. CIDP can be diagnosed as described by a joint working group of EFNS and PNS (Journal of the Peripheral Nervous System 15: 1-9 (2010)).

[0094] The following conditions are identical or considered to be essentially identical to CIDP and are therefore encompassed by the term "CIDP": "chronic relapsing polyneuropathy", "chronic idiopathic demyelinating polyneuropathy", "chronic inflammatory demyelinating polyradiculoneuropathy", and "chronic acquired demyelinating polyneuropathy" ("CADP").

[0095] The inventors found that AAT can reduce neuronal pathological pathways (Figures 2-4, Tables 1-10). This reduction in neuronal pathological pathways was observed in both resting cells (Figure 4B) and stimulated cells ( Figure 4C ) and can therefore be used to prevent and / or treat diseases or disorders of the nervous system and their symptoms.

[0096] Modulation of TACE / ADAM17 activity is involved in myelin regulation and serves as an inflammatory hallmark in chronic inflammatory demyelinating polyneuropathy.

[0097] The inventors have found that AAT is able to inhibit TACE / ADAM17 in a dose-dependent manner, which, without being bound by theory, rescues SCs from producing myelin and thus subsequently prevents or slows and / or reverses the progression of chronic inflammatory demyelinating polyneuropathy. Thus, the combined anti-inflammatory and neuroprotective / regenerative effects are surprisingly effective in treating chronic inflammatory demyelinating polyneuropathy.

[0098] Thus, the present invention is based, at least in part, on the discovery that AAT can be used to treat diseases or disorders of the nervous system as described herein.

[0099] According to some embodiments, the treatment described herein includes a single dose of the total amount of AAT. According to certain embodiments, the effective amount of AAT is about 10 mg / kg body weight / week to about 1000 mg / kg body weight / week of AAT, preferably about 10 mg / kg body weight / week to about 500 mg / kg body weight / week of AAT (or an equivalent amount of AAT variants, fragments, isoforms and / or corresponding nucleic acids). According to certain embodiments, the effective amount of AAT is about 30 mg / kg body weight / week to about 240 mg / kg body weight / week of AAT, preferably about 60 mg / kg body weight / week to about 120 mg / kg body weight / week of AAT (or an equivalent amount of AAT variants, fragments, isoforms and / or corresponding nucleic acids). According to certain embodiments, the effective amount of AAT (or an equivalent amount of AAT variants, fragments, isoforms and / or corresponding nucleic acids) 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, the effective amount of AAT (or an equivalent amount of an AAT variant, fragment, isoform and / or corresponding nucleic acid) is higher than about 100 mg / kg / day, preferably between about 100 mg / kg / day to about 1000 mg / kg / day, more preferably between about 100 mg / kg / day to about 500 mg / kg / day, more preferably between about 150 mg / kg / day to about 250 mg / kg / day, more preferably between about 150 mg / kg / day to about 210 mg / kg / day.

[0100] According to other embodiments, treatment as described herein includes multiple partial doses of multiple administrations to reach the total cumulative dose of AAT. According to certain embodiments, each partial dose comprises about 5 mg / kg to about 500 mg / kg, preferably 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 AAT variants, fragments, isoforms and / or corresponding nucleic acids or small molecules). Each possibility represents a separate embodiment of the present invention.

[0101] In one embodiment, the present invention relates to a kit for treating a disease or disorder caused by the nervous system, comprising: i) a) α1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments, wherein the variants, isoforms and / or fragments have inhibitory activity; and / or b) nucleic acids encoding AAT, its variants, isoforms and / or fragments having ADAM17 inhibitory activity, and ii) a plurality of IgG antibodies, their isoforms, their fragments and / or IgG variants.

[0102] As used herein, the term "multiple 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, multiple IgG antibodies recognize at least two different epitopes or antigens. In certain embodiments, multiple IgG antibodies include IgG antibodies of several IgG subtypes. In certain embodiments, multiple IgG antibodies are polyclonal antibodies. In certain embodiments, multiple IgG antibodies are not monoclonal antibodies. In certain embodiments, multiple IgG antibodies described herein include IgG antibodies derived from IgG antibody human plasma, preferably combined IgG antibodies. The isotype of IgG antibody, the fragment of IgG antibody and / or IgG variants can also be combined with multiple IgG antibodies (e.g., added to multiple IgG antibodies or not separated therefrom). In certain embodiments, these isotypes, fragments and variants are naturally occurring isotypes, fragments and / or variants. In other embodiments, isotypes, fragments and / or variants are produced separately and added to IgG antibodies.

[0103] In general, the term "antibody" is used in the broadest sense herein and covers various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), fully human antibodies and antibody fragments, as long as they show the desired antigen binding activity. In some embodiments, the IgG antibodies described herein are from IgG1, IgG2, IgG3 and / or IgG4 subtypes. In some embodiments, the IgG antibodies described herein include polyclonal IgG antibodies. In some embodiments, the IgG antibodies described herein are part of immunoglobulin therapy. As used herein, the term "immunoglobulin therapy" generally refers to intravenous, subcutaneous or intramuscular administration of IgG immunoglobulin compositions to patients to treat a variety of diseases, such as immunodeficiency, inflammatory diseases and autoimmune diseases. IgG immunoglobulins are generally combined and prepared from plasma. Whole antibodies or fragments can be used. IgG immunoglobulins can be formulated for subcutaneous administration in higher concentrations (e.g., greater than 10%), or formulated for intramuscular administration. This is especially common for special IgG preparations prepared with an average titer higher than that of a specific antigen (e.g., Rho D factor, pertussis toxin, tetanus toxin, botulism toxin, rabies, etc.). Preparations for immunoglobulin therapy are known in the art (see, e.g., US8940877B2). Immunoglobulin therapy can be derived from mammalian, preferably human, plasma. In certain embodiments, the plasma of multiple (usually 1000 or more) healthy donors is combined and optionally further processed. The term "healthy individual" means an individual who meets the current (when donating blood) blood donation standard qualification criteria, keeping in mind that such qualification criteria will continue to improve and change. In some embodiments, immunoglobulin fractions are enriched from the combined plasma. Preferably, immunoglobulins are purified from the combined plasma. More preferably, immunoglobulins are purified and concentrated. In various embodiments, purified and concentrated immunoglobulin G (IgG) is used. In certain embodiments, 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 a preferred embodiment, the IgA concentration is 25 μg or less per 100 mg of immunoglobulin. In order to avoid adverse events in patients with IgA deficiency, low IgA is desirable. In one embodiment, the IgM concentration is 10 μg or less per 100 mg of immunoglobulin. In a preferred embodiment, the IgM concentration is 5 μg or less per 100 mg of immunoglobulin. In various embodiments, the immunoglobulin therapy shows a purity of protein fraction> 90% IgG, more preferably> 95% IgG, even more preferably> 98% IgG. In various embodiments, the immunoglobulin therapy shows immunoglobulin monomer and dimer content> 90%, more preferably> 95%, even more preferably> 98%.The immunoglobulin therapy preferably shows a natural IgG subtype distribution. In one embodiment, the immunoglobulin subtype distribution in the immunoglobulin therapy is 62-74% IgG1, 22-34% IgG2, 2-5% IgG3 and 1-3% IgG4. The immunoglobulin therapy may contain additional ingredients such as stabilizers, for example amino acids such as proline or glycine, or sucrose, maltose, sorbitol, albumin nicotinamide, PEG, polysorbate 80 or other. Preferred stabilizers are amino acids, particularly proline. In various embodiments, the immunoglobulin therapy contains 10-30% (w / v) immunoglobulin. In certain embodiments, the immunoglobulin therapy is provided in the form of a solution containing at least 10% (w / v) immunoglobulin, more preferably at least 15% (w / v) immunoglobulin, most preferably about 20% (w / v) immunoglobulin. The immunoglobulin therapy may also contain about 30% (w / v) immunoglobulin. Immunoglobulin therapy is virus-safe for enveloped viruses (e.g., HIV, HBV, and HCV) and non-enveloped viruses (e.g., HAV and parvovirus B19). Immunoglobulin therapy can be provided in the form of a liquid product or a lyophilized product. In a preferred embodiment, immunoglobulin therapy is provided in the form of a liquid product. Such liquid products are readily available, i.e., the product does not need to be reconstituted before administration. Liquid products are easy to use because reconstruction is not required. Therefore, liquid products are particularly suitable for self-administration by patients. In some embodiments, the dosage of IgG antibodies is individually adjusted or a fixed dose. In some embodiments, the IgG antibodies described herein are administered in a dose selected from about 0.1 g / kg patient weight to about 0.4 g / kg patient weight, about 0.1 g / kg patient weight to about 0.3 g / kg patient weight, about 0.15 g / kg patient weight to about 0.25 g / kg patient weight, about 0.18 g / kg patient weight to about 0.22 g / kg patient weight, or about 0.2 g / kg patient weight every 5-10 days or every 6-8 days per week, preferably about 0.18 g / kg patient weight to about 0.22 g / kg patient weight every 6-8 days. In some embodiments, the dose of the IgG antibody is administered in a single dose or in 2, 3, 4, 5, 6, or 7 doses per week.

[0104] As used herein, the term "disease or disorder of the nervous system" refers to a group of diseases or disorders in which the pathology involves 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: 12q14 microdeletion syndrome, 15q13.3 microdeletion syndrome, 15q24 microdeletion syndrome, 22q11.2 microdeletion syndrome, 22q13.3 microdeletion 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-pyruvoyltetrahydropterin synthase deficiency, Aarskog syndrome, abetalipoproteinemia, Abri Amyloidosis, lack of septum pellucidum, aceruloplasminemia, acrocallosal syndrome, acrofacial dysostosis of Catania type, Catania type), acrofacial dysostosis Rodriguez type, acute cerebellar ataxia, acute cholinergic autonomic dysfunction, acute CNS demyelinating event, acute disseminated encephalomyelitis, acute inflammatory demyelinating polyneuropathy, acute intermittent porphyria, acute motor and sensory axonal neuropathy syndrome, ADCY5-related movement disorder, adenosine monophosphate deaminase 1 deficiency, adenylate succinate lyase deficiency, Addison syndrome, adrenomyoneuropathy, adult polysaccharidosis, adult-onset nemaline myopathy, advanced sleep phase syndrome, absence of corpus callosum, age-related peripheral neuropathy, age-related peripheral neuropathy, agnosia, Aicardi syndrome, Aicardi-Goutieres syndrome, AIDS dementia complex, Al Gazali AzizSalem syndromesyndrome), alaninuria, albino-deafness syndrome, sensory motor disorders caused by alcohol or malnutrition, 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), Allan-Herndon-Dudley syndrome, Moina's alopecia-epilepsy-infantilism syndrome, alopecia, epilepsy, pyorrhea, mental disorder, alopecia-epilepsy-pyorrhea-intellectual disability syndrome alopecia-mental disability syndrome, Alpers syndrome, alpha-ketoglutarate dehydrogenase deficiency, alpha-mannosidosis, alpha-thalassemia X-linked intellectual disability syndrome, alternating hemiplegia of childhood, Alzheimer's disease type 4, Alzheimer's disease, Alzheimer's disease without neurofibrillary tangles, aminoacylase 1 deficiency, aminolevulinic acid dehydratase deficiency porphyria, Amish lethal microcephaly, Amish nemaline myopathy, amyloid neuropathy, amyopathic dermatomyositis, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis type 6, amyotrophic lateral sclerosis-parkinsonism / dementia syndrome 1, amyotrophic lateral sclerosis, anaplastic astrocytoma, anaplastic ganglioglioma, anaplastic oligodendroglioma, Anderman syndrome, Anderson-Tawil syndrome syndrome), anemia sideroblastic ataxia, spinocerebellar ataxia, anencephaly, hemangioma hereditary neurocutaneous, aniridia, aniridia renal agenesis, psychomotor retardation, antisynthetase syndrome, aortic arch anomaly, apraxia, arachnoid cyst, arachnoiditis, aromatic L-amino acid decarboxylase deficiency, arthrogryposis multiplex congenita, distal, X-linked, arthrogryposis renal dysfunction cholestatic syndrome, Ellison syndrome, aspartylglucosaminuria, ataxia, ataxia-telangiectasia, ataxia with oculomotor ataxia type 1, ataxia with oculomotor ataxia type 2, ataxia with oculomotor ataxia type 4, ataxia with vitamin E deficiency, ataxia-telangiectasia, osteodysplasia type 2, osteodysplasia type 3, Atkin syndrome, atypical Rett syndromeRettsyndrome), aseptic meningitis, autism with port-wine stains, autosomal dominant centronuclear myopathy, autosomal dominant cerebellar ataxia / deafness / narcolepsy, autosomal dominant Charcot-Marie-Tooth disease type 2 with giant axons, autosomal dominant deafness-Adystrophy syndrome, autosomal dominant Charcot-Marie-Tooth disease intermediate, autosomal dominant leukodystrophy with autonomic disease, autosomal dominant neuronal ceroid lipofuscinosis 4B, autosomal dominant nocturnal frontal lobe epilepsy, autosomal dominant nonsyndromic intellectual disability, autosomal dominant optic atrophy superimposed syndrome, autosomal dominant partial epilepsy with auditory features, autosomal dominant spinal muscular atrophy, autosomal recessive axonal Synaptic neuropathy with neuromyotonia, autosomal recessive centronuclear myopathy, autosomal recessive Charcot-Marie-Tooth disease with hoarseness, autosomal recessive Charcot-Marie-Tooth disease type A, autosomal recessive 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 spastic ataxia 4, autosomal recessive spastic paraplegia 49, autosomal recessive spinocerebellar ataxia 9, B4GALT1-CDG (CDG-IId), Bannayan-Riley-Ruvalcaba syndrome (Bannayan-Riley-Ruvalcaba syndrome syndrome, Barth syndrome, Battaglia-Neri syndrome, Becker muscular dystrophy, behavioral variant of frontotemporal dementia, Behcet's disease disease), Bell's palsy, benign essential blepharospasm, benign familial neonatal epilepsy, benign familial neonatal-infantile epilepsy, benign hereditary chorea, benign Benignrolandic epilepsy (BRE), beta-propeller protein-related neurodegeneration, Bethlemmyopathy, bilateral frontal polymicrogyria, bilateral frontoparietal polymicrogyria, bilateral diffuse microgyria, bilateral parasagittal parieto-occipital polymicrogyria, bilateral perisylvian polymicrogyria, Binswanger's disease, biotinidase deficiency, biotin-thiamine-responsive basal ganglia, Birk-Barel syndrome, Bixler Christian Gorlin syndrome, blepharofacial dysmorphism syndrome, nodding doll syndrome, Bohring-Opitz syndrome, Borjeson-Forssman-Lehmann syndrome, Bowen-Conradi syndrome, brachiogenital syndrome, brachydactyly-midlimb malformation-mental disability-heart defect syndrome, brain dopamine-serotonin vesicular transport disease, brain-lung-thyroid syndrome, branchial arch syndrome X-linked, Brodymyopathy, Brooks Wisniewski Brown syndrome, hemisection of the cord syndrome, bullous dystrophy, C syndrome, Cabezas syndrome, CADASIL, kyphosis, flexor dorsiflexion-arthropathy-coxa vara-pericarditis syndrome, CANOMAD syndrome, Cantu syndrome, cap myopathy, cardiofacial-cutaneous syndrome, Carey-Fineman-Ziter syndrome, Carney syndrome complex), cataract ataxia deafness, CatelManzke syndrome, caudal deafness, caudal regression sequence, central axonal disease, CNS germ cell tumor, central neurocytoma, central pain syndrome, central pontine myelinolysis, cerebellar ataxia, cerebellar degeneration, cerebellar hypoplasia, cerebellitis, cerebellar parenchymal disease 3, hydrocephalus with cerebellar hypoplasia, autosomal recessive cerebral arteriopathy, cerebral cavernous malformation, cerebral dysplasia, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome , cerebral folate deficiency, brain gigantism, jaw cyst, cerebral palsy, cerebral palsy ataxia, cerebral palsy with athetoid arthritis, spastic cerebral palsy with hemiplegia, spastic cerebral palsy, cerebral palsy with spastic quadriplegia, cerebral sclerosis, cerebrofacial joint syndrome, cerebro-oculofacial skeletal syndrome, cerebro-oculonasal syndrome, cerebrospinal fluid leakage, cerebro-tendinous xanthomatosis, neuronal ceroid lipofuscinosis type 1, cervical hypertrichosis peripheral neuropathy, Chanarin-Dorfman syndrome 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, leukocytic hypochromia syndrome, Chiari malformation, Chiari malformation type 1, Chiari malformation type 2, Chiari malformation type 4, childhood apraxia of speech, childhood nemaline myopathy, chorea-acanthocytosis, choroid plexus carcinoma, choroid plexus papilloma, Christianson syndrome, 17p13.1 chromosome deletion syndrome, 17q11.2 chromosome deletion syndrome, 19q13.11 chromosome deletion syndrome, 1p36 chromosome deletion syndrome, 3p-chromosome syndrome, chronic hiccups, chronic lymphocytic inflammation, chronic progressive external ophthalmoplegia, Chudley Rozdilsky syndrome, cisplatin-induced sensory neuropathy, cleft palate, short stature, spinal anomalies, cluster headaches, COACH syndrome, COASY protein-related neurodegeneration, outer exudative retinopathy (coats disease), Cobb syndrome, Coffin's syndrome type I, Coffin's syndrome type II, Coffin's syndrome type III, coenzyme Q10 deficiency, Coffin-Lowry syndrome, Coffin-Siris syndromeSyndrome), COG1-CDG (CDG-IIg), COG4-CDG (CDG-IIj), COG5-CDG (CDG-IIi), COG7-CDG (CDG-IIe), COG8-CDG (CDG-IIh), Cohen's syndrome, cold-induced sweating syndrome, complex regional pain syndrome, congenital central hypoventilation syndrome, congenital cytomegalovirus, congenital fiber type imbalance, congenital extraocular muscle fibrosis, congenital generalized lipodystrophy type 4, congenital insensitivity to pain, congenital insensitivity to pain with anhidrosis, congenital intrauterine infection-like syndrome, congenital laryngeal paralysis, congenital mirror movement disorder, congenital muscular dystrophy, congenital myasthenic syndrome, congenital rubella, congenital toxoplasmosis, slow-wave sleep continuous spike-and-wave syndrome, tics, corneal hypoesthesia, De Lange syndrome, corpus callosum agenesis, cortical blindness, cortical dysplasia, cortical basal degeneration, Costello syndrome (Costello syndrome), Crane-Heise syndrome, cranial nerve palsy, craniopharyngioma, craniospinal fissure, craniocaudal dysplasia, Creutzfeldt-Jakob disease, Crome syndrome, Curry-Jones syndrome, cylindrical spiral myopathy, Cyprus facial neuromusculoskeletal syndrome, giant cell inclusion disease, D-2-hydroxyglutaric aciduria, Dandy-Walker cyst cyst), Dandy-Walker malformation, Dandy-Walker malformation, Danon disease, dapsone-induced neuropathy, DDOST-CDG (CDG-Ir), DEAF1-related disorders, dentatorubral pallidum Lewy body atrophy, dermatomyositis, familial developmental aphasia, diabetic neuropathy, dihydrolipoamide dehydrogenase deficiency, dihydropterin reductase deficiency, diphtheria, distal myopathy with vocal cord weakness, DOOR syndrome, dopamine beta-hydroxylase deficiency, dopamine transporter deficiency syndrome, dopa-responsive dystonia, DPAGT1-CDG (CDG-Ij), DPM1-CDG (CDG-Ie), DPM2-CDG, DPM3-CDG (CDG-Io), Dravet syndrome, Duane syndrome, Dubowitz syndrome, Duchenne muscular dystrophy dystrophy), Dykes MarkesHarper syndrome, paraautonomic dysregulation, dysequilibrium syndrome, dyskeratosis congenita, autosomal dominant dyskeratosis congenita, autosomal recessive dyskeratosis congenita, X-linked dyskeratosis congenita, myoclonic cerebellar dyssynergia, 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-mental disability syndrome, eastern equine encephalitis, vacuolar sella syndrome, epidemic encephalitis, craniocerebral lipoma, encephalopathy, eosinophilic fasciitis, eosinophilic granuloma, ependymoma, simplex epidermolysis bullosa with muscular dystrophy, juvenile absence epilepsy, epilepsy Occipital calcification, progressive myoclonic epilepsy type 3, epilepsy with myoclonic-asthenic seizures, epiphyseal dysplasia, hearing loss, malformations, paroxysmal ataxia, erythromelalgia, essential tremor, Fabry disease, facial-onset neuronopathy, facioscapulohumeral muscular dystrophy, Fallot syndrome, familial amyloidosis, familial bilateral striatal necrosis, familial caudal dysplasia, familial congenital trochlear nerve palsy, familial autonomic dysfunction, familial encephalopathy, familial exudative vitreoretinopathy, familial focal epilepsy, familial hemiplegic migraine, familial hemophagocytic lymphohistiocytosis, familial infantile seizures, familial paroxysmal infantile choreoathetosis, familial syringencephaly, familial transthyretin amyloidosis, familial or sporadic hemiplegic migraine, Farber disease disease), fatal familial insomnia, fatal infantile encephalomyopathies, fatty acid hydroxylase-associated neurodegenerative diseases, FBXL4-associated encephalomyopathies, mitochondrial DNA depletion syndrome, febrile infection-associated epilepsy syndrome, Feigenbaum Bergeron Richardson syndrome, Filippi syndrome, Fine-Lubinsky syndrome, fingerprint myopathy, Fitzsimmons Walson Mellor syndrome

[0105] , Fitzsimmons-Gilbert syndrome, Floating-Harbor syndrome, Flynn Aird syndrome, focal dermal dysplasia, focal motor weakness, focal segmental glomerulosclerosis, fountain syndrome, FOXG1 syndrome, fragile X syndrome, fragile XE syndrome, Friedreich's ataxia

[0106] , frontometaphyseal dysplasia, frontotemporal dementia, frontotemporal dementia, Fryns syndrome, fucosidosis, Fukuyama muscular dystrophy, fumarase deficiency, galactosialidosis, Galloway-Mowat syndrome, gamma-aminobutyric acid aminotransferase deficiency, ganglioneuroma, GAPO syndrome, Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Gemini syndrome, Genitopatellar syndrome, Genoa syndrome, Gerstmann syndrome, Gerstmann-Straussler-Scheinker disease, giant axonal neuropathy, Gillespie syndrome syndrome), gliomatosis cerebrovascularis, glucose transporter type 1 deficiency syndrome, 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 1, GM1 gangliosidosis type 2, GM1 gangliosidosis type 3, GM3 synthase deficiency, GMS syndrome, Goldberg-Shprintzen megacolon syndrome, Gomez Lopez Hernandez syndrome, GOSR2-associated progressive myoclonic ataxia, Graham-Cox syndrome, granulomatosis with polyangiitis, Griseli syndrome type 1, Grubben De Kock-Borggrave syndrome CockBorghgraefsyndrome), GTP cyclohydrolase I deficiency, GTPCH1 deficiency DRD, guanidine acetate methyltransferase deficiency, Guillain-Barré syndrome, Gurrieri syndrome, choroidal and retinal gyration atrophy, hair deficiency-photosensitivity-mental disability syndrome, craniofacial malformation syndrome (Hallermann-Streiffsyndrome), Hall-Riggs syndrome, Hamanishi Ueba Tsuji syndrome, Hansen'sdisease, Harding ataxia, Harlequin syndrome, HarrodDomanKeele syndrome, Hartnup disease, Hashimoto's encephalopathy, hemangioblastoma, persistent migraine, hemibrain megalencephaly,Hennekam Syndrome, hereditary vasculopathy, hereditary coproporphyria, hereditary 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 hyperekplexia, hereditary motor and sensory neuropathy type 5, hereditary pressure-prone peripheral neuropathy (HNPP), hereditary tendency 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 to 7 (HSAN I-VII), hereditary sensory and autonomic neuropathy type V, hereditary sensory neuropathy type 1, hereditary spastic paraplegia, hereditary vascular retinopathy, Hernández-Aguirre Negrete syndrome, herpes simplex encephalitis, herpes zoster oticus, HIBCH deficiency, homocystinuria, scoliosis with progressive horizontal gaze palsy, Hoyeraal Hreidarsson syndrome, HSD10 disease, HTLV-1-associated myelopathy / tropical spastic paraplegia, human HOXA1 syndrome, human immunodeficiency virus-induced neuropathy, Huntington disease, Huntington's disease, Hurler syndrome, Hurler-Scheie syndrome), hydrocephalus, hydrocephalus (e.g. due to congenital cerebral aqueductal stenosis), hydrocephalus-cleft palate-arthrogryposis syndrome, hydroxykynureninuria, hyperbeta-alaninemia, hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency, hyperkalemic periodic paralysis, hypermethioninemia, hyperphenylalaninemia, hyperprolinemia, hyperprolinemia type 2, Dejerine-Sottas hypertrophic neuropathy, hypocalcemia, autosomal dominant inheritance, hypokalemic periodic paralysis, hypochromia of Ito, Hypomyelination (e.g., with basal ganglia and / or cerebellar atrophy), hypoparathyroidism-intellectual disability-malformation syndrome, hypospadias-intellectual disability, Goldblatt-type syndrome, hypothalamic hamartoma, ichthyosis, alopecia, ectropion, ectropion, intellectual disability, idiopathic intracranial hypertension, idiopathic spinal cord herniation, inclusion body myositis, incontinence pigmenti, infantile axonal neuropathy, infantile cerebellar retinal degeneration, infantile choroidal cerebral calcification syndrome, infantile myofibromatosis, infantile neuroaxonal dystrophy, infantile-onset spinocerebellar ataxia,Infantile spasmodic broad thumb, ascending hereditary spastic palsy of infantile onset, infection-induced acute encephalopathy type 3, intellectual disability Buenos Aires type, athetosis intellectual disability, corpus callosum agenesis intellectual disability, intellectual disability-developmental delay-contracture syndrome, intellectual disability-malformation-hypogonadism-diabetes syndrome, intellectual disability-severe speech delay-mild malformation syndrome, intellectual disability-spasticity-ectodactyly syndrome, intermediate congenital linear myopathy, internal carotid artery agenesis, intraneural perineurial tumor, IRVAN syndrome, Isaacs' syndrome, chromosome 15 and other dicentric syndromes, Johanson-Blizzard syndrome, Johnson neuroectodermal syndrome, Joubert syndrome, Juberg Marsidi syndrome, juvenile amyotrophic lateral sclerosis, juvenile dermatomyositis, juvenile Huntington's disease, juvenile polymyositis, juvenile primary lateral sclerosis, Kabuki syndrome, Kanzaki disease, Kapur-Toriello syndrome, Kaufman oculocerebrofacial syndrome, KBG syndrome, KCNQ2-related disorders, Kearns-Sayre syndrome, Kennedy disease, keratosis pilaris dwarfism, brain atrophy, kernicterus, Keutel syndrome, King Denborough syndrome, Kleefstra syndrome, Kleine Levin syndrome syndrome), Klumpke paralysis, Kosztolanyi syndrome, Kozlowski-Krajewska syndrome, Krabbe's disease, Kuru, Cushing-Andermann syndrome, L-2-hydroxyglutaric aciduria, La Crosse encephalitis, lip and palate syndrome, Lafora disease, Laing distal myopathy, Lambert Eaton myasthenic syndrome,Acquired epileptic aphasia syndrome (Landau-Kleffner syndrome), L-arginine:glycine amidinotransferase deficiency, late-onset distal myopathy, Markesbery-Griggs 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., thalamic and brainstem involvement and hyperlactate), Levic Stefanovic Nikolic syndrome, Lewis-Sumner syndrome, cerebellar dysplastic ganglioneuroma (Lhermitte-Duclos disease), Li-Fraumeni syndrome, limb-girdle muscular dystrophy (e.g., 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, limited cutaneous systemic sclerosis, lipoic acid synthase deficiency, anencephaly 1, anencephaly 2, X-linked anencephaly, focal hypertrophic neuropathy, locked-in syndrome, progressive aphasia, Lowe oculocerebrorenal syndrome, Lowry-Maclean syndrome, Lujan syndrome, Lyme disease disease), Mac Dermot Winter syndrome, macrocephaly-dwarfism-paraplegia syndrome, giant thrombocytopenia progressive deafness, mal de debarquement syndrome, male pseudohermaphroditism intellectual disability syndrome, malignant hyperthermia, malignant hyperthermia torticollis joint contracture, malignant migratory partial epilepsy of infancy, MAN1B1-CDG, mandibular and facial dysostosis (e.g. with microcephaly), mannosidosis,Marchiafava Bignami disease, Marden-Walker syndrome, Marfanoid body type-autosomal recessive intellectual disability syndrome, Marinesco-Sjogren syndrome, Martsolf syndrome, Mcdonough syndrome, McLeodneuroacanthocytosis syndrome, Meckel syndrome, MECP2 duplication syndrome, medrano roldan syndrome, medulloblastoma, megalencephalic leukoencephalopathy (e.g. with subcortical cysts), megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, megaloblastic anemia, megalocornea-intellectual disability syndrome syndrome), Mehes syndrome, MEHMO syndrome, Meier-Gorlin syndrome, Meige syndrome, Melnick-Needles syndrome, meningioma, meningitis, Menkes disease, lateral femoral cortical pain, metaphyseal dysplasia-mental disability-conductive deafness syndrome, methionine adenosyltransferase deficiency, methylcobalamin deficiency cbl g type, methylmalonic acidemia with homocystinuria cblc type, mgat2-cdg (cdg-iia), micro syndrome syndrome), brachycephaly drooping cleft lip, microcephaly-osteodysplasia-primordial dwarfism syndrome type 1, microcephaly-osteodysplasia-primordial dwarfism syndrome type 2, microcephalic primordial dwarfism (e.g., Montreal type, Toriello type), microcephaly, autosomal dominant microcephaly, microcephalic cerebral defect spastic hypernatremia, microcephalic cervical fusion abnormality, microcephalic deafness syndrome, microcephalic glomerulonephritis marfanoid habitus, microcephaly microcornea syndrome, microcephalic cardiomyopathy, Xp11.22-p11.23 microduplication syndrome, microphthalmia syndrome 10, microphthalmia syndrome 4, microphthalmia syndrome 8, microphthalmia with linear skin loss syndrome, microscopic polyangiitis, migraine (e.g., with brainstem aura),Mild phenylketonuria, Miller-Dieker syndrome, Miller Fisher syndrome, micronuclear myopathy with external ophthalmoplegia, mitochondrial complex I deficiency, mitochondrial complex II deficiency, mitochondrial DNA depletion syndrome, encephalomyopathic forms with methylmalonic aciduria, mitochondrial DNA-associated Leigh syndrome, mitochondrial encephalomyopathic 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 neurogastroenteric encephalopathy syndrome, mitochondrial trifunctional protein deficiency, mixed connective tissue disease, Miyoshi myopathy, Moebius syndrome, MOGS-CDG (CDG-IIb), deafness-dystonia syndrome (Mohr-Tranebjaerg syndrome), molybdenum cofactor deficiency, monoamine oxidase A deficiency, monoclonal gammopathy of undetermined significance (MGUS), Morse-Rawnsley-Sargent syndrome, Morvan's 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 type IIIA, mucopolysaccharidosis type IIIB, mucopolysaccharidosis type IIIC, mucopolysaccharidosis type IID, multifocal motor neuropathy, multiple congenital malformations-hypotonia-epilepsy syndrome, multiple congenital congenital malformation - hypotonia - epilepsy syndrome type 2, multiple myeloma, multiple sulfatase deficiency, multiple system atrophy, multiple system atrophy, multiple system smooth muscle dysfunction syndrome, myoencephalopathy, muscular dystrophy white matter spongiosis, large cone-shaped granular muscular dystrophy, myophosphokinase deficiency, muscle contracture Ehlers-Danlos syndrome, myasthenia gravis, myelitis, spinocerebellar disease, myelomeningocele, MYH7-related scapulohumeral myopathy, myhre syndrome, myoclonic epilepsy with ragged-red fibers, myoclonic cerebellar ataxia deafness, myoclonic dystonia, recurrent myoglobinuria, myopathy with extrapyramidal signs, myosin accumulation myopathy, congenital myotonia,Myotonic dystrophy type 1, myotonic dystrophy type 2, N syndrome, Nance-Horan syndrome, narcolepsy, NBIA / DYT / PARK-PLA2G6, necrotizing autoimmune myopathy, neonatal adrenoleukodystrophy, neonatal meningitis, neonatal progeroid syndrome, Neu Laxova syndrome, neuroblastoma, neurocutaneous melanosis, neurofacial digital nephrotic syndrome 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, neuronal nuclear inclusion disease, neuropathic pain, neuropathy ataxia retinitis pigmentosa syndrome, neuropathies, distal hereditary motor, Jerash type, hereditary motor and sensory, Okinawa type, neurogenic bladder, hereditary motor and sensory, Russe type type), neutral lipid storage disease with myopathy, nevoid basal cell carcinoma syndrome, new onset refractory status epilepticus, Nicolaides-Baraitser Syndrome, Niemann-Pick type A, Niemann-Pick type B, Niemann-Pick type C1, Niemann-Pick type C2, nonsleep arousal disorder, nondystrophic myotonia, Noonan syndrome, Norrie disease, northern epilepsy, oculo-cerebro-cutaneous syndrome, oculofacial-cardio-dental syndrome, oculopharyngeal muscular dystrophy, distal oculopharyngeal myopathy, Okamoto syndrome, olfactory neuroblastoma, oligoastrocytoma, oligodendroglioma, Oliver syndrome, olivopontocerebellar atrophy, lethal omphalocele cleft palate syndrome, OPHN1 syndrome, opsoclonus-myoclonus syndrome, optic atrophy 2,Optic pathway glioma, optic neuritis, ornithine transcarbamylase deficiency, orofacial digital syndrome 1, orofacial digital syndrome 10, orofacial digital syndrome 2, orofacial digital syndrome 3, orofacial digital syndrome 4, orofacial digital syndrome 5, orofacial digital syndrome 6, orthostatic intolerance due to NET deficiency, osteopenia and sparse hair, osteoporosis-pseudoglioma syndrome, oto-palatine-digital syndrome type 1, oto-palatine-digital syndrome type 2, Ouvrier-Billson syndrome, pachygyria-mental disability-epilepsy syndrome, PACS1-related syndrome, painful orbital and systemic neurofibromas-Marfanoid syndrome, pallid pyramidal syndrome, Pallister W syndrome, Pallister-Killian mosaic syndrome syndrome), pantothenate kinase-related neurodegeneration, Parkinson's disease, Parkinson's disease type 3, Parkinson's disease type 9, paroxysmal exertional dyskinesia, paroxysmal extreme pain disorder, paroxysmal migraine, paroxysmal kinesigenic choreoathetosis, paroxysmal nonkinesigenic dyskinesia, Parsonage Turner syndrome, Partington syndrome, PCDH19-related focal epilepsy in women, childhood autoimmune neuropsychiatric disorders associated with streptococcal infection, PEHO syndrome, Pelizaeus-Merzbacher disease, periventricular heterotopia, periventricular leukomalacia, Perry syndrome, Peters Plus Syndrome, Pfeiffer Mayer 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 anomaly syndrome (POEMS), poliomyelitis, POLR3-related leukodystrophy, polyarteritis nodosa, polycystic membranous skeletal dysplasia with sclerosing leukoencephalopathy, polyneuropathy-mental disability-acromial malformations-premature menopause syndrome, pontine tegmental dysplasia, cerebellopontine dysplasia,pontine dysgenesis type 1, pontine dysgenesis type 2, pontine dysgenesis type 3, pontine dysgenesis type 4, pontine dysgenesis type 5, pontine dysgenesis type 6, postpolio syndrome, porphyria, posterior column ataxia, posterior column ataxia with retinitis pigmentosa, progressive microcephaly postpartum, postherpetic neuralgia, postpartum epilepsy and postpartum brain atrophy, potassium-aggravated myotonia, Potocki-Lupski syndrome, PPM-X syndrome, Prader-Willi body type habitus), primary amebic meningoencephalitis, primary CNS angiitis, primary basilar indentation, primary carnitine deficiency, primary CNS lymphoma, primary familial brain calcification, primary lateral sclerosis, primary CNS melanoma, primary orthostatic tremor, primary progressive aphasia, Primrose syndrome, progressive bulbar palsy, progressive encephalomyelitis with rigidity and myoclonus, progressive external ophthalmoplegia, autosomal recessive 1, progressive hemifacial atrophy, progressive nonfluent aphasia, progressive supranuclear palsy, prolylase deficiency, Proteus syndrome, Proud syndrome, pseudoaminopterin syndrome, pseudocholinesterase deficiency, pseudoneonatal adrenoleukodystrophy, pseudoprogeroid syndrome, pseudotrisomy 13 13syndrome), pseudoxanthoma elasticum, pudendal neuralgia, pure autonomic failure, pyridoxal 5'-phosphate-dependent epilepsy, pyridoxine-dependent epilepsy, pyruvate dehydrogenase phosphatase deficiency, Qazi Markouizos Syndrome, radiation brachial plexopathy, Ramos Arroyo Clark syndrome, Ramsay Hunt syndrome I, Ramsay Hunt syndrome II, rapid-onset dystonia-parkinsonism, Rasmussen encephalitis, ReardonWilson Cavanagh syndrome, reduction body myopathy, Refsum disease, renal dysplasia-limb deficiency syndrome, Renier Gabreels Jasper syndrome, restless legs syndrome, retinal artery aneurysm with supravalvular pulmonary artery stenosis, retinal vasculopathy with leukodystrophy, retrobulbar neuritis, Rett syndrome, reversible cerebral vasoconstriction syndrome, RFT1-CDG (CDG-In), rhabdoid tumor, punctate limb chondrodysplasia type 1, riboflavin transporter deficiency,Richards-Rundle Syndrome, Richieri Costa Da Silva syndrome, ankylosing spondylosis, ring chromosome 10, ring chromosome 14, ring chromosome 20, rippling myopathy, RNAse T2-deficient leukoencephalopathy, Roussy-Levy syndrome, RRM2B-related mitochondrial DNA depletion syndrome, Ruvalcaba syndrome, Salla disease, Sandhoff disease, Sandifer syndrome, sarcoidosis-induced neuropathy, Say BarberMiller syndrome, Say Meyer syndrome, scapulo-peroneal syndrome, SCARF syndrome, Schaaf-Yang syndrome, Scheie syndrome, Schimke immune-osseous dysplasia, Schinzel disease type 1, Schinzel-Gideon syndrome Giedion syndrome, schizophrenia, schizencephaly, schwannomatosis, Schwartz Jampel syndrome, Scott Bryant Graham syndrome, Seaver Cassidy syndrome, Seckel syndrome, semantic dementia, sensory ataxic neuropathy, septo-optic dysplasia spectrum, SeSAME syndrome, SETBP1 disorder, severe congenital nematode myopathy, severe intellectual disability-progressive spastic diplegia syndrome, severe X-linked intellectual disability of the Gustafson type, Shapiro syndrome, short-chain acyl-CoA dehydrogenase deficiency, Shprintzen omphalocele syndrome, Shprintzen-Goldbergcraniosynostosis syndrome), sialidosis type I, sialidosis type II, sickle cell anemia, Simpson-Golabi-Behmel syndrome, single upper central incisor,Sjogren-Larsso 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 Syndrome), spastic dysphonia, spastic ataxia of Charlevoix-Saguenay type, spastic diplegia cerebral palsy, spastic diplegia infantile type, spastic paraplegia 1, spastic paraplegia 10, spastic paraplegia 11, spastic paraplegia 12, spastic paraplegia 13, spastic paraplegia 14, spastic paraplegia 15, spastic paraplegia 16, spastic paraplegia 17, spastic paraplegia 18, spastic paraplegia 19, spastic paraplegia 2, spastic paraplegia 23, spastic paraplegia 24, spastic paraplegia 25, spastic paraplegia 26, Spastic paraplegia 29, Spastic paraplegia 3, Spastic paraplegia 31, Spastic paraplegia 32, Spastic paraplegia 39, Spastic paraplegia 4, Spastic paraplegia 51, Spastic paraplegia 5a, Spastic paraplegia 6, Spastic paraplegia 7, Spastic paraplegia 8, Spastic paraplegia 9, Spastic paraplegia facial skin lesions, Spastic paraplegia-epilepsy-mental disability syndrome, Spastic paraplegia-glaucoma-mental disability syndrome, Spastic quadriplegia-retinitis pigmentosa-mental disability syndrome, Spastic quadriplegia-thin corpus callosum-progressive postnatal microcephaly Spinal syndrome, spina bifida occulta, spinal atrophy ophthalmoplegia pyramidal syndrome, spinal meningioma, spinal muscular atrophy 1, spinal muscular atrophy type 2, spinal muscular atrophy type 3, spinal muscular atrophy-progressive myoclonic epilepsy syndrome, spinal shock, spinocerebellar ataxia, spinocerebellar ataxia 1, spinocerebellar ataxia 10, spinocerebellar ataxia 11, spinocerebellar ataxia 12, spinocerebellar ataxia 13, spinocerebellar ataxia 14, spinocerebellar ataxia 15, spinocerebellar ataxia ataxia 17, spinocerebellar ataxia 18, spinocerebellar ataxia 19 and 22, spinocerebellar ataxia 2, spinocerebellar ataxia 20, spinocerebellar ataxia 21, spinocerebellar ataxia 23, spinocerebellar ataxia 25, spinocerebellar ataxia 26, spinocerebellar ataxia 27, spinocerebellar ataxia 28, spinocerebellar ataxia 29, spinocerebellar ataxia 3, spinocerebellar ataxia 30, spinocerebellar ataxia 31, spinocerebellar ataxia 34,Spinocerebellar ataxia 4, Spinocerebellar ataxia 5, Spinocerebellar ataxia 7, Spinocerebellar ataxia 8, Spinocerebellar ataxia 9, Autosomal recessive spinocerebellar ataxia 3, Autosomal recessive spinocerebellar ataxia 4, Autosomal recessive spinocerebellar ataxia 5, Autosomal recessive spinocerebellar ataxia 6, Autosomal recessive spinocerebellar ataxia 7, Autosomal recessive spinocerebellar ataxia 8, Spinocerebellar ataxia type 6, Spinocerebellar ataxia with axonal neurosis disease type 1, spinocerebellar ataxia with malformations, spinocerebellar ataxia x-linked type 2, spinocerebellar ataxia x-linked type 3, spinocerebellar ataxia x-linked type 4, spinocerebellar degeneration and corneal dystrophy, hand fissure urinary tract abnormalities spina bifida, spinal cord bifida malformation, congenital spondyloepiphyseal dysplasia, SRD5A3-CDG (CDG-Iq), SSR4-CDG, STAC3 disorder, status epilepticus, Steinfeld syndrome, stiff-person syndrome, Stocco dos Santos syndrome (Stocco dos Santos syndrome, infantile striatonigral degeneration, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical band heterotopia, subependymal giant cell astrocytoma, subependymoma, succinic semialdehyde dehydrogenase deficiency, Susac syndrome, symmetric thalamic calcifications, syndromic X-linked intellectual disability 7, Tangier disease, TANGO2-related metabolic encephalopathy and arrhythmias, sacral canal cysts, Tay-Sachs disease, Tel Hashomer camptodactyly syndrome, Telfer Sugar Jaeger syndrome, Temple syndrome syndrome), Temple-Baraitser syndrome, temporal lobe epilepsy, Temtamy syndrome, tethered cord syndrome, thoracic dysplasia-hydrocephalus syndrome, thoracic outlet syndrome, thyrotoxic periodic paralysis, TMEM165-CDG (CDG-IIk), Toriello-Carey syndrome, Tourette syndrome, toxic neuropathy (e.g., alcoholic neuropathy, chemotherapy-induced neuropathy), Tranebjaerg Svejgaard syndrome, transverse myelitis, trichinosis, trichodactyly syndrome type 2, trigeminal neuralgia, triosephosphate isomerase deficiency, triple A syndrome, Troy syndrome, tuberous sclerosis, tubular aggregate myopathy, tumescent multiple sclerosis, classic congenital nematode 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, variant porphyria, vasculitis-induced neuropathy, venous aneurysm, Vici syndrome, Viljoen Kallis Voges syndrome, vincristine-induced neuropathy, visual snow syndrome, vitamin B6-induced neuropathy, VLCAD deficiency, Vogt-Koyanagi-Harada disease, Von Hippel-Lindaudisease, Walker-Warburg syndrome, Weaver syndrome, Welander's distal myopathy, Wernicke-Korsakoff syndrome, West syndrome syndrome), Whippledisease, leukodysplasia-corpus callosum dysgenesis-mental retardation syndrome, Wiedemann Oldigs-Oppermann syndrome, Williams syndrome, Wilsondisease, Wilson-Turner syndrome, Wolf-Hirschhorn syndrome, Wolman disease, Woodhouse Sakati syndrome, Worster Drought syndrome, wrinkled skin syndrome, Wyburn-Mason syndrome, xeroderma pigmentosum, Xia-Gibbs syndrome syndrome), XK anencephaly, X-linked cerebral 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 complex corpus callosum agenesis, X-linked complex spastic paraplegia type 1, X-linked creatine deficiency,X-linked dystonia-parkinsonism / Lubag, X-linked hereditary sensory and autonomic neuropathy with deafness, X-linked intellectual disability-genesis of the corpus callosum-spastic quadriplegia, X-linked intellectual disability-short stature-obesity, X-linked intellectual disability Najm type, X-linked intellectual disability Schimke type, X-linked intellectual disability Siderius type, X-linked intellectual disability Turner type 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 and American Psychiatric Association, 2013, Diagnostic and statistical manual of mental disorders): DSM-5. Arlington, Virginia (Arlington, VA.)). In some embodiments, the disease or disorder of the nervous system is a disease or disorder classified according to DSM-V (American Psychiatric Association and American Psychiatric Association, 2013, Diagnostic and statistical manual of mental disorders): DSM-5. Arlington, Virginia (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's disease, corpus callosum loss associated with peripheral neuropathy, Duchenne muscular dystrophy,Guillain-Barré syndrome, Charcot-Marie-Tooth disease type 1A, hereditary pressure-prone peripheral neuropathy, diabetic neuropathy, toxic neuropathy, age-related peripheral neuropathy, epilepsy, sleep disorders, encephalopathy, and neuropathic pain. In some embodiments, the disease or disorder of the nervous system is a neurodegenerative disease or disorder.

[0107] 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, induced in part, or suspected of being induced by at least one agent selected from the group consisting of: a chemotherapeutic agent, a TNFα inhibitor, an antiretroviral agent, a cardiac drug, a statin, and an antibiotic.

[0108] 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, colchicine, phenytoin, lithium, chloroquine, hydroxychloroquine, cisplatin, oxaliplatin, paclitaxel, vinca alkaloids, bortezomib, suramin, misonidazole, einfliximab, etanercept, zalcitabine, didanosine, stavudine, amiodarone, perhexiline, metronidazole, dapsone, podophyllin, fluoroquinolones, isoniazid, and nitrofurazone.

[0109] In certain embodiments, a disease or disorder of the nervous system described herein is a disease or disorder of the peripheral nervous system.

[0110] In some embodiments, the toxin-induced neuropathy described herein is induced, induced in part, or suspected of being induced by at least one agent selected from the group consisting of: an organic solvent, a heavy metal, and an organophosphate.

[0111] In some embodiments, the toxin and / or drug-induced neuropathy described herein is induced, induced in part, or suspected of being induced by alcohol and / or cigarette smoke.

[0112] 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 gating abnormalities, sodium channel abnormalities, and demyelination.

[0113] The inventors found that AAT can reduce neuronal pathological pathways (Figures 2-4, Tables 1-10). This reduction in neuronal pathological pathways was observed in both resting cells (Figure 4B) and stimulated cells ( Figure 4C) and can therefore be used to prevent and / or treat diseases or disorders of the nervous system and their symptoms.

[0114] Thus, the combination of AAT and IgG antibodies provides immunomodulatory, anti-inflammatory and neuroprotective / regenerative effects in diseases and disorders of the nervous system beyond the expectations of those skilled in the art.

[0115] Thus, the present invention is based, at least in part, on the discovery that combining AAT activity with IgG antibody activity can be used to treat diseases or disorders of the nervous system as described herein.

[0116] In one embodiment, the present invention relates to a pharmaceutical composition for treating a disease or disorder of the nervous system, the composition comprising: i) a) α1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having protease inhibitory activity; and / or b) nucleic acids encoding AAT, its variants, isoforms and / or fragments having protease inhibitory activity; iii) a plurality of IgG antibodies, their isoforms, their fragments and / or IgG variants; and ii) at least one pharmaceutically acceptable carrier.

[0117] In some embodiments, a pharmaceutically acceptable carrier described herein is a pharmaceutically acceptable diluent or carrier.

[0118] "Pharmaceutically acceptable diluent or carrier" means a carrier or diluent that can be used to prepare a pharmaceutical composition, which is generally safe, non-toxic and desirable, and includes carriers or diluents that are acceptable for human pharmaceutical use.

[0119] Such pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water is a preferred carrier. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions.

[0120] Pharmaceutically acceptable diluents or carriers include starch, glucose, lactose, sucrose, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, ethanol and the like.

[0121] The pharmaceutical composition may also contain one or more pharmaceutically acceptable salts, such as, for example, mineral acid salts, such as hydrochlorides, hydrobromides, phosphates, sulfates, etc.; and organic acid salts such as acetates, propionates, malonates, benzoates, etc. Additionally, auxiliary substances, such as wetting agents or emulsifiers, pH buffer substances, gels or gelling materials, flavoring agents, coloring agents, microspheres, polymers, suspending agents, etc., may also be present herein. In addition, one or more other conventional pharmaceutical ingredients, such as preservatives, wetting agents, suspending agents, surfactants, antioxidants, anticaking agents, fillers, chelating agents, coating agents, chemical stabilizers, etc., may also be present, particularly when the dosage form is a reconstructible form. Suitable exemplary ingredients include macrocrystalline cellulose, sodium carboxymethylcellulose, polysorbate 80, phenylethyl alcohol, chlorobutanol, potassium sorbate, sorbic acid, sulfur dioxide, propyl gallate, parabens, ethyl vanillin, glycerol, phenol, p-chlorophenol, gelatin, albumin, and combinations thereof. A detailed discussion of pharmaceutically acceptable excipients can be found in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., NJ 1991), which is incorporated herein by reference.

[0122] In some embodiments, the pharmaceutically acceptable carrier described herein is an agent (e.g., a molecule or cell) that improves the drug delivery properties of the agents used in the present invention. In some embodiments, the drug delivery properties described herein include at least one property selected from the group consisting of: permeability (e.g., cell membrane and / or blood-brain barrier), site-specific delivery (e.g., brain-specific delivery), controlled release delivery, and stability (e.g., reduced enzymatic degradation). In some embodiments, the drug carrier described herein is an agent selected from the group consisting of delivery cells, liposomes, nanoparticles, fusion proteins, liposomes, nanospheres, micelles, nanocapsules, nanoshells, lipid particles, and dendrimers.

[0123] In one embodiment, the invention relates to a method of treatment comprising administering to a subject an effective amount of a pharmaceutical composition comprising an AAT protein and / or a nucleic acid encoding AAT, wherein the subject suffers from a disease or disorder of the nervous system and wherein the subject is undergoing a therapy comprising the administration of a plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants.

[0124] An "effective amount" of an agent (e.g., a therapeutic agent) refers to an amount effective to achieve the desired therapeutic or preventive result at the necessary dosage and time period. In addition, the effective amount may depend on the individual patient's medical history, age, weight, family medical history, genetic makeup, stage of thyroid-related autoimmune disease, type of previous or concurrent treatment (if any), and other individual characteristics of the subject to be treated.

[0125] In some cases, an effective amount of a composition / compound / product described herein may be any amount that reduces the severity of symptoms of the disease, disorder, and / or condition to be treated or reduces its incidence without causing significant toxicity to the subject. In some cases, an effective amount of a composition / compound / product described herein may be any amount that reduces the number of diseased cells, autoantibodies, and / or other disease markers (e.g., cytokines) without causing significant toxicity to the subject.

[0126] As used herein, the terms "subject" / "subject in need" or "patient" / "patient in need" are 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 suffering from a disease or condition. In some embodiments, the subject to be treated is a subject aged 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 12 years old or older, preferably a subject aged 1 year or older. 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 a female.

[0127] In one embodiment, the invention relates to a method of treatment comprising administering to a subject an effective amount of a pharmaceutical compound comprising a plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants, wherein the subject suffers from a disease or disorder of the nervous system, and wherein the subject is undergoing a therapy comprising administering an AAT protein and / or a nucleic acid encoding AAT.

[0128] In certain embodiments, the invention relates to a kit of parts for use in the invention, wherein the disease or disorder of the nervous system is chronic inflammatory demyelinating polyneuropathy.

[0129] In certain embodiments, the present invention relates to a pharmaceutical composition for use in the present invention, wherein the disease or disorder of the nervous system is chronic inflammatory demyelinating polyneuropathy.

[0130] In certain embodiments, the present invention relates to the methods of treatment of the present invention, wherein the disease or disorder of the nervous system is chronic inflammatory demyelinating polyneuropathy.

[0131] In certain embodiments, the invention relates to a pharmaceutical product for use in the invention, wherein the subject 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.

[0132] In certain embodiments, the invention relates to a kit-of-parts for use in the invention, wherein the subject 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.

[0133] In certain embodiments, the invention relates to a pharmaceutical composition for use in the present invention, wherein the subject 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.

[0134] In certain embodiments, the present invention relates to the methods of treatment of the present invention, wherein the subject 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.

[0135] As used herein, the term "symptoms 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, numbness, tingling, pain, difficulty walking, proximal muscle weakness of the limbs, and distal muscle weakness of the limbs.

[0136] In certain embodiments, the present invention relates to a kit of parts for use in the present invention, wherein the plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants are recombinant IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants.

[0137] In certain embodiments, the present invention relates to a pharmaceutical composition for use in the present invention, wherein the plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants are recombinant IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants.

[0138] In certain embodiments, the present invention relates to the therapeutic methods of the present invention, wherein the plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants are plasma-derived IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants.

[0139] In certain embodiments, the present invention relates to a kit of parts for use in the present invention, wherein the plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants are recombinant IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants.

[0140] In certain embodiments, the present invention relates to a pharmaceutical composition for use in the present invention, wherein the plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants are recombinant IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants.

[0141] In certain embodiments, the present invention relates to the therapeutic methods of the present invention, wherein the plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants are recombinant IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants.

[0142] In certain embodiments, the invention relates to a kit-of-parts for use in the invention, wherein the IgG antibody, isotype thereof, fragment thereof and / or IgG variant is formulated for intravenous administration.

[0143] In certain embodiments, the invention relates to a pharmaceutical composition for use in the invention, wherein the IgG antibody, isotype thereof, fragment thereof and / or IgG variant is formulated for intravenous administration.

[0144] In certain embodiments, the invention relates to the methods of treatment of the invention, wherein the IgG antibody, isotype thereof, fragment thereof and / or IgG variant is formulated for intravenous administration.

[0145] In certain embodiments, the invention relates to a kit-of-parts for use in the invention, wherein the IgG antibody, isotype thereof, fragment thereof and / or IgG variant is formulated for subcutaneous administration.

[0146] In certain embodiments, the invention relates to a pharmaceutical composition for use in the invention, wherein the IgG antibody, isotype thereof, fragment thereof and / or IgG variant is formulated for subcutaneous administration.

[0147] In certain embodiments, the invention relates to the methods of treatment of the invention, wherein the IgG antibody, isotype thereof, fragment thereof and / or IgG variant is formulated for subcutaneous administration.

[0148] In certain embodiments, the invention relates to a pharmaceutical product for use in the invention, wherein the AAT protein is recombinant AAT.

[0149] In certain embodiments, the invention relates to a kit of parts for use in the invention, wherein the AAT protein is recombinant AAT.

[0150] In certain embodiments, the present invention relates to the pharmaceutical composition for use in the present invention, wherein the AAT protein is recombinant AAT.

[0151] In certain embodiments, the present invention relates to the methods of treatment of the present invention, wherein the AAT protein is recombinant AAT.

[0152] In certain embodiments, the invention relates to a pharmaceutical product for use in the invention, wherein the AAT protein is plasma-derived AAT.

[0153] In certain embodiments, the invention relates to a kit of parts for use in the invention, wherein the AAT protein is plasma-derived AAT.

[0154] In certain embodiments, the invention relates to a pharmaceutical composition for use in the invention, wherein the AAT protein is plasma-derived AAT.

[0155] In certain embodiments, the invention relates to the methods of treatment of the invention, wherein the AAT protein is plasma-derived AAT.

[0156] In certain embodiments, the present invention relates to a pharmaceutical product for use in the present invention, wherein a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof, wherein the variants, isoforms and / or fragments have inhibitory activity; and / or b) nucleic acids encoding AAT, variants, isoforms and / or fragments thereof having ADAM17 inhibitory activity are formulated for intravenous administration.

[0157] In certain embodiments, the present invention relates to a kit of parts for use in the present invention, wherein a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof, wherein the variants, isoforms and / or fragments have inhibitory activity; and / or b) nucleic acids encoding AAT, variants, isoforms and / or fragments thereof having ADAM17 inhibitory activity are formulated for intravenous administration.

[0158] In certain embodiments, the present invention relates to a pharmaceutical composition for use in the present invention, wherein a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof, wherein the variants, isoforms and / or fragments have inhibitory activity; and / or b) nucleic acids encoding AAT, variants, isoforms and / or fragments thereof having ADAM17 inhibitory activity are formulated for intravenous administration.

[0159] In certain embodiments, the present invention relates to a pharmaceutical treatment method of the present invention, wherein a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof, wherein the variants, isoforms and / or fragments have inhibitory activity; and / or b) nucleic acids encoding AAT, variants, isoforms and / or fragments thereof having ADAM17 inhibitory activity are formulated for intravenous administration.

[0160] In certain embodiments, the present invention relates to a pharmaceutical product for use in the present invention, wherein a) α1-antitrypsin (AAT) protein, its variant, isoform and / or fragment, wherein the variant, isoform and / or fragment has inhibitory activity; b) nucleic acid encoding AAT, its variant, isoform and / or fragment having ADAM17 inhibitory activity is formulated for subcutaneous administration.

[0161] In certain embodiments, the present invention relates to a kit of parts for use in the present invention, wherein a) α1-antitrypsin (AAT) protein, its variant, isoform and / or fragment, wherein the variant, isoform and / or fragment has inhibitory activity; b) nucleic acid encoding AAT, its variant, isoform and / or fragment having ADAM17 inhibitory activity is formulated for subcutaneous administration.

[0162] In certain embodiments, the present invention relates to a pharmaceutical composition for use in the present invention, wherein a) α1-antitrypsin (AAT) protein, its variant, isoform and / or fragment, wherein the variant, isoform and / or fragment has inhibitory activity; b) nucleic acid encoding AAT, its variant, isoform and / or fragment having ADAM17 inhibitory activity is formulated for subcutaneous administration.

[0163] In certain embodiments, the present invention relates to a drug treatment method of the present invention, wherein a) α1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments, wherein the variants, isoforms and / or fragments have inhibitory activity; b) nucleic acids encoding AAT, its variants, isoforms and / or fragments having ADAM17 inhibitory activity are formulated for subcutaneous administration.

[0164] The present invention also contemplates gene delivery vectors encoding AAT (or its isoforms, fragments or variants) and pharmaceutical compositions comprising the same. The gene delivery vector can be used for any therapeutic use 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 of the present invention, its variants, isoforms and / or fragments. Examples of gene delivery vectors include, for example, viral vectors, non-viral vectors, particle carriers and liposomes. Gene delivery is preferably performed in vitro or ex vivo.

[0165] The kit, pharmaceutical composition and / or product of the present invention can be administered to the subject by different routes, including oral, parenteral, sublingual, transdermal, rectal, transmucosal, topical, via inhalation, buccal administration, intrapleural, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intranasal intrathecal and intraarticular or a combination thereof. For human use, the composition can be administered as an appropriate acceptable preparation according to normal human practice. Those skilled in the art will easily determine the dosing regimen and route of administration that best suits a particular patient. The kit, pharmaceutical composition and / or product of the present invention can be administered by traditional syringes, needleless injection devices, "microprojectile bombardment gone guns" or other physical methods such as electroporation ("EP"), "fluid dynamics method" or ultrasound. The composition can also be administered by intravenous injection, intravenous infusion, infusion using a metered pump, inhaled nasal spray, eye drops, skin patches, sustained-release preparations, ex vivo gene therapy or ex vivo cell therapy, preferably by intravenous injection.

[0166] The pharmaceutical compositions of the present invention can also be delivered to patients by several techniques, including DNA injection of nucleic acids encoding the AAT proteins, variants, isoforms and / or fragments thereof of the present invention (also known as DNA vaccination), with or without the use of in vivo electroporation, liposome mediation, nanoparticle promotion, recombinant vectors such as recombinant lentiviruses, recombinant adenoviruses and recombinant adeno-associated viruses as described herein.

[0167] Where applicable and unless otherwise indicated, all definitions and combinations provided herein apply to these embodiments.

[0168] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and 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 only provided for their disclosure before the filing date of the present application.Nothing herein should be construed as admitting that the present invention has no right to precede such publications because of previous inventions.In addition, materials, methods and examples are only illustrative and are not intended to be restrictive.

[0169] In the event of a conflict, the present specification (including definitions) shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of this document belongs. As used herein, the following definitions are provided to facilitate understanding of the present invention.

[0170] In particular, the term "about" referring to a given amount is intended to cover deviations of ±20%, preferably 10%, preferably 5%, even more preferably 2%, and most preferably 1%.

[0171] As used in the specification and claims, the singular form "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0172] As used herein, "at least one" means "one or more," "two or more," "three or more," and the like.

[0173] "Or" should be understood to mean any one, two, or any combination of the alternatives.

[0174] "And / or" should be understood to mean either or both of the alternatives.

[0175] Throughout the specification, unless the context requires otherwise, the words "comprise", "comprises" and "comprising" will be understood to imply the inclusion of stated steps or elements or groups of steps or elements but not the exclusion of any other steps or elements or groups of steps or elements.

[0176] The terms "include" and "comprise" are used synonymously. "Preferably" means one option in a series of options not excluding other options. "For example" means one example without being limited to the mentioned example. "Consisting of" means including and limited to whatever follows the phrase "consisting of".

[0177] References throughout this specification to "one embodiment," "an embodiment," "a specific embodiment," "a related embodiment," "an embodiment," "additional embodiments," "some embodiments," "specific embodiments," or "another embodiment," or combinations thereof, mean that a particular feature, structure, or characteristic described in conjunction with the embodiment is included in at least one embodiment of the present invention. Thus, the foregoing phrases appearing in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. It should also be understood that positive recitation of a feature in one embodiment serves as a basis for excluding the feature in a particular embodiment.

[0178] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the invention belongs. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, suitable methods and materials are described below. In the event of a conflict, this specification (including definitions) shall prevail. In addition, materials, methods and examples are illustrative only and are not intended to be limiting.

[0179] Unless otherwise indicated, the general methods and techniques described herein can be performed 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. See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1989) and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992), and Harlow and Lane Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1990).

[0180] Although embodiments of the present invention are illustrated and described in detail in the drawings and the foregoing description, such illustration and description are to be considered illustrative or exemplary rather than restrictive. It should be understood that changes and modifications may be made by one of ordinary skill in the art within the scope and spirit of the following claims. In particular, the present invention encompasses additional embodiments having any combination of features from the different embodiments described above and below. BRIEF DESCRIPTION OF THE DRAWINGS

[0181] Figure 1: IFNγ-mediated microglial activation

[0182] Figure 2: AAT reduces IFNγ-mediated microglial activation

[0183] Figure 3: Validation of the anti-inflammatory effect of AAT in an RNAseq experiment

[0184] Figure 4: GSEA analysis to verify microglial activation and anti-inflammatory effects of AAT

[0185] Figure 5: AAT (SigmaAldrich, lot A6150) inhibits TACE activity in a cell-free assay, shown as relative fluorescence units (A) or as a percentage of control activity (B), IC 50 It is 15.3μM (C).

[0186] Figure 6: Results of sciatic nerve electrophysiology (EMG): (A) amplitude and (B) conduction velocity

[0187] Figure 7: Grip strength test results (A) absolute value, (B) % at 6 weeks

[0188] Figure 8: Rotarod test results (A) Absolute value, (B) % at 6 weeks

[0189] Fig. 9 : DNAJB9 and PLA2G4B gene expression in response to AAT treatment

[0190] Fig.10 : Number of axons

[0191] Fig.11 : Axon diameter

[0192] Fig.12 :g ratio

[0193] Figure 13: Individual histological images of semi-thin cross sections of sciatic nerves. Scale bar 10 μm A) Group 1: WT control, B) CMT1A+Vehicle, C) CMT1A+AAT

[0194] Fig.14 : Plasma IL-6 concentration

[0195] Fig.15 : Plasma TNFα concentration

[0196] Fig.16 :Study plan for CMT1A mouse model and AAT administration

[0197] Figure 17: Cell morphology and counts after treatment: SH-SY5Y morphology analysis and cell counts after 6-OHDA administration and AAT treatment. Bright field images (20x) and cell counts (D0 vs. D4 of culture) show the effects of treatment on SH-SY5Y cell phenotype and proliferation and the positive action of AAT.

[0198] A) Example image B) Quantification

[0199] Fig.18 : Cell viability: Graph represents the cell viability of control and samples measured by absorbance (450nm)

[0200] Fig.19: Quantification of IL-6 in cell supernatants

[0201] Fig. 20 : Research plan

[0202] Figure 21: Neuromuscular testing: A Rotarod latency; B Grip strength; C Von Frey test

[0203] Fig. 22 :Sciatic nerve electrophysiology: A: Compound muscle action potential; B: Nerve conduction velocity

[0204] Fig.23 :A) Graphical representation of plasma TMPRSS5 B) Graphical representation of plasma NfL conc

[0205] Fig.24 : Graphical representation of plasma TNFα concentrations

[0206] Fig.25 : Latency to fall from the rotarod in CMT mice treated with AAT (180 mg / kg sc)

[0207] Fig.26 : Grip strength (Newtons) of CMT mice treated with AAT (180 mg / kg sc)

[0208] Fig. 27 :CMAP (mV) of CMT mice treated with AAT (180 mg / kg sc)

[0209] Fig.28 :NCV (m / s) of CMT mice treated with AAT (180 mg / kg sc)

[0210] Fig.29 : Plasma IL-6 concentration

[0211] Fig.30 : Plasma TNFα concentration

[0212] Fig.31 : Effect of peptide 8 on ADAM17 activity (***, ****: P < 0.001, P < 0.0001, one-way ANOVA (multiple comparisons); ns = not significant compared with DMSO

[0213] Fig.32 :Effects of AAT on the expression of NF-κB pathway genes after TNFα-dependent activation of Schwann cells

[0214] Fig.33 :Effects of AAT on the expression of genes related to oxidative stress response after TNFα-dependent activation of Schwann cells

[0215] Fig.34 Effects of AAT on the expression of genes associated with NRF2-dependent oxidative stress responses following TNFα-dependent activation of Schwann cells

[0216] Fig.35 : Effects of AAT and its derived peptides on TNF-induced Schwann cells.

[0217] Fig.36 :Axon number / 100μm 2

[0218] Fig.37 : Axon diameter

[0219] Fig.38 :g-ratio

[0220] Figure 39: A) Number of axons / 100 μm 2 B) Axon diameter and C) g-ratio

[0221] Fig.40 : Plasma NfL concentration

[0222] Fig.41 :Effects of AAT and its derived peptides on IFNγ-induced microglia

[0223] Fig.42 : Synthesis of peptides #8 and #9 (Synthesis: Syro-1 automatic peptide synthesizer; double coupling conditions: DIC (4 equivalents) / Oxyma (4 equivalents), 40 min; HATU (4 equivalents) / DIPEA (8 equivalents), 30 min; deprotection: 40% piperidine in DMF, 3 min and 20% piperidine in DMF, 12 min)

[0224] Fig.43 : Synthesis of peptide mimetic #14 (Synthesis: manual synthesis; Coupling conditions: DIC (3 equivalents) / Oxyma (3 equivalents), 2h; Deprotection: 20% piperidine in DMF, 5min; 20% piperidine in DMF, 20min) Example

[0225] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It should be understood that the present invention includes all such variations and modifications without departing from its spirit or essential characteristics. The present invention also includes all steps, features, compositions and compounds mentioned or indicated individually or jointly in this specification, and any and all combinations of the steps or features or any two or more thereof. Therefore, the disclosure should be considered to be in all embodiments shown and non-restrictive, the scope of the present invention is indicated by the attached claims, and all changes occurring within the meaning and scope of equivalents are intended to be included therein. Various references are cited throughout the specification, and each of the references is incorporated herein by reference as a whole. The foregoing description will be more fully understood with reference to the following examples.

[0226] Example 1

[0227] A) Human microglial cells HMC3-MHCII Luc Cells were plated on day 0, activated with IFNγ on day 1 to day 2, and luciferase activity and cell viability were measured on day 4.

[0228] B) Activation is measured by the activity of the luciferase driven by MHCII and is normalized to cell viability. The luciferase activity under all conditions is expressed as the multiple of the untreated control. The potential effect of the buffer (IFNγ, AAT) of the highest concentration for drug presentation is excluded. All conditions are carried out in triplicate, and the error bars represent standard deviation (Fig. 1).

[0229] Example 2

[0230] A) Human microglial cells HMC3-MHCII Luc and HMC3-MHCII Luc ;Ubi AAT Cells were plated on day 0, IFNγ was presented on day 1 to day 2, and luciferase activity and cell viability were measured on day 4.

[0231] B) AAT was applied to HMC3-MHCII from day 0 to day 4 Luc Cells. Activation was measured by MHCII-driven luciferase activity and normalized to cell viability. Luciferase activity under all conditions was expressed as a percentage of IFNγ control. All conditions were performed in triplicate, and error bars represent standard deviations. (Figure 2)

[0232] Example 3

[0233] A) Human microglial cells HMC3-MHCII LucCells were plated on day 0, IFNγ was presented on day 1 to day 2, and luciferase activity and cell viability were measured on day 4.

[0234] B) AAT was applied to HMC3-MHCII from day 0 to day 4 Luc Activation was measured by MHCII-driven luciferase activity and expressed as a percentage of IFNγ control for all conditions. All conditions were performed in triplicate and error bars represent standard deviation.

[0235] C) Large amounts of RNA were extracted from the same HMC3-MHCII Luc Cultures were performed. Quality control (QC) was applied to RNA before sequencing. Sequencing was QCed before mapping the human genome. Mapped reads were counted and differential gene expression between conditions was measured (see Tables 1-10). (Figure 3)

[0236] Example 4

[0237] The RNAseq data of plasma-derived and recombinant AAT were merged, 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 (grey bars) and downregulated gene families (black bars) are shown according to the normalized enrichment scores.

[0238] A) The inflammatory signature induced by IFNγ was confirmed by upregulation of several processes associated with inflammation (bold italics).

[0239] BC) AAT treatment in the absence (B) or presence (C) of IFNγ was able to significantly downregulate some of these pathways (bold italics). Importantly, AAT attenuated both IFNγ and inflammatory responses. However, downregulation of inflammatory response genes in (C) was not significant.

[0240] Regarding other gene families, KRAS signaling is important because it has been involved in carcinogenesis and immune regulation (Dias Carvalho, P., et al., 2018, Cancer Res, 78:7-14.). Similarly, the p53 pathway is noteworthy as a mediator of stress response. (Figure 4)

[0241] Example 5

[0242] AAT treatment counteracted the expression of inflammatory genes.

[0243] Table of genes associated with 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) are defined by differential expression between untreated and IFNγ treated cells (inflammation; middle column). Top genes significantly reversely regulated by AAT treatment are highlighted (right column; bold underline).

[0244] A considerable number (about 35%) of the top inflammatory genes were found to be affected by AAT treatment (6 genes out of 23 genes were related to antigen presentation; 14 genes out of 33 genes were related to cytokine signaling; 1 gene out of 7 genes was related to complement activation; 5 / 13 genes were related to interferon signaling), indicating its anti-inflammatory potential. Luc The promoter of the HLA-DRA gene, the driver of luciferase expression in the lines, was consistently up-regulated and down-regulated in inflammation and AAT treatment, respectively (bold italics). It is worth noting that the FCs shown under inflammatory conditions with AAT treatment should not be directly compared with those found in inflammation, because for the former, FC=2 already represents a 50% offset of inflammation-induced / repressed genes.

[0245] The bottom of the table presents the second order inflammatory genes that were significantly oppositely regulated by AAT treatment under inflammatory conditions or resting conditions (regulated in AAT) (p value < 0.05; FC < 2). (Figure 5)

[0246] Table 1

[0247]

[0248]

[0249] Table 2

[0250]

[0251]

[0252] Table 3

[0253]

[0254]

[0255] Table 4

[0256]

[0257]

[0258] Example 6 - AAT treatment enhances the expression of marker genes associated with M2 anti-inflammatory microglia .

[0259] M2 microglial gene expression was promoted after M2 type induction (FC study; Satoh 2017). AAT treatment in resting microglia (FC AAT) and AAT treatment in activated microglia (FC inflammation + AAT) were able to similarly enhance the expression of M2 genes, although to a lower extent. About 60% of the modified genes were common in the AAT treatment condition (Table 5 bold part).

[0260] Table 5

[0261]

[0262]

[0263] Example 7 - AAT treatment affects the expression of neurodegenerative disease risk genes

[0264] 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 a public library (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 evaluated in AAT-treated resting microglia (FC Figure 3. Expression of cytokines in AAT-treated and activated microglia (FC-inflammation+AAT). Genes commonly modified in AAT-treated conditions are highlighted (bold underlined). Notably, expression of several risk genes in all of the above diseases was modified by AAT.

[0265] Table 6

[0266]

[0267] Table 7

[0268]

[0269] Table 8

[0270]

[0271] Table 9

[0272]

[0273]

[0274] Table 10

[0275]

[0276] Example 8

[0277] Other experiments include CSF-1 treatment for optimization of (MΦ) to M1 macrophage transition, dose dependence of IFNγ for M1 macrophage activation, AAT treatment of resting and IFNγ activated macrophages, and RNA extraction and RNAseq and analysis. The cells are thus human primary resting (Mφ) or M1 differentiated macrophages. Treatments include pretreatment with AAT for 24h, followed by activation (or non-activation) of cells with CSF-1 or IFN in the presence of AAT for 24h. Cells are further treated in AAT for 48h, and finally the culture supernatant is used to test proinflammatory cytokine release (IL-6, TNFα, IL-1β, IL-8; multiplexed readout) or alternatively luciferase activity (MHCII Luc The cultures were tested in 100 μg / ml cells and RNA was extracted for microarray analysis. Cultures with consistent readouts of cytokine release or luciferase assays were used as samples for RNA extraction and microarray analysis.

[0278] Experimental conditions: Each condition was performed in triplicate.

[0279] - Untreated (no AAT, no CSF-1) resting macrophage controls

[0280] -IFNγ: activated macrophage control

[0281] -AAT (plasma-derived; Sigma or recombinant; Lonza): Effects of AAT on resting macrophages

[0282] -IFNγ and AAT (plasma-derived; Sigma or Lonza): anti-inflammatory effects of AAT on activated macrophages

[0283] Output:

[0284] - Resting macrophage gene expression

[0285] - Pro-inflammatory differentially regulated genes (fold over untreated; significant p-value; fold up / down regulation threshold)

[0286] - AAT-driven gene expression changes on resting and activated macrophages

[0287] - Differences between recombinant and plasma-derived AAT gene regulation

[0288] method

[0289] Human microglial cell line culture

[0290] 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 of the University of Geneva. It was transduced with a lentiviral vector to obtain HMC3-MHCII Luc ;Ubi AAT Cell lines (see Figure 3). HMC3-MHCII Luc and HMC3-MHCII Luc ;Ubi AAT Cell lines were grown in TC-treated cell culture dishes ( Greiner, 7.664160), in DMEM high glucose + glutamine (Gibco, 41965039) supplemented with 10% (vol / vol) fetal bovine serum (FBS, Gibco, 10270106) and 100 μg / ml penicillin / streptomycin (Pen / Strep, ThermoFisher, 15070063). The culture was maintained at 37°C in a 5% CO2 atmosphere. The cells were quickly rinsed in PBS 1X, trypsinized for 3min at RT (Tryple Express, ThermoFisher, 12604021), then centrifuged (5min, 1000RPM) and resuspended in the above-supplemented DMEM to complete the passage. The cells were counted and plated at the desired concentration.

[0291] Transduction of human microglial cell lines

[0292] 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-Laterrière, Els Verhoeyen, and Patrick Salmon, 2011, Methods in molecular biology. 6 HEK cells were plated The cells were plated and transfected 16 h later with 15 μg pCWXPG-UBI-SP::AAT, 10 μg packaging plasmid (psPAX2, a gift from Didier Trono [Addgene plasmid 12260]) and 5 μg capsid (pMD2G, a gift from Didier Trono [Addgene plasmid 12259]). The medium was changed 8 h after transfection. After 48 h, the viral supernatant was collected and filtered using a 45 μm PVDF filter and stored at -80°C. Virus titration was completed and HMC3-MHCII with approximately 100% and 50% AAT expressing cells were selected. Luc ;Ubi AAT Cell lines were used for experimental conditions.

[0293] IFNγ-mediated activation of human microglia

[0294] HMC3-MHCII Luc Cell lines were seeded into 96-well plates at a density of approximately 2500 cells / well. After 24 h, activation was induced with a 24-hour presentation of IFNγ (Sigma, SRP3058) at varying concentrations (0.1; 1; 10 or 100 ng / ml). IFNγ was then removed and cells were cultured for 48 h before evaluating cell viability and activation (see Figure 2).

[0295] Treatment of IFNγ-activated human microglia by exogenous / endogenous AAT

[0296] HMC3-MHCII Luc and HMC3-MHCII Luc ;Ubi AAT (endogenous AAT) cell lines were seeded into 96-well plates at a density of approximately 2500 cells / well. LucCell lines were plated and plasma-derived AAT and recombinant AAT (produced in CHO cells, AAT 1 and AAT 2) were added 3 h later and at varying concentrations (1; 10 μM or 25 μM). 24 h later, microglial activation was induced using a 24 h long IFNγ presentation (10 ng / ml), still in the presence of exogenous or endogenous AAT. IFNγ was then removed and HMC3-MHCII Luc and HMC3-MHCII Luc ;Ubi AAT Cells were cultured in the presence of exogenous or endogenous AAT for 48 h, and then the cell cultures were evaluated for cell viability and activation (see Figures 3 and 4).

[0297] Human microglial viability and activation measurements

[0298] HMC3-MHCII was measured according to the manufacturer's protocol Luc and HMC3-MHCII Luc ;Ubi AAT Cell culture viability (Cell Counting Kit-8, Sigma, 96992) and activation ( Luciferase assay system, Promega, E2710).

[0299] RNA collection, sequencing, and differential expression analysis

[0300] RNA extraction was achieved using the RNeasy micro kit (Qiagen) according to the manufacturer's protocol. The quality of RNA samples from plasma-derived AAT and recombinant AAT Nr.2 was checked (2100 Bioanalyzer, Agilent) and libraries prepared with the Truseq RNA library kit (Illumina, RS-122-2001). The libraries were sequenced (HiSeq 4000, Illumina), the sequencing quality was controlled (FastQC), the human genome (STAR ​​v.2.7.0f; UCSC hg38) was mapped, the reads were counted (HTSeq v0.9.1), and differential expression analysis was performed using the R / Bioconductor package (ReMeS 1.30.1.).

[0301] RNA collection, sequencing, and differential expression analysis

[0302] Human monocyte-derived M1 macrophages (GM-CSF, PromoCell, C-12916) were cultured on fibronectin-coated cell culture dishes in M1-macrophage generation medium XF and 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.

[0303] Cytokine multiplexing assay

[0304] 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.

[0305] Cell-free TACE / ADAM17 activity

[0306] TACE activity and the inhibition of human AAT (AAT) were determined in black 96-well immunoplates (437111, ThermoFisher Scientific) using a recombinant human TACE / ADAM17 kit (930-ADB and ES003, R&D Systems). The activity of TACE / ADAM17 was measured by mixing 0.005 μg of rhTACE with 10 μM Mca-PLAQAV-Dpa-RSSSR-NH2 fluorescent peptide substrate III in a final volume of 100 μl in an assay buffer (25 mMTris, 2.5 μM ZnCl2, 0.005% Brij-35 (weight / volume), pH 9.0). AAT (Sigma Aldrich, batch A6150) was resuspended in water (vehicle) and control TACE / ADAM17 activity was evaluated in the presence of a vehicle (amount for AAT 100 μM). The AAT of different concentrations (0 μM, 6.25 μM, 12.5 μM, 25 μM, 50 μM and 100 μM) is added to assess its dose-dependent inhibition of TACE / ADAM17. All conditions are carried out in triplicate. Using SpectraMax iD3 microplate reader (low PMT gain, 1s exposure, top reading at 1mm, wavelength: excitation 320nm, emission 405nm) in kinetic mode (9 time points in 5min) with relative fluorescence units (RFU) to measure activity. By averaging the values ​​obtained in 5min for each condition, a bar graph as a percentage of control activity is obtained.

[0307] animal

[0308] As a murine model of CMT1A, we used C3-PMP22 transgenic mice (B6.Cg-Tg (PMP22) C3Fbas / J, The Jackson Laboratory) expressing 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 covers in a continuous air filter room to avoid contamination. During the experiment, paired animals were caged at a constant temperature using a 12 / 12 hour day / night cycle. Animals were fed ad libitum (controlled feeding of tap water and nutrition). Animal procedures were approved by the Animal Research Committee of Languedoc Roussillon. This protocol and laboratory procedures follow the French legislation implementing the European Directives (reference number: D3417223, APAFIS #23920-2020020320279696v3). Animal health was followed daily to ensure that only animals in good health entered the testing procedure and followed the study.

[0309] In vivo study paradigm

[0310] The animals were divided into 3 groups (wild-type control (0.9% NaCl subcutaneously), CMT1A-vehicle (0.9% NaCl subcutaneously), CMT1A-human alpha-1 antitrypsin (subcutaneously, twice daily, 50 mg / kg per injection)), with 3 mice per group (3-week-old males weighing 18±2.5 g at the beginning of the study), and all underwent the following procedures after 7 days of field acclimatization.

[0311] Starting from 4 weeks of age, blood samples were taken from animals to determine interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) levels, as Fig.16 As described in.

[0312] Plasma levels of AAT were assessed every 5 days from the first to the last day of treatment.

[0313] On the first and last day of treatment, the animals were tested for neuromuscular performance using the rotarod test, the grasping test, and the sciatic nerve electrophysiological test. After the last treatment at week 8, these tests were repeated, the animals were sacrificed, and the left sciatic nerve was sampled for histological evaluation of neuron number and size.

[0314] Example 9

[0315] TACE activity was evaluated in kinetic mode in the absence or presence of different AAT concentrations according to the manufacturer's instructions (recombinant human TACE / ADAM17 kit, 930-ADB, RD systems). All conditions were performed in triplicate and are shown as mean ± SD (Figure 5).

[0316] Example 10

[0317] The most common type of CMT is CMT1A, which is characterized by duplication of the PMP22 gene, leading to accumulation of the pmp22 protein in Schwann cells and progressive demyelination. PMP22 is a tetraspan glycoprotein contained in the dense myelin of the peripheral nervous system. Duplication of PMP22 is associated with the pathogenesis 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 causal relationship between the additional PMP22 gene and CMT1A is still not fully understood and remains elusive to date. However, several plausible hypotheses can be used to link the genetic abnormality (i.e., duplication of the PMP22 gene) to the pathological manifestations. Without being bound by theory, PMP22 overexpression can have a negative effect on the formation of myelin in the peripheral nervous system (PNS). These mice present an age-dependent demyelinating neuropathy characterized by loss of primarily distal strength and sensation. C3-PMP mice show no overt clinical signs at 3 weeks and develop progressive and observable neuromuscular impairment after 4 weeks. The mice have stable, low nerve conduction velocities, 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 is used to study the effects of AAT in different paradigms.

[0318] Positive effects of AAT administration were observed in CMT1A mice after two weeks by increasing rotarod latency, grip strength, and nerve conduction performance compared to untreated controls. In addition, there was no observable weight loss in the AAT-treated group compared to the vehicle group, indicating that there was no systemic toxicity of the compound under these experimental conditions (Table 11).

[0319] Table 11 Weight

[0320]

[0321] Sciatic nerve electrophysiology (EMG) provides a sensitive and quantitative method to measure the compound muscle action potential and nerve conduction velocity amplitude in animals, and is completed by stimulating the sciatic nerve. Similar compound muscle action potential (CMAP) amplitudes were observed between groups at baseline (6 weeks of age). As expected, at 8 weeks of age, a significant and significant reduction in CMAP amplitude was observed in the CMT1A+vehicle group compared to the wild-type control group. The results show that compared with the control, the EMG parameters of CMT1A mice treated with AAT were improved (Figure 6 and Table 12, Table 13, Table 14), which shows that AAT is positive for axonal degeneration induced by CMT1A disease.

[0322] At baseline (6 weeks of age), lower nerve conduction velocity (NCV) was 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, at 8 weeks of age, a significant and significant reduction in NCV was observed in the CMT1A+vehicle group compared to the wild-type control group. Compared with the vehicle-treated group, the CMT1A+AAT-treated group showed an increase in NCV. Because nerve conduction velocity depends on myelin integrity, these data also show the positive effect of AAT on Schwann cell demyelination induced by CMT disease.

[0323] Table 12 - Sciatic nerve electrophysiology

[0324]

[0325] Table 13 - Average compound muscle action potentials

[0326]

[0327] Two-way ANOVA and Pontferroni t-test for repeated measures

[0328] ***: p < 0.001 compared with WT control; p<0.05 compared to CMT1A+vehicle

[0329] Table 14: Mean Nerve Conduction Velocity

[0330]

[0331] Two-way ANOVA and Pontferroni t-test for repeated measures

[0332] *; ***; p<0.01; p<0.001 compared with WT control

[0333] The grip strength test measures neuromuscular strength by evaluating the animal's grip on 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, there was no statistically significant difference in grip strength between the groups. As expected, at 8 weeks of age, a substantial and significant decrease in grip strength was observed in the CMT1A+vehicle group compared to the wild-type control group. The results showed that the grip strength of CMT1A mice treated with AAT was improved compared to the control group (Figure 7 and Table 15, Table 16).

[0334] Table 15 Grip strength

[0335]

[0336] Table 16 Average grip strength

[0337]

[0338] Two-way ANOVA and Pontferroni t-test for repeated measures

[0339] **; ***; p<0.01; p<0.001 compared with WT control

[0340] The rotarod test measures neuromuscular coordination by evaluating the ability of animals to maintain balance on a rotating cylinder. Similar rotarod latencies were observed between groups at baseline (6 weeks of age). As expected, at 8 weeks of age, a substantial and significant reduction in rotarod latency was observed in the CMT1A+vehicle group compared to the wild-type control group. The results showed that the rotarod latency of CMT1A mice treated with AAT was improved compared to the control group (Figure 8 and Table 17, Table 18).

[0341] Table 17 Rotarod latency

[0342]

[0343] Table 18 Average Rotarod Latency

[0344]

[0345] Two-way ANOVA and Pontferroni t-test for repeated measures

[0346] *; ***: p<0.05; p<0.001 compared with WT control

[0347] Embodiment 11

[0348] It seems that the PMP22 protein is particularly important in protecting nerves from physical stress, helping them to restore their structure after being pinched or squeezed (compression). Compression can interrupt nerve signaling, resulting in a sensation commonly referred to as a limb "falling asleep." The ability of nerves to recover from normal, everyday compression (such as when sitting for a long time) prevents the limbs from constantly losing sensation. In CMT1A patients, the myelination process is not completed correctly, and the pathological symptoms associated with the disease most often become apparent after the second decade of life.

[0349] The PMP22 gene also plays a role in the growth of Schwann cells and the maturation of cells to perform specific functions (differentiation). Before they become part of myelin, newly produced PMP22 proteins are processed and packaged in specialized cellular structures called the endoplasmic reticulum and the Golgi apparatus. Completion of these processing and packaging steps is critical for proper myelin function. The pathomechanics of CMT1A is characterized by the absence of myelin due to an extra PMP22 gene, which results in abnormally high concentrations of peripheral myelin protein 22 (PMP22) in Schwann cells. GSEA analysis of human microglia has shown upregulation of genes associated with the unfolded protein response (UPR) pathway and cell survival (anti-apoptosis) with AAT treatment ( Figure 4C , Fig. 9 ).

[0350] Example 12

[0351] ADAM17, also known as TACE, is a transmembrane protein that includes 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). It is hypothesized that AAT is able to cross the blood-nerve barrier (BNB) and interact with ADAM17 to successfully inhibit its activity, and by doing so allows SCs to "manually" overcome the distress signal generated by the overloaded ER with PMP22 and promote the formation of myelin around axons.

[0352] Example 13 Plasma AAT Levels

[0353] AAT was not detected in the plasma of wild-type controls and CMT1A mice treated with vehicle at the analyzed time points (days 14, 19, 24, and 29). AAT with a mean of 6.07 μg / mL, 6.99 μg / mL, 8.14 μg / mL, and 5.22 μg / mL was detected in the plasma of the CMT1A+AAT group on days 14, 19, 24, and 29, respectively.

[0354] Example 14A Sciatic Nerve Histology

[0355] As expected, at 8 weeks of age, a decrease in the total number of axons per surface, a decrease in axon diameter, and a significant increase in g-ratio were observed in the CMT1A+vehicle group compared to the wild-type control group (Table 19, Fig.10 to Figure 13).

[0356] A slight increase in the total number of axons per surface was observed in the CMT1A+AAT treated group compared to the vehicle group. In addition, a significant increase in axon diameter and a decrease in g-ratio (equal to the ratio of the inner diameter to the outer diameter of myelinated axons) were observed in CMT1A animals treated with AAT compared to the vehicle treated group. Even so, CMT1A+AAT animals presented statistically different axon numbers, axon diameters, and g-ratios from wild-type controls (Table 19, Fig.10 To sum up, these data indicate that AAT has a positive but incomplete efficacy against the histopathology induced by CMT1A disease when administered at 50 mg / kg twice daily by the subcutaneous route.

[0357] Table 19 Sciatic nerve histology

[0358]

[0359] Example 14B-IL-6

[0360] Similar plasma IL-6 concentrations were observed between groups at baseline (Day 1) and Day 8.

[0361] As expected, a significant increase in plasma IL-6 concentrations was observed in the CMT+Vehicle group on days 14 and 29. The terms CMT and CMT1A are used interchangeably in the Examples section.

[0362] The CMT+AAT treatment group also presented a significant increase in plasma IL-6 concentrations compared to baseline concentrations. However, at day 29, the plasma IL-6 concentrations of animals treated with AAT were lower than those of animals treated with vehicle (Tables 20 and Fig.14 ), suggesting a direct or indirect effect of AAT on this inflammatory cytokine.

[0363] Table 20: Mean plasma IL-6 concentrations in CMT mice treated with and without AAT

[0364]

[0365] Student's t-test *; **; ***: p < 0.05; p < 0.01; p < 0.001 compared with WT control at this time point; p<0.05 compared to CMT1A+Vehicle at this time point

[0366] Example 15-TNFα

[0367] Significant increases in plasma TNFα concentrations were observed in the CMT1A+Vehicle group on days 14 and 29.

[0368] Compared with baseline concentrations, the CMT1A+AAT treatment group also showed a significant increase in plasma TNFα concentrations on days 14 and 29 (Table 21 and Fig.15 ), indicating that AAT has no effect on the levels of this inflammatory cytokine in this CMT1A model.

[0369] Table 21: Plasma TNFα Levels

[0370]

[0371] Student's t-test **; ***; p < 0.01; p < 0.001 compared to WT control at this time point.

[0372] Example 16

[0373] The effect of AAT on SH-SY5Y treated with 6-OHDA was evaluated by cell morphology and cell proliferation followed by quantification of cell viability.

[0374] Cells and treatments

[0375] SH-SY5Y cells, which are commonly used to model neurodegenerative disorders, were used to generate an in vitro Parkinson's disease model (QueR, et al., 2021, Front. Immunol. 12). Cells were cultured in DMEMF12 / Glutamax supplemented with 10% FBS.

[0376] Cells were treated with 50 μM, 100 μM concentrations of neurotoxin 6-hydroxydopamine (6-OHDA, Sigma Aldrich 162957) or in combination with AAT 25 μM (plasma-derived AAT, Sigma Aldrich batch A9024) for 24 hours. Cells were treated with AAT alone or in combination with 6-OHDA for 24 hours, and then incubated with fresh AAT for another 24 hours. Control cells were treated with PBS.

[0377] Cell growth and viability assays

[0378] On day 0 (the day after they were treated as described above), cells were plated in 24-well plates in the same number, and a final total cell count was performed on the 4th day of culture (cell growth). Cell viability was evaluated using a cell counting kit-8 (CCK-8; SigmaAldrich 96992). After treatment, cells were incubated in an incubator with 10 μl of CCK-8 solution for 2 hours. The absorbance was measured at 450 nm using a SpectraMax iD3 microplate reader. The experiment was performed in triplicate.

[0379] Human IL-6 immunoassay

[0380] The cell supernatant was subjected to human IL-6 immunoassay (R&D D6050). In brief, 40,000 cells were plated in 24-well plates and treated on the day after as described in the "Cells and Treatments" paragraph. At the end of the treatment, the cells were washed with PBS and incubated with 2% FBS culture medium for 24 hours, then the cell culture supernatant was collected and centrifuged to remove particles. As described in the manufacturer's instructions, the standard and duplicate samples were assayed. The absorbance was measured at 450nm using a SpectraMax iD3 microplate reader. A standard curve was prepared from seven IL-6 standard dilutions and the IL-6 sample concentration was determined.

[0381] After 4 days of culture, 50 μM to 100 μM 6-OHDA for 24 hours induced cell proliferation impairment by inducing cell death and reducing cell number (Figure 17). In contrast, combined treatment with AAT significantly increased the number of cells counted compared to 6-OHDA alone (Figure 17), indicating the positive effect of AAT on cell survival / proliferation. T-test p values ​​are significant for the following: control compared to 6ohda p=0.001; 6ohda compared to AAT+6ohda p=0.003. Control was not significant compared to AAT. Error bars are SEM.

[0382] The treated cells were then challenged in a cell viability assay. SH-SY5Y treated with 6-OHDA alone showed a substantial decrease in cell viability compared to control cells and cells treated with AAT alone ( Fig.18 ).

[0383] When 6-OHDA treatment was combined with AAT, cell counts as well as cell viability were significantly enhanced compared to 6-OHDA treatment alone ( Fig.18). P values ​​were calculated using a t-test, and non-significant differences were observed between the control and AAT alone. All conditions were performed in triplicate. Based on these results, we can conclude that administration of AAT has a favorable effect on cell growth and viability in a PD cell model (SH-SY5Y induced by 6-OHDA), and may protect cells from 6-OHDA-induced death.

[0384] In addition, to explore the effect of AAT on proinflammatory cytokines, we performed IL-6 quantification in cell supernatants. The culture medium of cells induced by 6-OHDA had increased IL-6 levels compared to the control culture medium, whereas the culture medium collected from cells treated with AAT showed lower concentrations of IL-6 ( Fig.19 ). T-test p value was significant for control vs. 6-OHDA at p=0.05, and the other comparison was not significant.

[0385] Embodiment 17

[0386] 8-week-old C57BL / 6 mice were received and housed under controlled conditions during the study. Three groups of animals (4 per group) were assigned to the following subcutaneous treatments twice daily at 7:00 AM and 7:00 PM for 2 weeks, starting from 20 to 35 days after disease induction:

[0387] Wild-type (WT) mice received vehicle, 0.9% NaCl (positive control)

[0388] CIDP mice received vehicle, 0.9% NaCl (negative control)

[0389] CIDP mice received AAT (AAT), 50 mg / kg per injection

[0390] Disease induction included subcutaneous injection of mouse sciatic nerve homogenate in phosphate buffered saline (PBS) + Freund's adjuvant mixture at 10 mL / kg. For each treatment, 3 injections were performed at different body sites. Control mice also received three subcutaneous injections of PBS + Freund's adjuvant at the same 3 different body sites.

[0391] Blood samples were taken from animals on the day before disease induction (day 1), the first (day 20), and the last (day 35) treatment day for determination of neurofilament light chain (NfL), tumor necrosis factor α (TNFα), and TMPRSS5 levels, as Fig. 20 In addition, plasma levels of AAT were assessed on the last treatment day.

[0392] On the first day (day 20) and the last day (day 35) of treatment, the animals were tested for neuromuscular and performance using the rotarod test, the grasp test, and sensory testing using the Von Frey filament test, as well as sciatic nerve electrophysiology. After the last treatment on day 35, these tests were repeated, the animals were sacrificed, and the left sciatic nerve was sampled for histological evaluation of neuron number and size.

[0393] Rotarod test

[0394] A significant decrease in rotarod latency was observed in the CIDP group compared to the control group on day 20. On day 35, the CIDP+AAT treated group presented increased rotarod latency compared to the vehicle treated group (Table 22, Figure 21A).

[0395] Table 22: Mean Rotarod Latency

[0396]

[0397] Grip strength test

[0398] 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 treated group exhibited increased grip strength compared to the vehicle treated group (Table 23 and Table 21B).

[0399] Table 23: Average grip strength

[0400]

[0401] VonFrey Test

[0402] At baseline (day 20), lower paw withdrawal thresholds were observed in the CIDP group compared to the wild-type control group. On day 35, the CIDP+AAT treated group presented an increased paw withdrawal threshold compared to the vehicle treated group (Table 24 and Fig. 21C ). The results of this test showed that AAT exhibited a statistically significant positive effect (reduced pain) on the pain threshold of these CIDP mice when AAT was administered at 50 mg / kg twice daily by the subcutaneous route.

[0403] Table 24: Average foot withdrawal threshold

[0404]

[0405] Compound muscle action potential

[0406] At day 20, a large and significant decrease in CMAP amplitude was observed in both CIDP groups compared to wild-type controls.

[0407] On day 35, the CIDP+AAT treated group showed an increase in CMAP amplitude compared to the CIDP+vehicle treated group (Table 25 and Fig. 22 A).

[0408] Table 25: Average compound muscle action potentials

[0409]

[0410] Nerve conduction velocity

[0411] On day 20, a substantial decrease in NCV was observed in both CIDP groups compared to the wild-type control group. The CIDP+AAT treated group presented an increase in NCV compared to the vehicle treated group (Table 26 and Table 27). Fig. 22 B).

[0412] Table 26: Mean Nerve Conduction Velocity

[0413]

[0414] Neuromuscular impairment and reduction in nerve conduction amplitude and velocity were observed in a preclinical CIDP mouse model treated with vehicle compared with wild-type controls 20 days after disease induction.

[0415] Increases in rotarod latency, grip strength, paw withdrawal threshold, and nerve conduction velocity and amplitude were observed in AAT-treated CIDP mice compared with vehicle-treated groups.

[0416] These data suggest that AAT shows a trend towards a positive effect on CIDP when administered at 50 mg / kg twice daily by the subcutaneous route in CIDP mice.

[0417] Raw data

[0418] Table 27A: Rotarod latency

[0419]

[0420] Table 27B: Rotarod latency

[0421]

[0422] Table 28A: Grip Strength

[0423]

[0424] Table 28B: Grip Strength

[0425]

[0426] Table 29A: VonFrey Test

[0427]

[0428] Table 29B: VonFrey Test

[0429]

[0430] Table 30: Electrophysiology

[0431]

[0432] Table 31A: Weight

[0433]

[0434] Histology

[0435] 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 Fig.37 To Figure 39). A slight but insignificant increase in the total number of axons per surface was observed in the CIDP+AAT treated group compared to the vehicle treated group. At day 35, a significant increase in axon diameter and a decrease in g-ratio were also observed in the CIDP+AAT treated group compared to the CIDP+vehicle treated group.

[0436] Table 31B: Sciatic Nerve Histology

[0437]

[0438] Example 18: Plasma NfL Quantification

[0439] Similar plasma NfL concentrations were observed among the three groups at baseline (day 1, before model induction).

[0440] On day 20, a significant increase in plasma NfL concentrations was observed in the CIDP+vehicle and CIDP+AAT groups compared to the sham control group before compound treatment (Tables 32, 33 and Fig.23 B).

[0441] Importantly, on day 35, a significant decrease in plasma NfL concentrations was observed in the CIDP+AAT treated group compared to the CIDP+vehicle treated group (Tables 32, 33 and Fig.23 B), which confirms the positive efficacy of this compound under these experimental conditions against the peripheral axonopathy induced by this inflammatory neuropathy.

[0442] Example 19: Quantification of plasma TNFα

[0443] At baseline (day 1, before model induction), similar plasma TNFα concentrations were observed among the three groups. On day 20, a significant increase in plasma TNFα concentrations was observed in the CIDP+vehicle group and the CIDP+AAT group compared to the sham control group before compound treatment (Tables 34, 35, and Fig.24 ).

[0444] Importantly, on day 35, a significant decrease in plasma TNFα concentrations was observed in the CIDP+AAT treated group compared to the CIDP+vehicle treated group (Tables 34, 35 and Fig.24 ), which confirms the positive efficacy of this compound on cytokine activation induced by autoimmune chronic inflammatory demyelinating polyneuropathy under these experimental conditions.

[0445] In summary, neuromuscular impairment and reduction in nerve conduction amplitude and velocity were observed in a preclinical CIDP mouse model treated with vehicle compared with wild-type controls 20 days after disease induction.

[0446] Compared with the CIDP+vehicle treated group, increases in rotarod latency, grip strength, and nerve conduction velocity were observed in the CIDP+AAT treated group. No statistical significance was observed in the plasma TMPRSS5 concentrations in the CIDP+AAT treated group compared with the vehicle group. However, at day 35, a significant increase in compound muscle action potential amplitude, a decrease in neuropathic pain, and a decrease in plasma TNFα and NfL concentrations were observed in the CIDP+AAT treated group compared with the CIDP+vehicle treated group. Finally, histopathological analysis of the sciatic nerve showed a significant increase in axon diameter and myelin sheath diameter in CIDP+AAT compared with the vehicle treated group (reduced g-ratio), which confirmed the positive efficacy of the compound from a histological perspective.

[0447] In summary, these data demonstrate that AAT exhibits positive efficacy against autoimmune chronic inflammatory demyelinating polyneuropathy targeting the peripheral nervous system, increasing neuromuscular and electrophysiological manifestations and reducing neuropathic pain and plasma neuropathy biomarkers when administered at 50 mg / kg twice daily by subcutaneous route in a preclinical CIDP mouse model.

[0448] Table 32A :

[0449]

[0450] Table 32B :

[0451]

[0452] Table 33 :

[0453]

[0454] Table 34A :

[0455]

[0456] Table 34B :

[0457]

[0458] Table 35 :

[0459]

[0460] Embodiment 20

[0461] Compound muscle action potential (CMAP) increased significantly after two weeks of AAT therapy.

[0462] CMT mouse model: non-humanized CMT1A mouse B6.Cg-Tg(PMP22)C3Fbas / J (three copies of the PMP22 gene), three groups, 8 animals in each group.

[0463] Dose: 180 mg / kg / day nonclinical grade AAT (Sigma)

[0464] Dosing: Subcutaneous (SC) (90 mg / kg twice daily)

[0465] Key disease progression parameters improved significantly after two weeks of AAT treatment (180 mg / kg / day), see Figures 25 to 30 .

[0466] Table 36: Rotarod latency

[0467]

[0468] Table 37: Grip strength

[0469]

[0470] Table 38: Electrophysiology

[0471]

[0472] Table 39: TNFα

[0473]

[0474] Example 21 - Efficacy of AAT in a Charcot-Marie-Tooth Disease Mouse Model

[0475] Charcot-Marie-Tooth Disease (CMT) is an inherited motor and sensory neuropathy of the peripheral nervous system characterized by progressive loss of muscle tissue and dysfunction of the sense of touch in different parts of the body. Currently incurable, this disease is the most prevalent inherited neurological disorder and affects approximately one in 2,500 people. The most common type of CMT is CMT1A, which is characterized by a duplication of the pmp22 gene, leading to accumulation of the pmp22 protein in Schwann cells and progressive demyelination. PMP22 is a tetraspan glycoprotein contained in the dense myelin of the peripheral nervous system. Duplication of PMP22 is associated with the onset of Charcot-Marie-Tooth Disease type 1A (CMT1A).

[0476] 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 present an age-dependent demyelinating neuropathy characterized by loss of primarily distal strength and sensation. C3-PMP mice show no overt clinical signs at 3 weeks and develop mild neuromuscular impairment in an age-dependent manner. They have stable, low nerve conduction velocities 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.

[0477] In CMT1A, a major component of the disease is a developmental abnormality in myelin formation (dysmyelination). Myelin is produced by SCs in the peripheral nervous system and is essential for the proper transmission of electrical impulses in nerves. The primary dysmyelination seen in CMT1A patients results in abnormal SC organization around axons and a uniform slowing of nerve conduction velocity.

[0478] It has been shown that the transmembrane protein ADAM17 (also known as TACE for tumor necrosis factor-α-converting enzyme) blocks myelination of axons in SCs by inhibiting neuregulin type 1 III signaling (NRG1-III) (La Marca et al., 2011; Pisciotta et al., 2021). AAT, through its pharmacological inhibition of ADAM17, may hold promise for the treatment of CMT by modulating NRG1-III signaling. AAT inhibition of ADAM17 promotes SC myelination in the peripheral nervous system and may therefore reduce CMT disease progression.

[0479] In addition to its inhibitory function on ADAM17, another mechanism of AAT in the treatment of CMT is its anti-inflammatory activity. AAT exhibits a wide range of anti-inflammatory and immunomodulatory activities. Increasing AAT serum concentrations above normal levels by administration of exogenous AAT is expected to be therapeutic for CMT.

[0480] B6.Cg-Tg (PMP22) C3Fbas / J transgenic mice express three copies of the wild-type human peripheral myelin protein 22 (PMP22) gene. They present an age-dependent demyelinating neuropathy characterized by loss of distal strength and sensation. These mice show no obvious clinical signs at 3 weeks and develop mild neuromuscular impairment in an age-dependent manner, which is fully established at 8 weeks of age. Similar to adults with human CMT1A, they have stable, low nerve conduction velocities. Myelination is delayed in these mice, and they contain a reduced number of myelinated axons.

[0481] Materials and methods

[0482] 6-week-old animals were received and housed under controlled conditions during the study. The study included two groups of 8 transgenic mice (CMT mice) and a group of 8 age-matched wild-type (WT) C57B16 mice that served as positive controls. Starting from 8 weeks of age up to 10 weeks of age, animals were assigned to the following subcutaneous treatments, twice a day at 7:00 am and 7:00 pm for 2 weeks:

[0483] Wild-type (WT, disease-free) mice received vehicle, 0.9% NaCl (positive control)

[0484] CMT1A mice received vehicle, 0.9% NaCl (negative control)

[0485] CMT1A mice received 90 mg / kg of AAT per injection (daily dose 180 mg / kg)

[0486] Efficacy parameters include:

[0487] Neuromuscular performance (latency to fall from rotarod and grip strength test)

[0488] Sciatic nerve electrophysiology (CMAP amplitude and NCV)

[0489] Cytokine (IL-6 and TNFα), and NfL analysis

[0490] Sciatic nerve histology (axon number and axon diameter)

[0491] On the first day of treatment (Day 1), the animals were tested for neuromuscular and performance using the rotarod test and grip strength test as well as sciatic nerve electrophysiological tests measuring compound muscle action potential (CMAP) and nerve conduction velocity (NCV). These tests were repeated after the last treatment on Day 15. The animals were then left without treatment for another 2 weeks to assess the duration of the treatment effect. Behavioral and electrophysiological tests were repeated after a 2-week treatment-free period until 12 weeks of age (Day 30).

[0492] As supportive information for the mode of action of AAT in CMT, plasma concentrations of interleukin 6 (IL-6) and TNFα were measured on days 1 (week 8), 15 (week 10), and 30 (week 12). At the same time points, plasma levels of NfL, a biomarker of neurological damage, were determined.

[0493] result

[0494] At 8 weeks of age (baseline), CMT mice showed clear clinical signs / symptoms of the disease compared to normal wild-type mice. Neuromuscular impairment (reduced latency to fall) can be seen in Fig.25 and Table 40A.

[0495] Table 40A: Mean Rotarod Latency in CMT Mice Treated with and Without AAT

[0496]

[0497] The reduced grip strength of CMT mice compared to wild-type mice can be seen in Fig.26 and Table 40B.

[0498] Table 40B Mean grip strength of CMT mice treated with and without AAT

[0499]

[0500] A decrease in neural CMAP amplitude was shown in Fig. 27 and Table 40C.

[0501] Table 40C: Mean CMAP of CMT mice treated with and without AAT

[0502]

[0503] And the decrease in sciatic nerve velocity is shown in Fig.28 and Table 40D.

[0504] Table 40D: Mean NCV of CMT mice treated with and without AAT

[0505]

[0506] Plasma cytokine levels of IL-6 and TNFα were increased in CMT mice (Table 40E, Table 40F and Table 40F). Fig.29 and Fig.30 ), and an increase in NfL, a biomarker of neurological damage (Table 40G and Fig.40 ).

[0507] Table 40E: Mean plasma IL-6 concentrations in CMT mice treated with and without AAT

[0508]

[0509] Table 40F: Mean plasma TNFα concentrations in CMT mice treated with and without AAT

[0510]

[0511] Table 40G: Mean plasma NfL concentrations in CMT mice treated with and without AAT

[0512]

[0513] Table 40H: Mean histological data of CMT mice treated with and without AAT

[0514]

[0515] All these clinical signs / symptoms present in CMT mice were fully established at 8 weeks of age as expected. In addition, in control CMT mice, the signs evolved over time and became more severe at 10 weeks of age, and their severity was still increasing at 12 weeks of age.

[0516] Treatment with AAT was started at 8 weeks of age and continued for 2 weeks until 10 weeks of age. The results showed that AAT increased neuromuscular and electrophysiological performance when administered at 90 mg / kg twice daily by subcutaneous route in CMT mice. CMT mice treated with AAT showed a significant increase in latency to fall from the rotarod (****: 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 Fig.25 ), grip strength was significantly increased (****: P < 0.0001 compared with WT + vehicle; #, ####: P < 0.05, P < 0.0001 compared with CMT + vehicle, two-way ANOVA and Bonferroni test; ns: not significant, P > 0.05 Fig.26 ), the compound muscle potential amplitude was significantly increased (****: P < 0.0001 compared with WT + vehicle; #, ###: P < 0.05, compared with CMT + vehicle, P < 0.001, two-way ANOVA and Bonferroni test; ns: not significant, P > 0.05 Fig. 27), and the nerve conduction velocity was significantly increased (****: P < 0.0001 compared with WT + vehicle; ###: P < 0.001 compared with CMT + vehicle, two-way ANOVA and Bonferroni test; ns: not significant, P > 0.05 ( Fig.28 ), when compared with CMT mice not treated with AAT. AAT reduced the plasma levels of inflammatory cytokines IL-6 (P<0.01) and TNFα (P<0.0001); (Table 40E, Table 40F, Fig.29 and Fig.30 ) and NfL levels (Table 40G and Fig.40 ).

[0517] At 12 weeks of age, after a 2-week treatment-free period, the effect of AAT decreased, suggesting that repeated administration of AAT is necessary to obtain a sustained effect. At this point, grip strength and CMAP in AAT-treated mice had decreased relative to the end of the treatment period, but were still significantly higher than in untreated CMT animals (P<0.05 for both parameters). The positive effects on IL-6, TNFα, and NfL plasma levels remained significant, and even after a 2-week treatment-free period, the number of axons was significantly higher and the size of myelin sheaths was significantly larger in treated animals. The only parameters that were not significantly different from the untreated group were the latency to fall from the rotarod and the NCV.

[0518] in conclusion

[0519] AAT therapy was evaluated in a relevant mouse model of 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. Relative to untreated CMT animals, AAT treatment was associated with improvements in neuropathy, as shown by a significant increase in neuromuscular and electrophysiological manifestations and an increase in the number of axons and axon diameter and an increase in the g-ratio. A reduction in plasma cytokines (TNFα and IL-6) and NfL biomarkers was also observed in treated animals. AAT has been shown to reduce the progression of the disease. The effect of treatment with AAT is limited in time, and 2 weeks after treatment was discontinued, symptoms have worsened, although not to the level of untreated CMT animals.

[0520] Together, these data demonstrate the potential of AAT to improve outcomes in patients with CMT1A by not only slowing disease progression but also reversing its symptoms.

[0521] Example 22 Inhibitory Effects of AAT-Related Peptides and Peptide Mimetics on ADAM17 ActivityBioactive immunomodulatory sites on the surface of AAT (not associated with classical antiprotease activity) were identified by computer simulation methods, and several peptides were derived from those 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 a peptide mimetic (peptide 14) to modulate ADAM17 activity was studied.

[0522] Peptide 8 (sequence: Ac-YRAHQGE-NH2; MW: 945.4) and peptide 9 (sequence: Ac-LFLYVIH-NH2; MW: 901.3) were synthesized using the Syro-1 automated peptide synthesizer and the Fmoc / tBu strategy ( Fig.42 Peptide 14 (4-hydroxy-Bzl-His-Phg-NH2 [TFA salt]; MW: 394.2) was manually synthesized using the Fmoc / tBu strategy ( Fig.43 ).

[0523] ADAM-17 activity and inhibition thereof by human peptide 8 were measured using 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; RD system) in a black 96-well immunoplate (437111; ThermoFisher Scientific). The enzymatic activity of ADAM-17 was measured by mixing 0.005 μg of rhADAM-17 with 10 μM Mca-PLAQAV-Dpa-RSSSR-NH2 fluorescent peptide substrate III in an assay buffer (25 mM Tris, 2.5 μM ZnCl2, 0.005% Brij-35 (weight / volume), 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. The control ADAM-17 activity was evaluated in the presence of assay buffer. Different concentrations of peptide 8 (0 μM, 10 μM and 50 μM in experiment 1; 0 μM, 100 μM, 200 μM and 250 μM in experiment 2) were added in 2 separate experiments to evaluate its dose-dependent inhibition of ADAM-17. All conditions were performed in triplicate. Activity was measured in relative fluorescence units (RFU) using a SpectraMax iD3 microplate reader (automatic PMT gain, wavelength: excitation 320 nm, emission 405 nm) in endpoint mode (endpoint mode) (5 min).

[0524] No significant inhibition of ADAM17 activity was noted at concentrations up to 50 μM ( Fig.31Left panel), while significant concentration-dependent inhibition was observed at concentrations of 100 (36% inhibition) and 200 (65% inhibition). Fig.31 right).

[0525] Example 23 Regulatory Effects of AAT on TNFα-Induced Schwann Cell Activation

[0526] Human Schwann cells (P10351, Innoprot) were seeded in DMEM in 12-well plates at 120,000 cells per well. Cells were pretreated with 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.

[0527] The principle of gene selection is explained as follows.

[0528] By binding to TNFR1, TNF can activate nuclear factor kappa B (NF-κB), which drives cell survival signaling as well as cell death. NF-κB activation induces transcriptional upregulation of inflammasome regulators such as IL-1β, IL-18, TNFα, and IFN-γ, mediating inflammatory responses. In addition, TNFR1 can directly induce oxidative stress by activating enzymes that produce reactive oxygen species (ROS) and reactive nitrogen species (RNS).

[0529] Genes assessed for their regulation included the NF-κB early gene response NFKBIA as well as the TNFα and TNFR1 genes. Expression of the gene encoding the IL-6 proinflammatory cytokine was also assessed.

[0530] Nuclear factor E2-related factor 2 (Nrf2) plays a key role in regulating the cellular redox state in various physiological and pathological processes. Under normal physiological conditions, Nrf2 has neither biological activity nor activation of downstream genes. By interacting with the antioxidant response element (ARE) of cytoprotective genes, Nrf2 activates antioxidant enzymes such as SOD, CAT, HO-1, NAD(P)H oxidase (G6PD), etc.

[0531] The TXN system plays an important role in maintaining a reducing environment in cells. Thioredoxin (TXN) is a thiol-oxidoreductase, which is a major regulator of cellular redox signaling, which protects cells from oxidative stress. TXNIP interacts directly with TXN, inhibiting the ability of TXN to scavenge reactive oxygen species (ROS). It has been shown that TXNIP is upregulated in diseases such as type 2 diabetes and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

[0532] As a potential early response gene, TXNIP is tightly regulated and highly correlated with changes in both mRNA and protein levels, and it has been shown to play an important role in Schwann cell dysfunction in diabetic peripheral neuropathy.

[0533] like Figure 32 to Figure 34 As shown, NF-κb pathway transcripts are downregulated by AAT treatment after TNF induction. AAT inhibits the expression of genes regulated by TNF-induced oxidative stress response. In conclusion, these results show the regulatory effect of AAT on TNFα-induced gene expression in human Schwann cells.

[0534] Embodiment 24

[0535] Microglia (HMC3) were seeded into 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) were added, and microglial activation was induced for 24 h using interferon gamma (IFNγ) (10 ng / mL) without pre-incubation. Then, RNA was extracted (RNAeasy micro kit, Qiagen) and the expression of interleukin-6 (IL6) and interleukin-1β (IL1B) genes was analyzed. 10 ng / well of cDNA was used in all gene expression results, and qPCR was performed with Syber Green POWER UP master mix.

[0536] The results showed that AAT and its derived peptides reduced IL6 expression by 30%-40% and IL1B expression by 60%-70% ( Fig.41 ), indicating that all three peptides mimic AAT function in inflammatory responses.

[0537] Example 25 Effects of AAT and its derivative peptides on TNF-induced Schwann cells .

[0538] Schwann cells were seeded at a density of 75,000 cells / well. At seeding, plasma-derived AAT (50 uM) or peptide 8, peptide 9, peptide 14 (Syngene, 50 uM) were added. The next day, cells were treated with 10 ng / ml TNFα for 24 hours with or without AAT and its derived peptides.

[0539] NAD(P)H oxidase (G6PD) expression was induced by TNF treatment in Schwann cells and was reduced by 40%-30% in stimulated cells treated with AAT and its derived peptides ( Fig.35 ). G6PD plays an important role in the generation of ROS.

[0540] The present invention also relates to the following items:

[0541] 1. A pharmaceutical product for treating chronic inflammatory demyelinating polyneuropathy, the pharmaceutical product comprising:

[0542] a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof having ADAM17 inhibitory activity; and / or

[0543] b) A nucleic acid encoding AAT, a variant, an isoform and / or a fragment thereof having ADAM17 inhibitory activity.

[0544] 2. A kit for treating a disease or condition of the nervous system, the kit comprising:

[0545] i) a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof having ADAM17 inhibitory activity; and / or

[0546] b) a nucleic acid encoding AAT, a variant, an isoform and / or a fragment thereof having ADAM17 inhibitory activity; and

[0547] ii) various IgG antibodies, IgG variants, isotypes and / or fragments thereof.

[0548] 3. A pharmaceutical composition for treating a disease or disorder of the nervous system, the composition comprising:

[0549] i) a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof having ADAM17 inhibitory activity; and / or

[0550] b) a nucleic acid encoding AAT, a variant, an isoform and / or a fragment thereof having ADAM17 inhibitory activity; and

[0551] ii) a plurality of IgG antibodies, IgG variants, isotypes and / or fragments thereof; and

[0552] iii) at least one pharmaceutically acceptable carrier.

[0553] 4. A method of treatment comprising administering to a subject an effective amount of a pharmaceutical composition comprising an AAT protein and / or a nucleic acid encoding AAT, wherein the subject suffers from a disease or disorder of the nervous system, and wherein the subject is undergoing a therapy comprising the administration of a plurality of IgG antibodies, IgG variants, isotypes and / or fragments thereof.

[0554] 5. A method of treatment comprising administering to a subject an effective amount of a pharmaceutical compound comprising a plurality of IgG antibodies, IgG variants, isotypes and / or fragments thereof, wherein the subject suffers from a disease or disorder of the nervous system, and wherein the subject is undergoing a therapy comprising administration of an AAT protein and / or a nucleic acid encoding AAT.

[0555] 6. The 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.

[0556] 7. The pharmaceutical product used according to item 1, the kit used according to item 6, the pharmaceutical composition used according to item 6, the treatment method according to item 6, wherein the subject 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.

[0557] 8. A 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 method of treatment according to any one of items 4 to 7, wherein the plurality of IgG antibodies, IgG variants, isotypes and / or fragments thereof are plasma-derived IgG antibodies, IgG variants, isotypes and / or fragments thereof.

[0558] 9. A kit for use according to any one of items 2, 6 to 7, a pharmaceutical composition for use according to any one of items 3, 6 or 7, or a method of treatment according to any one of items 4 to 7, wherein the plurality of IgG antibodies, IgG variants, isotypes and / or fragments thereof are recombinant IgG antibodies, IgG variants, isotypes and / or fragments thereof.

[0559] 10. A kit for use according to any one of items 2, 6 to 9, a pharmaceutical composition for use according to any one of items 3, 6 to 9, or a method of treatment according to any one of items 4 to 9, wherein the plasma-derived IgG antibody, IgG variant, isotype and / or fragment thereof is configured for intravenous administration.

[0560] 11. A kit for use according to any one of items 2, 6 to 9, a pharmaceutical composition for use according to any one of items 3, 6 to 9, or a method of treatment according to any one of items 4 to 9, wherein the plasma-derived IgG antibody, IgG variant, isotype and / or fragment thereof is formulated for subcutaneous administration.

[0561] 12. A pharmaceutical product for use according to any one of items 1 or 7, a kit for use according to any one of items 2, 6 to 11, a pharmaceutical composition for use according to any one of items 3, 6 to 11, a method of treatment according to any one of items 4 to 11, wherein the AAT protein is recombinant AAT.

[0562] 13. A pharmaceutical product for use according to any one of items 1 or 7, a kit for use according to any one of items 2, 6 to 11, a pharmaceutical composition for use according to any one of items 3, 6 to 11, a method of treatment according to any one of items 4 to 11, wherein the AAT protein is plasma-derived AAT.

[0563] 14. A pharmaceutical product for use according to any one of items 1, 7, 12 or 13, a 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 method of treatment according to any one of items 4 to 13, wherein

[0564] a) the α1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having ADAM17 inhibitory activity; and / or

[0565] b) the nucleic acid encoding AAT, its variants, isoforms and / or fragments having ADAM17 inhibitory activity,

[0566] Formulated for intravenous administration.

[0567] 15. A pharmaceutical product for use according to any one of items 1, 7, 12 or 13, a 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 method of treatment according to any one of items 4 to 13, wherein

[0568] a) the α1-antitrypsin (AAT) protein, its variants, isoforms and / or fragments having ADAM17 inhibitory activity; and / or

[0569] b) the nucleic acid encoding AAT, its variants, isoforms and / or fragments having ADAM17 inhibitory activity,

[0570] Formulated for subcutaneous administration.

[0571] SEQ ID NO: 1:

[0572] MPSSVSWGILLLAGLCCLVPVSLAEDPQGDAAQKTDTSHHDQDHPTFNKITPNLAEFAFSLYRQLAHQSNSTNIFFSPVSIATAFAMLSLGTKADTHDEILEGLNFNLTEIPEAQIHEGFQELLRTLNQPDSQLQLTTGNGLFLSEGLKLVDKFLEDVKKLYHSEAFTVNFGDTEEAKKQINDYVEKGTQGKIVDLVKELDRDTVFALVNYIFFKGKWERPFEVKDTEEEDFHVDQVTTVKVPMMKRLGMFNIQHCKKLSSWVLLMKYLGNATAIFFLPDEGKLQHLENELTHDIITKFLENEDRRSASLHLPKLSITGTYDLKSVLGQLGITKVFSNGADLSGVTEEAPLKLSKAVHKAVLTIDEKGTEAAGAMFLEAIPMSIPPEVKFNKPFVFLMIEQNTKSPLFMGKVVNPTQK

[0573] SEQ ID NO:2:

[0574] VFALVNYIFFKGKWERPFEVKDTEEEDFHVDQVTTVKVPMMKRLGMFNIQHCKKLSSWVLLMKYLGNATAIFFLPDEGKLQHLENELTHDIITKFLENEDRRSASLHLPKLSITGTYDLKSVLGQLGITKVFSNGADLSGVTEEAPLKLSKAVHKAVLTIDEKGTEAAGAMFLEAIPMSIPPEVKFNKPFVFLMIEQNTKSPLFMGKVVNPTQK

Claims

1. A pharmaceutical product for treating an inflammatory disease or condition, the pharmaceutical product comprising: a) α1-antitrypsin (AAT) protein, its variant, isoform and / or fragment, wherein the variant, isoform and / or fragment has ADAM17 inhibitory activity, or a small molecule having ADAM17 inhibitory activity; and / or b) a nucleic acid encoding AAT, a variant, an isoform and / or a fragment thereof, wherein said variant, isoform and / or fragment has inhibitory activity.

2. The pharmaceutical product for use according to claim 1, wherein the inflammatory disease or disorder is an autoimmune inflammatory disease.

3. The pharmaceutical product for use according to claim 1 or 2, wherein the inflammatory disease or disorder is an inflammatory disease or disorder of the nervous system, preferably wherein the inflammatory disease or disorder is neuropathic pain.

4. The pharmaceutical product for use according to any one of claims 1 to 3, wherein the inflammatory disease or disorder is chronic inflammatory demyelinating polyneuropathy.

5. Pharmaceutical product for use according to claims 1 to 3, wherein the inflammatory disease or disorder is Complex Regional Pain Syndrome.

6. The pharmaceutical product for use according to any one of claims 1 to 3, wherein the inflammatory disease or disorder is inflammatory pain.

7. A kit for treating a disease or disorder of the nervous system, preferably an inflammatory disease or disorder of the nervous system, the kit comprising: i) a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof, wherein the variants, isoforms and / or fragments have inhibitory activity, or small molecules having ADAM17 inhibitory activity; and / or b) a nucleic acid encoding AAT, a variant, isoform and / or fragment thereof, wherein the variant, isoform and / or fragment has inhibitory activity; and ii) various IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants thereof.

8. A pharmaceutical composition for treating a disease or disorder of the nervous system, preferably an inflammatory disease or disorder of the nervous system, the composition comprising: i) a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof, wherein the variants, isoforms and / or fragments have inhibitory activity, or small molecules having ADAM17 inhibitory activity; and / or b) a nucleic acid encoding AAT, a variant, isoform and / or fragment thereof, wherein the variant, isoform and / or fragment has inhibitory activity; and ii) a plurality of IgG antibodies, IgG variants, isotypes and / or fragments thereof; and iii) at least one pharmaceutically acceptable carrier.

9. A method of treatment, comprising administering to a subject an effective amount of a pharmaceutical composition, wherein the subject suffers from a disease or disorder of the nervous system, preferably an inflammatory disease or disorder of the nervous system, and wherein the subject is undergoing a therapy comprising the administration of a plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants, the pharmaceutical composition comprising a) AAT protein, its variant, isoform and / or fragment, wherein the variant, isoform and / or fragment has inhibitory activity, or a small molecule having ADAM17 inhibitory activity; and / or b) a nucleic acid encoding AAT, a variant, an isoform and / or a fragment thereof, wherein said variant, isoform and / or fragment has inhibitory activity.

10. A method of treatment, the method comprising administering to a subject an effective amount of a pharmaceutical compound comprising a plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants, wherein the subject suffers from a disease or disorder of the nervous system, preferably an inflammatory disease or disorder of the nervous system, and wherein the subject is undergoing a therapy comprising administering: a) AAT protein, its variant, isoform and / or fragment, wherein the variant, isoform and / or fragment has inhibitory activity, or a small molecule having ADAM17 inhibitory activity; and / or b) a nucleic acid encoding AAT, a variant, an isoform and / or a fragment thereof, wherein said variant, isoform and / or fragment has inhibitory activity.

11. The kit for use according to claim 7, the pharmaceutical composition for use according to claim 8, the method of treatment according to claim 9 or 10, wherein the disease or disorder of the nervous system is pain caused by the disease or disorder of the nervous system, preferably chronic pain caused by the disease or disorder of the nervous system.

12. The kit for use according to claim 7 or 11, the pharmaceutical composition for use according to claim 8 or 11, the method of treatment according to claims 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 claim 12, the pharmaceutical composition for use according to claim 12, the method of treatment according to claim 12, wherein the disease or disorder of the nervous system, preferably the inflammatory disease or disorder of the nervous system is chronic inflammatory demyelinating polyneuropathy.

14. A pharmaceutical product for use according to claim 4 or 6, a kit for use according to claim 13, a pharmaceutical composition for use according to claim 13, a method of treatment according to claim 13, wherein the subject 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.

15. A kit for use according to any one of claims 7, 11 to 14, a pharmaceutical composition for use according to any one of claims 8, 11 to 14, a method of treatment according to any one of claims 9 to 14, wherein the plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants are plasma-derived IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants.

16. A kit for use according to any one of claims 7, 11 to 14, a pharmaceutical composition for use according to any one of claims 8, 11 to 14, a method of treatment according to any one of claims 9 to 14, wherein the plurality of IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants are recombinant IgG antibodies, isotypes thereof, fragments thereof and / or IgG variants.

17. A kit for use according to any one of claims 7, 11 to 16, a pharmaceutical composition for use according to any one of claims 8, 11 to 16, a method of treatment according to any one of claims 9 to 16, wherein the plasma-derived IgG antibody, its isotype, its fragment and / or IgG variant is formulated for intravenous administration.

18. A kit for use according to any one of claims 7, 11 to 16, a pharmaceutical composition for use according to any one of claims 8, 11 to 16, a method of treatment according to any one of claims 9 to 16, wherein the plasma-derived IgG antibody, isotype thereof, fragment thereof and / or IgG variant is formulated for subcutaneous administration.

19. A pharmaceutical product for use according to any one of claims 1 to 6, a kit of parts for use according to any one of claims 7, 11 to 18, a pharmaceutical composition for use according to any one of claims 8, 11 to 18, a method of treatment according to any one of claims 9 to 18, wherein the AAT protein is recombinant AAT.

20. A pharmaceutical product for use according to any one of claims 1 to 6, a kit of parts for use according to any one of claims 7, 11 to 18, a pharmaceutical composition for use according to any one of claims 8, 11 to 18, a method of treatment according to any one of claims 9 to 18, wherein the AAT protein is plasma-derived AAT.

21. A pharmaceutical product for use according to any one of claims 1 to 6, 19 or 20, a kit for use according to any one of claims 7, 11 to 20, a pharmaceutical composition for use according to any one of claims 8, 11 to 20, a method of treatment according to any one of claims 9 to 20, wherein a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof, wherein the variants, isoforms and / or fragments have inhibitory activity, or small molecules having ADAM17 inhibitory activity; and / or b) a nucleic acid encoding AAT, a variant, an isoform and / or a fragment thereof, wherein said variant, isoform and / or fragment has inhibitory activity, The above are formulated for intravenous administration.

22. A pharmaceutical product for use according to any one of claims 1 to 6, 19 or 20, a kit for use according to any one of claims 7, 11 to 20, a pharmaceutical composition for use according to any one of claims 8, 11 to 20, a method of treatment according to any one of claims 9 to 20, wherein a) α1-antitrypsin (AAT) protein, variants, isoforms and / or fragments thereof, wherein the variants, isoforms and / or fragments have inhibitory activity, or small molecules having ADAM17 inhibitory activity; and / or b) a nucleic acid encoding AAT, a variant, an isoform and / or a fragment thereof, wherein said variant, isoform and / or fragment has inhibitory activity, The above are formulated for subcutaneous administration.

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