Use of short chain fatty acids for the treatment and prevention of diseases and disorders

Abstract

To solve the problem in which: there is a need in the art for safe effective compositions comprising SCFA for use in the treatment or prevention of diseases and disorders.SOLUTION: The invention relates to compositions and methods that include short chain fatty acids (SCFAs), related therapeutic compounds, and other compounds, including combinations thereof, for the treatment or prevention of diseases or disorders.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 451,192, filed January 27, 2017, U.S. Provisional Patent Application No. 62 / 510,867, filed May 25, 2017, U.S. Provisional Patent Application No. 62 / 510,872, filed May 25, 2017, U.S. Provisional Patent Application No. 62 / 530,371, filed July 10, 2017, U.S. Provisional Patent Application No. 62 / 539,572, filed August 1, 2017, and U.S. Provisional Patent Application No. 62 / 588,961, filed November 21, 2017, the contents of which are incorporated herein by reference in their entireties. [Background technology]

[0002] Short-chain fatty acids (SCFAs) are the main metabolic products of anaerobic bacterial fermentation in the gut and have been shown to regulate various processes in the gastrointestinal (GI) tract, such as metabolic function and homeostasis, in adipose tissue, and in the immune and nervous systems. Quantitative and qualitative changes in the gut microbiome, and consequently, alterations in the concentrations of metabolites produced, have been suggested to promote the development of pathological conditions, such as inflammatory bowel disease (IBD), colon cancer, obesity, and type 1 and type 2 diabetes.

[0003] SCFAs are saturated fatty acids consisting of one polar carboxylic acid moiety and a hydrophobic hydrocarbon chain, of which acetate (C2), propionate (C3) and butyrate (C4) are the most common and well-studied molecules.

[0004] SCFAs affect several cellular processes, including gene expression, chemotaxis, differentiation, proliferation, and apoptosis, through activation of G protein-coupled receptors (GPCRs), inhibition of histone deacetylases (HDACs), and binding to butyrate-responsive elements in the gene promoter regions of several transcription factors, which may explain the pleiotropic effects of butyrate. SCFAs are key regulators of inflammation by controlling the migration of immune cells to sites of inflammation and regulating their activation state. Importantly, SCFAs affect the balance between pro- and anti-inflammatory cells and act as a means of communication between the microbiota and the immune system. The main mechanisms by which SCFAs exert their anti-inflammatory effects are suppression of TNFα and NF-κB activation, inhibition of IFN-γ production, and upregulation of peroxisome proliferator-activated receptor γ (PPARγ, a nuclear hormone receptor that can inhibit NF-κB-dependent transcriptional activation). Summary of the Invention [Problem to be solved by the invention]

[0005] Current SCFA therapeutic compounds have limited or insufficient efficacy due to rapid absorption in the small intestine and very short half-life.Therefore, there is a need in the art for a safe and effective composition comprising SCFA for use in treating or preventing disease and disorders.The present invention addresses this unsolved problem. [Means for solving the problem]

[0006] In one embodiment, the present invention relates to a composition comprising at least one compound selected from the group consisting of short chain fatty acids (SCFAs), SCFA precursors, SCFA biosynthetic precursors, compounds containing an SFCA moiety, derivatives thereof, and combinations thereof.

[0007] In one embodiment, the composition comprises at least one SCFA moiety linked to at least one additional moiety.

[0008] In one embodiment, the at least one further moiety comprises polyethylene glycol (PEG).

[0009] In one embodiment, the composition hydrolyzes under low pH conditions to yield PEG and SCFAs.

[0010] In one embodiment, the SCFA or SCFA moiety is selected from the group consisting of acetic acid, butyric acid (BA), C3-C12 fatty acids, C3-C10 fatty acids, C3-C8 fatty acids, methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, butyrate, propionate, N-acetylbutyrate (and other forms of butyrate, such as phenylbutyrate, isobutyrate, pivaloyloxymethylbutyrate, monoacetone glucose 3-butyrate), isovaleric acid, valeric acid, isocaproic acid, and the like. The at least one selected from the group consisting of carboxylic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-ethylhydracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, and combinations thereof.

[0011] In one embodiment, the SCFA precursor or the SCFA precursor portion of the SCFA precursor derivative comprises at least one selected from the group consisting of lactate, succinate, formate, 1,2-propenedol, trypamine, indole, indole-3-acetate, and combinations thereof.

[0012] In one embodiment, the SCFA biosynthetic precursor or the SCFA biosynthetic precursor portion of the SCFA biosynthetic precursor derivative comprises an acetyl-CoA carboxylase inhibitor, an adenosine monophosphate kinase (AMPK) activator, vitamin D, or a combination thereof.

[0013] In one embodiment, the composition comprises butyrate.

[0014] In one embodiment, the composition comprises at least two SCFAs.

[0015] In one embodiment, the composition comprises a butyrate and a propionate.

[0016] In one embodiment, the present invention relates to a pharmaceutical composition comprising at least one compound selected from short chain fatty acids (SCFAs), SCFA precursors, SCFA biosynthetic precursors, compounds containing an SFCA moiety, derivatives thereof, and combinations thereof.

[0017] In one embodiment, the pharmaceutical composition comprises at least one SCFA moiety linked to at least one additional moiety, hi one embodiment, the at least one additional moiety comprises polyethylene glycol (PEG).

[0018] In one embodiment, the pharmaceutical composition hydrolyzes under low pH conditions to yield PEG and SCFAs.

[0019] In one embodiment, the SCFA or SCFA moiety is selected from the group consisting of acetic acid, butyric acid (BA), C3-C12 fatty acids, C3-C10 fatty acids, C3-C8 fatty acids, methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, butyrate, propionate, N-acetylbutyrate (and other forms of butyrate, such as phenylbutyrate, isobutyrate, pivaloyloxymethylbutyrate, monoacetone glucose 3-butyrate), isovaleric acid, valeric acid, isocaproic acid, and the like. The at least one selected from the group consisting of carboxylic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-ethylhydracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, and combinations thereof.

[0020] In one embodiment, the SCFA precursor or the SCFA precursor portion of the SCFA precursor derivative comprises at least one selected from the group consisting of lactate, succinate, formate, 1,2-propenedol, trypamine, indole, indole-3-acetate, and combinations thereof.

[0021] In one embodiment, the SCFA biosynthetic precursor or the SCFA biosynthetic precursor portion of the SCFA biosynthetic precursor derivative comprises an acetyl-CoA carboxylase inhibitor, an adenosine monophosphate kinase (AMPK) activator, vitamin D, or a combination thereof.

[0022] In one embodiment, the pharmaceutical composition comprises between 100 milligrams (mg) and 6 grams (g) of at least one SCFA.

[0023] In one embodiment, the pharmaceutical composition comprises butyrate. In one embodiment, the pharmaceutical composition comprises 900-1800 mg of butyrate.

[0024] In one embodiment, the pharmaceutical composition comprises at least two SCFAs.

[0025] In one embodiment, the pharmaceutical composition comprises butyrate and propionate. In one embodiment, the pharmaceutical composition comprises 900-1800 mg of butyrate and 100 mg-200 mg of propionate.

[0026] In one embodiment, the pharmaceutical composition further comprises a pharma- ceutically acceptable excipient.

[0027] In one embodiment, the pharmaceutical composition is an enterically coated sustained release capsule.

[0028] In one embodiment, the pharmaceutical composition comprises 900 mg of butyrate, 100 mg of propionate, 10 mg of apremilast, 10 mg of magnesium, and 50 IU of vitamin D3.

[0029] In one embodiment, the pharmaceutical composition is formulated as an eye drop. In one embodiment, the eye drop comprises 10 micromolar (μM) to 100 μM butyrate. In one embodiment, the eye drop comprises 10 μM to 100 μM propionate. In one embodiment, the eye drop comprises 10 μM to 100 μM butyrate and 10 to 100 μM propionate.

[0030] In one embodiment, the present invention relates to a method for treating or preventing a disease or disorder comprising administering to a subject a composition or pharmaceutical composition comprising at least one compound selected from short chain fatty acids (SCFAs), SCFA precursors, SCFA biosynthetic precursors, compounds containing an SFCA moiety, derivatives thereof, and combinations thereof.

[0031] In one embodiment, the disease or disorder is a skin disease or disorder, an allergic or autoimmune disease or disorder, an eye disease or disorder, an adverse effect associated with immunotherapy, cancer, or a combination thereof.

[0032] In one embodiment, the method comprises administering a composition or pharmaceutical composition comprising 100 mg to 6 g of butyrate.

[0033] In one embodiment, the method comprises administering the composition or pharmaceutical composition daily for at least one week.

[0034] In one embodiment, the method comprises administering the composition or pharmaceutical composition 1 to 3 times daily for at least one week.

[0035] In one embodiment, the method further comprises administering to the subject at least one additional treatment or therapeutic agent.

[0036] In one embodiment, the at least one additional treatment is immunotherapy.

[0037] In one embodiment, the present invention relates to a method of treating or preventing a skin disease or disorder comprising administering a composition comprising at least 900 mg of butyrate and at least 100 mg of propionate in an enteric coated sustained release capsule three times a day for at least two weeks. In one embodiment, the method further comprises administering a dose of at least 900 mg of butyrate twice a day for at least two weeks after completion of the first dosing regimen.

[0038] In one embodiment, the present invention relates to a method of treating or preventing a skin disease or disorder comprising administering a dose of at least 900 mg butyrate, at least 100 mg propionate, and at least 10 mg apremilast in an enteric coated sustained release capsule three times daily for at least two weeks.

[0039] In one embodiment, the present invention relates to a method of treating or preventing an ocular disease or disorder comprising administering a daily oral dose of at least 4 g butyrate and at least 1.5 g propionate in an enteric coated sustained release capsule three times a day for at least two weeks.

[0040] In one embodiment, the present invention relates to a method of treating or preventing an ocular disease or disorder comprising administering an eye drop containing at least 20 μM butyrate and at least 10 μM propionate at least twice daily for at least three days.

[0041] In one embodiment, the present invention relates to a method of treating or preventing adverse effects associated with immunotherapy comprising administering a daily oral dose of at least 5 g butyrate and at least 2 g propionate in an enteric coated sustained release capsule three times a day for at least two weeks. In one embodiment, administration is performed prior to immunotherapy, concurrently with immunotherapy, after immunotherapy, or a combination thereof.

[0042] In one embodiment, the present invention relates to a method of treating or preventing an allergic disease, an autoimmune disease, or asthma comprising administering a daily oral dose of at least one of butyrate, at least 0.5 g of propionate, and at least 0.5 g of acetate in an enteric coated sustained release capsule three times a day for at least two weeks.

[0043] In one embodiment, the present invention relates to a method of treating or preventing allergic diseases, autoimmune diseases and asthma comprising administering a daily oral dose of at least 80 mg butyrate, at least 20 mg propionate, and at least 20 mg acetate as a dietary supplement to a newborn delivered by C-section.

[0044] In one embodiment, the present invention relates to a method of treating or preventing vasculitis comprising administering a daily oral dose of at least 5 g of butyrate in an enteric coated sustained release capsule three times a day for at least two weeks. In one embodiment, the method further comprises administering a daily oral dose of at least 3 g of butyrate twice a day for at least two weeks after completion of the first dosing regimen.

[0045] The following detailed description of the embodiments of the invention will be better understood when read in conjunction with the accompanying drawings, in which it is understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings. [Brief description of the drawings]

[0046] [Figure 1] Figure 1 shows signaling pathways affected by SCFAs. Among the proteins included in the figure, IL-18, TLR3, IFN-γ, TNFα, TGF-β, MyD88, PI3K / Akt, JAK / STAT, Smad2 / 3, Smad4, and IL-10 were found to be downregulated by SCFA treatment. Levels of IL-6, TRIF, PKR, TRAF2, TAK1, and TRAF6 were not assessed in this study. [Diagram 2] Figures 2A-C, which include images of a psoriasis patient undergoing a butyrate treatment regimen, show images of the patient receiving a butyrate treatment regimen. The treatment regimen used was one 600 mg butyrate tablet three times a day for 16 days. Figure 2A shows images of the patient's left elbow before and after treatment. Figure 2B shows images of the patient's right elbow before and after treatment. Figure 2C shows images of the reappearance of psoriasis on the patient's left elbow after the patient discontinued the butyrate treatment regimen for 20 days. [Diagram 3] 1 shows an image of another psoriasis patient undergoing a butyrate treatment regimen, which consisted of two 600 mg butyrate tablets three times a day for 10 days, followed by one butyrate tablet three times a day for three weeks. [Figure 4] Shown are images of a third psoriasis patient undergoing a butyrate treatment regimen. The treatment regimen used was two 600 mg butyrate tablets three times a day for seven days, followed by one 600 mg butyrate tablet three times a day for 24 days. Images are of the patient's left elbow before and after treatment. The patient consumed high doses of alcohol during the treatment period. [Diagram 5]5A-5C, which include images from a fourth patient with severe psoriasis over approximately 50% of the skin, undergoing a butyrate treatment regimen. The patient began a regimen of two 600 mg butyrate tablets three times a day for four weeks, followed by one 600 mg butyrate tablet three times a day for several months. Significant improvement was noted, and no side effects were noted during the extended treatment. The patient was asked to discontinue the regimen to ensure that the observed positive effects were due to treatment with our formulation. The psoriasis recurred in approximately 20-25 days (before photograph). The patient began a regimen of two 600 mg butyrate tablets three times a day for ten days, followed by one 600 mg butyrate tablet three times a day for three weeks, and the psoriasis disappeared (after photograph). FIG. 5A shows images of the patient's left buttock before and after treatment with the second treatment regimen. Figure 5B shows images of the patient's right hip before and after the second treatment regimen, and Figure 5C shows images of the patient's coccyx before and after the second treatment regimen. [Figure 6] Images of a patient with plaque psoriasis are shown. The initial treatment regimen used was two 600 mg butyrate tablets three times a day for 20 days, then the regimen was reduced to one 600 mg butyrate tablet three times a day for 25 days. Significant improvement was observed 3-5 months after the patient stopped the treatment. The patient was not taking any medications before (at least 3 months), during and after the treatment (at least 2 months). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] In one embodiment, the present invention relates to a composition comprising at least one SCFA for the treatment or prevention of one or more diseases and / or disorders in a subject.

[0048] In one embodiment, the SCFA includes at least one selected from the group including, but not limited to, SCFA, SCFA precursor, SCFA biosynthetic precursor, a compound containing an SCFA moiety, a derivative thereof, a salt thereof, an ester thereof, a conjugated base thereof (e.g., a PEGylated conjugate), and combinations thereof. In one embodiment, the SCFA or SCFA moiety includes, but is not limited to, acetic acid, butyric acid (BA), C3-C12 fatty acid, C3-C10 fatty acid, C3-C8 fatty acid, methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, butyrate, propionate, N-acetylbutyrate (and other forms of butyrate, such as phenylbutyrate, isobutyrate, pivaloyloxymethylbutyrate, monoacetone glucose 3-butyrate), isobutyric acid, acetyl ... Examples of SCFAs include valeric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-ethylhydracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, and combinations thereof. In one embodiment, the SCFA or SCFA moiety includes a compound or structure having at least 12 carbon atoms, at least 11 carbon atoms, at least 10 carbon atoms, at least 9 carbon atoms, at least 8 carbon atoms, at least 7 carbon atoms, at least 6 carbon atoms, at least 5 carbon atoms, at least 4 carbon atoms, at least 3 carbon atoms, and at least 2 carbon atoms. In one embodiment, the SCFA or SCFA moiety is not a branched fatty acid. In one embodiment, the SCFA or SCFA moiety comprises a compound or structure having less than 13 carbon atoms, less than 12 carbon atoms, less than 11 carbon atoms, less than 10 carbon atoms, less than 9 carbon atoms, less than 8 carbon atoms, or less than 7 carbon atoms. In one embodiment, the SCFA or SCFA moiety is not a branched fatty acid. In one embodiment, the SCFA or SCFA moiety is a branched fatty acid.

[0049] In one embodiment, the present invention relates to a method for treating or preventing one or more diseases and / or disorders in a subject, comprising administering to the subject at least one composition comprising SCFAs. In one embodiment, the at least one composition comprising SCFAs is administered to the subject in combination with at least one additional agent or therapy for treating or preventing the disease and / or disorder in the subject. In one embodiment, the at least one SCFA and the at least one additional therapeutic agent are administered together in one composition. In one embodiment, the at least one SCFA and the at least one additional therapeutic agent are administered separately as two or more compositions.

[0050] In one embodiment, the subject is a human. In one embodiment, the subject is a non-human animal.

[0051] definition It should be understood that the figures and descriptions of the present invention have been simplified for clarity to show elements relevant to a clear understanding of the present invention while excluding many other elements found in the present invention. Those skilled in the art may recognize that other elements and / or steps are desirable and / or necessary to practice the present invention. However, because such elements and steps are well known in the art and because they do not facilitate a better understanding of the present invention, a discussion of such elements and steps is not provided herein. The disclosure herein covers all variations and modifications to such elements and methods known to those skilled in the art.

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are described.

[0053] As used herein, each of the following terms has the meaning associated with it in this section.

[0054] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0055] As used herein, "about" when referring to a measurable value, such as an amount, a time period, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate.

[0056] The term "abnormal" when used in the context of an organism, tissue, cell, or component thereof, refers to an organism, tissue, cell, or component thereof that differs in at least one observable or detectable characteristic (e.g., age, treatment, time of day, etc.) from an organism, tissue, cell, or component thereof that exhibits the "normal" (expected) respective characteristic. A characteristic that is normal or expected for one cell or tissue type may be abnormal for a different cell or tissue type.

[0057] The term "adverse effect of cancer immunotherapy" as used herein may refer to at least one of the following types of adverse effects of cancer immunotherapy: cytokine release syndrome (CRS), neurotoxicity, on-target / off-tumor recognition, anaphylaxis, graft-versus-host disease (GVHD), off-target antigen recognition, and macrophage activation syndrome (MAS).

[0058] "Allergy" or "allergic disease or disorder" means any one or more of a number of conditions caused by hypersensitivity of the immune system to one or more substances in the environment.

[0059] A subject is "at risk" of developing a condition if that individual is more likely to develop the condition compared to a population (e.g., the general population, an age-matched population, a population of the same sex). The increased likelihood can be due to one or a combination of factors, including the presence of particular alleles / mutations of a gene or exposure to a particular environment.

[0060] "Autoimmune disease or disorder" refers to an immune response to self-antigens that results in inflammation or destruction of healthy tissues in a subject. Desirably, the subject is a mammal, such as a human. Exemplary autoimmune diseases include, but are not limited to, arthritis (e.g., rheumatoid arthritis, such as acute arthritis, chronic rheumatoid arthritis, gouty arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, spondyloarthritis, and juvenile onset rheumatoid arthritis, osteoarthritis, progressive chronic arthritis, osteoarthritis, early chronic polyarthritis, reactive arthritis, and ankylosing spondylitis), inflammatory hyperproliferative skin diseases, psoriasis, such as plaque psoriasis, guttatte psoriasis, pustular psoriasis, plaque psoriasis, inverse psoriasis, erythrodermic psoriasis, seborrheic psoriasis, and nail psoriasis, contact dermatitis, chronic contact dermatitis, allergic dermatitis, allergies, and the like. Dermatitis including allergic contact dermatitis, dermatitis herpetiformis, atopic dermatitis, X-linked hyper IgM syndrome, urticaria such as chronic allergic urticaria and chronic idiopathic urticaria (including chronic autoimmune urticaria), polymyositis / dermatomyositis, juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma (including systemic sclerosis), sclerosis such as systemic sclerosis, multiple sclerosis (MS) (including spino-optical MS, primary progressive MS (PPMS) and relapsing-remitting MS (RRMS)), progressive systemic sclerosis, disseminated sclerosis, and ataxic sclerosis, inflammatory bowel disease (IBD) (e.g., Crohn's disease, autoimmune-mediated gastrointestinal diseases, colitis (ulcerative colitis, ulcerative colitis, ulcerosa), microscopic colitis, collagenous colitis, polypoid colitis, necrotizing enterocolitis, transmural colitis, and autoimmune inflammatory bowel disease), pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, episcleritis, respiratory distress syndrome (including adult or acute respiratory distress syndrome (ARDS)), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, autoimmune blood disorders, rheumatoid spondylitis, sudden hearing loss, IgE-mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis such as Rasmussen's encephalitis and limbic and / or brainstem encephalitis, uveitis (such as anterior uveitis, acute anterior uveitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, or autoimmune uveitis),Glomerulonephritis (GN) with or without nephrotic syndrome such as chronic or acute glomerulonephritis (such as primary GN, immune-mediated GN, membranous GN (membranous nephropathy), idiopathic membranous GN or idiopathic membranous nephropathy), membranoproliferative or membranous proliferative GN (MPGN), including types I and II, and rapidly progressive GN, allergic conditions, allergic reactions, eczema including allergic or atopic eczema, asthma (such as asthma bronchiale, bronchial asthma, and autoimmune asthma), conditions with T cell infiltration and chronic inflammatory responses, chronic pulmonary inflammatory diseases, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE) or systemic lupus erythematosus (SLE) erythematodes (e.g. cutaneous SLE), subacute cutaneous lupus erythematosus, neonatal lupus erythematosus syndrome (NLE), disseminated lupus erythematosus, lupus (including nephritis, encephalitis, pediatric, non-renal, extra-renal, discoid, alopecia), juvenile-onset (type I) diabetes mellitus including insulin-dependent diabetes mellitus (IDDM) of childhood, adult-onset (type II) diabetes mellitus, autoimmune diabetes mellitus, idiopathic diabetes insipidus, immune responses related to cytokines and T-lymphocyte-mediated acute and delayed hypersensitivity, tuberculosis, sarcoidosis, granulomatous diseases including lymphomatoid granulomatosis, Wegener's granulomatosis, agranulocytosis, vasculitis (mature Multiple vasculitis including vascular vasculitis (including polymyalgia rheumatica and giant cell (Takayasu) arteritis), medium vessel vasculitis (including Kawasaki disease and polyarteritis nodosa), microscopic polyarteritis, CNS vasculitis, necrotizing, cutaneous, or hypersensitivity vasculitis, systemic necrotizing vasculitis, and ANCA-associated vasculitis such as Churg-Strauss vasculitis or syndrome (CSS)), temporal arteritis, aplastic anemia, autoimmune aplastic anemia, Coombs positive anemia, Diamond Blackfan anemia, hemolytic anemia or immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia (anemia perniciosa), Addison's disease, true red cell anemia or pure red cell aplasia (PRCA), factor VIII deficiency, hemophilia A, autoimmune neutropenia,pancytopenia, leukopenia, diseases with leukocyte leakage, CNS inflammatory disorders, multiple organ injury syndromes (e.g. secondary to sepsis, trauma or hemorrhage), antigen-antibody complex-mediated diseases, antiglomerular basement membrane disease, antiphospholipid syndrome, allergic neuritis, Behçet's disease or Behçet's disease, Castleman syndrome, Goodpasture's syndrome, Raynaud's syndrome, Sjögren's syndrome, Stevens-Johnson syndrome, pemphigoid such as bullous pemphigoid and cutaneous pemphigoid, pemphigus (including pemphigus vulgaris, pemphigus foliaceus, mucous membrane pemphigus, and pemphigus erythematosus), autoimmune polyendocrinopathy, Reiter's disease or syndrome, immune complex nephritis, antibody-mediated nephritis, neuromyelitis optica, chronic neuropathies such as polyneuropathy, IgM polyneuropathy or IgM-mediated neuropathy, thrombotic thrombocytopenic purpura (TTP) and autoimmune thrombocytopenia (e.g. occurring in patients with myocardial infarction), including immune-mediated thrombocytopenia (such as idiopathic thrombocytopenic purpura (ITP) including chronic or acute ITP), autoimmune diseases of the testes and ovaries including autoimmune orchitis and oophoritis, primary hypothyroidism, hypoparathyroidism, autoimmune endocrine diseases (including thyroiditis such as autoimmune thyroiditis, Hashimoto's disease, chronic thyroiditis (Hashimoto's thyroiditis), or subacute thyroiditis), autoimmune thyroid diseases, idiopathic hypothyroidism, Graves' disease, polyglandular syndromes such as autoimmune polyglandular syndrome (or polyendocrinopathy syndrome), paraneoplastic syndromes including neuro-paraneoplastic syndromes such as Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome, stiff-man syndrome or stiff-person syndrome, allergic encephalomyelitis (AEMS), Encephalomyelitis, such as allergic encephalomyelitis (encephalomyelitis allergica) and experimental allergic encephalomyelitis (EAE), myasthenia gravis, such as thymoma-associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus myoclonus syndrome (OMS), and sensory neuropathy, multifocal motor neuropathy, Sheehan syndrome, lymphocytic interstitial pneumonia, bronchiolitis obliterans (non-transplant) vs. NSIP, Guillain-Barre syndrome, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, primary biliary cirrhosis, pulmonary cirrhosis, autoimmune enteropathy syndrome, celiac disease,Coeliac disease, celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia, amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune ear disease (autoimmune inner ear disease (AIED), autoimmune hearing loss, opsoclonus-myoclonus syndrome (OMS), etc.), polychondritis such as refractory or relapsing polychondritis, pulmonary alveolar proteinosis, amyloidosis, scleritis, noncancerous lymphocytosis, monoclonal B Primary lymphocytosis including cellular lymphocytosis (e.g., benign monoclonal gammopathy and monoclonal gammopathy of undetermined significance, MGUS), peripheral neuropathy, paraneoplastic syndromes, channelopathies (such as epilepsy, migraine, arrhythmias, muscle disorders, hearing loss, blindness, periodic paralysis, and CNS channelopathies), autism, inflammatory myopathy, focal segmental glomerular sclerosis (FSGS), endocrine ophthalmopathy, uveoretinitis, chorioretinitis, fibromyalgia, multiple endocrine deficiencies, Schmidt syndrome , adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases such as autoimmune demyelinating diseases, diabetic nephropathy, Dressler's syndrome, alopecia areata, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal motility disorders, sclerodactyly, and telangiectasia), male and female autoimmune infertility, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent abortions, farmer's lung, erythema multiforme, postcardiotomy syndrome, Cushing's syndrome, bird fancier's lung, allergic granulomatous vasculitis, benign lymphocytic vasculitis, Alport syndrome, allergic alveolitis, such as alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reactions, leprosy, malaria, leishmaniasis, kypanosomiasis, schistosomiasis, ascariasis, aspergillosis, Sumpter's syndrome, Kaplan's syndrome, dengue fever, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, fibrosis of organs or tissues, cystic fibrosis, endophthalmitis, persistent erythema elevatum, erythroblastosis fetalis, eosinophilic faciitis, Schulman's syndrome, Felty's syndrome, flariasis, cyclitis (such as chronic cyclitis, heterochronic cyclitis, iridocyclitis, or Fuchs' cyclitis), Henoch-Schönlein purpura,Human immunodeficiency virus (HIV) infection, echovirus infection, cardiomyopathy, Alzheimer's disease, parvovirus infection, rubella virus infection, post-vaccination syndrome, congenital rubella infection, Epstein-Barr virus infection, mumps, Evan's syndrome, autoimmune gonadal dysfunction, Sydenham's chorea, post-streptococcal nephritis, thromboangitis obliterans ubiterans, thyrotoxicosis, tabes dorsalis, choroiditis, giant cell polymyalgia, endocrine ophthalmopathy, chronic hypersensitivity pneumonitis, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, idiopathic nephritic syndrome, minimal change nephropathy, benign familial and ischemia-reperfusion injury, retinal autoimmunity, joint inflammation, bronchitis, chronic obstructive airway disease, silicosis, aphthous stomatitis, arteriosclerotic disorders, aspermiogenese, autoimmune hemolysis, Beck's disease, cryoglobulinemia, Dupuytren's contracture, phacosensitivity endophthalmitis, allergic enterocolitis, erythema nodosum leprosum, idiopathic facial palsy, chronic fatigue syndrome, rheumatic fever, Hammann-Rich disease, sensorineural hearing loss, haemoglobinuria attacks paroxysmatica), hypogonadism, endemic ileitis, leukopenia, infectious monocytosis, transverse myelitis, primary idiopathic myxedema, nephrosis, sympathetic ophthalmia, granulomatous orchitis, pancreatitis, acute polyradiculitis, pyoderma gangrenosum, Kerbein thyroiditis, acquired splenic atrophy, infertility due to antisperm antibodies, non-malignant thymoma, vitiligo, SCID and Epstein-Barr virus-related diseases, acquired immune deficiency syndrome (AIDS), parasitic diseases such as Leishmania, toxic shock syndrome, food poisoning, T cell infiltration, leukocyte adhesion deficiency, immune disorders related to cytokines and T lymphocyte-mediated acute and delayed hypersensitivity. response, diseases with leukocyte absorption, multiorgan injury syndrome, antigen-antibody complex-mediated diseases, anti-glomerular basement membrane disease, allergic neuritis, autoimmune polyendocrinopathy, oophoritis, primary myxedema, autoimmune atrophic gastritis, sympathetic ophthalmia, rheumatic diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, polyendocrine deficiency, peripheral neuropathy, autoimmune polyglandular syndrome type I, adult-onset idiopathic hypoparathyroidism (AOIH), alopecia totalis, dilated cardiomyopathy, epidermolysis bullosa acquisita (EBA), hemochromatosis, myocarditis, nephrotic syndrome, primary sclerosing cholangitis, suppurative or non-suppurative sinusitis, acute or chronic sinusitis,Ethmoid, frontal, maxillary, or sphenoid sinusitis, eosinophil-related disorders (such as eosinophilia, pulmonary infiltrative eosinophilia, eosinophilic myalgia syndrome, Loeffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopulmonary aspergillosis, aspergilloma, or eosinophil-containing granuloma), anaphylaxis, seronegative spondyloarthritis, polyendocrine autoimmune disease, sclerosing cholangitis, scleroderma, , episcleral, chronic mucocutaneous candidiasis, Bruton's syndrome, transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome, ataxia telangiectasia, autoimmune diseases associated with connective tissue diseases, rheumatism, neurological diseases, ischemia-reperfusion injury, decreased blood pressure response, vascular insufficiency, antgiectasis, tissue damage, cardiovascular ischemia, hyperalgesia, cerebral ischemia, and diseases associated with angiogenesis, allergic hypersensitivity disorders, glomerulonephritis, reperfusion injury, reperfusion injury of the myocardium or other tissues, skin diseases with an acute inflammatory component, acute purulent meningitis or other central nervous system inflammatory disorders, ocular and orbital inflammatory diseases, granulocyte transfusion-related syndrome, cytokine-induced toxicity, acute severe inflammation, chronic refractory inflammation, pyelitis, pulmonary cirrhosis, diabetic retinopathy, diabetic aortopathy, intra-arterial hyperplasia, peptic ulcer, valvulitis, and endometriosis. Other examples of autoimmune diseases may be disclosed elsewhere herein.

[0061] The term "cancer" as used herein is defined as a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or to other parts of the body via the bloodstream and lymphatic system. Examples of various cancers include, but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, bladder cancer, renal cancer, brain cancer, lymphoma, leukemia, lung cancer, etc.

[0062] As used herein, "combination" in the phrase "a first agent in combination with a second agent" includes co-administration of the first agent and the second agent, which may be dissolved or mixed in the same pharma- ceutically acceptable carrier, or administration of the first agent followed by the second agent, or administration of the second agent followed by the first agent.

[0063] The term "combined" in the phrase "combined therapeutic treatment" includes administering an agent in the presence of a second agent. Combination therapeutic treatment methods include methods in which a first agent, a second agent, a third agent, or an additional agent are co-administered. Combination therapeutic treatment also includes methods in which a first agent or an additional agent is administered in the presence of a second agent or an additional agent, where the second agent or an additional agent may, for example, have been administered previously. Combination therapeutic treatment methods may be performed stepwise by different actors. For example, one actor may administer a first agent to a subject, and a second actor may administer a second agent to a subject, and the administering steps may be performed simultaneously, or at about the same time, or at separate times, as long as the first agent (and additional agent) is administered after the administration in the presence of the second agent (and additional agent). The actor and the subject may be the same entity (such as a human being).

[0064] As used herein, the term "combination therapy" refers to the administration of two or more therapies, two or more therapeutic agents, or a combination of at least one therapeutic agent and at least one of a treatment modality, such as radiation, immunotherapy, and chemotherapy.

[0065] A "disease" is an animal's health condition in which the animal cannot maintain homeostasis and, if the disease is not ameliorated, the animal's health will continue to deteriorate.In contrast, an "injury" in an animal is an animal's health condition in which the animal can maintain homeostasis, but the animal's health condition is worse than in the absence of the disorder.If left untreated, the disorder does not necessarily cause further deterioration of the animal's health condition.

[0066] A disease or disorder is "alleviated" if the severity of a sign or symptom of the disease or disorder, the frequency with which a patient experiences such sign or symptom, or both, are reduced.

[0067] The term "human microbiome" refers to the totality of microorganisms, their genetic components (genomes), and the environmental interactions in the human body.

[0068] The term "immune response" encompasses both cellular and humoral immune responses, including stimulation of cytokine production, stimulation of immune cell proliferation, stimulation of immune cell activation, or stimulation of immune cell lytic activity. Examples of immune responses stimulated by the methods of the invention are secretion of cytokines, activation of NK cells, proliferation of B cells, T cells, macrophages, monocytes, and other immune cells, and other immune responses. To detect a cellular immune response, for example, T cell effector activity against cells expressing an antigen can be detected using standard assays, for example, target cell killing, macrophage activation, B cell activation, or lymphokine production. A humoral response can be measured, for example, by detecting the appearance or increase in titer of antigen-specific antibodies using methods known in the art, such as ELISA. The progression of an antibody response can be determined by measuring class switching, such as switching from an initial IgM response to a later IgG response.

[0069] As used herein, the term "inhibit" refers to suppressing or blocking an activity or function by at least about 10% compared to a control value. Illustratively, the activity is suppressed or blocked by 50%, 75%, or 95% or more compared to a control value.

[0070] As used herein, the term "psoriasis" includes at least seven types of psoriasis: plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, plaque psoriasis, seborrheic psoriasis, erythrodermic psoriasis, nail psoriasis, and psoriatic arthritis.

[0071] The term "regulatory T cells" or "Treg" refers to T cells that suppress abnormal or excessive immune responses and play a role in immune tolerance. Regulatory T cells are typically transcription factor Foxp3-positive CD4-positive T cells. The regulatory T cells of the present invention also include transcription factor Foxp3-negative regulatory T cells, which are IL-10-producing CD4-positive T cells.

[0072] The term "inducing the proliferation or accumulation of regulatory T cells" refers to the effect of inducing the differentiation of immature T cells into regulatory T cells, which differentiation results in the proliferation and / or accumulation of regulatory T cells. Furthermore, the meaning of "inducing the proliferation or accumulation of regulatory T cells" includes in vivo effects, in vitro effects, and ex vivo effects.

[0073] The term "uveitis" as used herein refers to an inflammation of the eye that can affect not only the uvea, or intermediate layers of the eye, but also the lens, retina, optic nerve, and vitreous cavity. Uveitis (pronounced you-vee-EYE-tis) can be an inflammation of the uvea, the intermediate layer of the eye, including the iris, ciliary body, and choroid. Uveitis can be caused by (1) an autoimmune disorder (due to an abnormal T-cell-mediated response to the retina or cross-reactive antigens triggered by inflammation), (2) infection, (3) trauma, or (4) idiopathic (unknown cause). Types of uveitis are classified according to where in the uvea inflammation occurs. Anterior uveitis is inflammation of the iris (iritis) or the iris and ciliary body. Intermediate uveitis is inflammation of the ciliary body. Posterior uveitis is inflammation of the choroid. Diffuse uveitis (also called pan-uveitis) is inflammation of all areas of the uvea. Uveitis may involve the entire eye (panuveitis) or a portion of the eye (anterior, intermediate, or posterior). Examples of uveitis include, but are not limited to, anterior uveitis (including iritis, iridocyclitis, and anterior cylitis), intermediate uveitis (including pars planitis, posterior cyclitis, and cataract), posterior uveitis (focal, multifocal, or diffuse choroiditis, chorioretinitis, retinochoroiditis, retinitis, and neuroretinitis), panuveitis, acute uveitis, recurrent uveitis, and chronic uveitis. In one embodiment, the uveitis is non-infectious uveitis. Examples of causes of non-infectious uveitis include, but are not limited to, systemic autoimmune disorders (such as, for example, Behcet's disease and Vogt-Koyanagi-Harada (VKH) disease); trauma, and surgery. In one example, the non-infectious uveitis is idiopathic non-infectious uveitis.

[0074] The terms "tolerance" and "immune tolerance" refer to the process by which the immune system does not attack an antigen.

[0075] The terms "tolerance induction" or "induction of tolerance" refer to a process by which the immune system can be manipulated to create tolerance to foreign antigens.

[0076] The terms "treatment", "treating" and the like are generally used herein to mean obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic, in that a disease or disorder, or a symptom thereof, is completely or partially prevented, and / or may be therapeutic, in that a disease or disorder and / or adverse effects resulting from the disease or disorder are partially or completely cured. The term "treatment" as used herein encompasses any treatment of a disease or disorder in a subject, including (a) prevention of a disease or disorder occurring in a subject who may be predisposed to the disease or disorder; (b) inhibition of a disease or disorder, i.e., arresting its progression, or (c) remission of a disease or disorder, i.e., causing regression of a disease or disorder.

[0077] The terms "effective amount" and "pharmacologically effective amount" refer to a sufficient amount of an agent to provide a desired biological result, which may be reduction and / or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system.

[0078] The term "leukemia" as used herein may refer to at least one of the following types of leukemia: myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocytosis (ET), idiopathic / myelofibrosis (MF), acute myeloid leukemia (AML), and childhood acute lymphoblastic leukemia (ALL). The term "leukemia" may also generally refer to cancer of the blood-forming tissues, or blood cancer.

[0079] The term "microbiota" collectively refers to the entire set of microorganisms found associated with higher organisms, such as humans.

[0080] "Therapeutically effective amount" refers to an amount that provides a therapeutic effect for a given condition and administration regimen. In particular, "therapeutically effective amount" means an amount effective to prevent, alleviate or ameliorate symptoms of a disease or disorder, or prolong the survival of the subject being treated, which can be a human or non-human animal.

[0081] The term "macular degeneration" as used herein refers to any form of macular degeneration, including "wet" and "dry" macular degeneration. There are two types of age-related macular degeneration (AMD): dry (atrophic) and wet (exudative). Dry AMD affects approximately 90 percent of AMD patients and typically begins with the formation of small yellow deposits called drusen in the macula. Drusen do not usually cause serious vision loss, but they can cause distortion of vision. However, for reasons that are not yet understood, drusen can thin and destroy the macula, slowly causing vision loss. Wet AMD occurs in approximately 10 percent of AMD patients. It is caused by abnormal blood vessel growth under the macula, which can leak fluid and blood to form exudate. Wet AMD typically causes significant vision problems in the affected eye and can progress very rapidly to cause permanent central vision loss.

[0082] As used herein, the term "pharmaceutical composition" refers to a mixture of at least one compound of the present invention with other chemical components and entities, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients. Pharmaceutical compositions facilitate the administration of a compound to an organism. In the art, there are multiple techniques for administering a compound, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ocular administration, pulmonary administration and topical administration.

[0083] "Pharmaceutically acceptable" refers to properties and / or substances that are acceptable to a patient from a pharmacological / toxicological standpoint, and acceptable to a pharmaceutical chemist from a physical / chemical standpoint with regard to composition, formulation, stability, patient acceptability, and bioavailability.

[0084] As used herein, the term "pharmaceutical acceptable carrier" refers to a pharma- ceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, involved in carrying or transporting a compound useful within the invention into or to a patient so that it can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation containing the compound useful within the invention and not harmful to the patient. Some examples of materials which can function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, polyethylene glycol, and glycerol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations. As used herein, "pharmacologically acceptable carriers" also include any coatings that are compatible with the activity of the compounds useful within the invention and are physiologically acceptable to the patient, antibacterial and antifungal agents, absorption delaying agents, and the like. Supplementary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carriers" can further include pharma- ceutically acceptable salts of the compounds useful within the invention.Other additional ingredients that may be included in pharmaceutical compositions used to practice the invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0085] As used herein, the term "neonatal" generally refers to an infant or young mammal, such as a human.

[0086] The term "nutritional composition" may refer to a food product for human consumption, such as a drink, a beverage, a bar, a snack, an ice cream, a dairy product, such as a refrigerated or shelf-stable dairy product, a fermented dairy product, a beverage, such as a dairy-based drink, an infant formula, a growing milk, a confectionery product, a chocolate, a cereal product, such as a breakfast cereal, a sauce, a soup, an instant drink, a frozen product for consumption after heating in a microwave oven or a conventional oven, a ready-to-cook product, a fast food or a nutritional formulation.

[0087] The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal or cells thereof suitable for the methods described herein, whether in vitro or in situ. A patient, subject, or individual can be a human or non-human animal.

[0088] As used herein, the term "container" includes any receptacle for holding a pharmaceutical composition. For example, in one embodiment, the container is a package containing the pharmaceutical composition. In other embodiments, the container is not a package containing the pharmaceutical composition, i.e., the container is a receptacle such as a box or a vial that contains a packaged or unpackaged pharmaceutical composition and instructions for use of the pharmaceutical composition. Packaging technology is also well known in the art. It should be understood that instructions for use of the pharmaceutical composition may be included in the package containing the pharmaceutical composition, and such instructions form a highly functional relationship with the packaged product. However, it should be understood that the instructions may contain information regarding the ability of the compound to perform its intended function (e.g., treat or prevent a disease in a subject).

[0089] The term "instructional material" as used herein includes publications, records, diagrams, or any other medium of expression that can be used to communicate the usefulness of the components of the present invention in the kit for identifying or alleviating or treating various diseases or disorders listed herein. Optionally or alternatively, the instructional material can describe one or more methods of identifying or alleviating a disease or disorder in a cell or tissue of a subject. The instructional material of the kit can be, for example, attached to a container containing the composition of the present invention or can be sent together with a container containing the composition of the present invention. Alternatively, the instructional material can be sent separately from the container, with the intention that the recipient will use the instructional material and the composition in a coordinated manner.

[0090] The term "lymphoma" as used herein may refer to at least one of the following types of lymphoma: activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue lymphoma (MALT), Hodgkin's lymphoma (HL), and primary mediastinal B-cell lymphoma (PMBL).

[0091] "Short chain fatty acids" (SCFAs) are fatty acids that typically have an aliphatic tail that is shorter than that of a long chain fatty acid. As used herein, the term short chain fatty acid can also refer to a salt or ester of a fatty acid, particularly pharma- ceutically acceptable salts and esters of fatty acids (e.g., sodium butyrate, arginine butyrate).

[0092] As used herein, the term "stimulating an immune response" includes stimulating, inducing, increasing, enhancing, sustaining, and / or improving the stimulation of a new immune response or an existing immune response. Thus, "stimulating an immune response" as an immunotherapy refers to enhancing the efficacy of treatment, extending survival time, delaying the progression of cancerous tumors or reducing the size of cancerous tumors, preventing the spread of tumors or metastases, preventing or delaying the recurrence of a treated cancer, eliminating cancer cells that were not killed in a previous treatment, targeting potential cancer cells, or targeting antigens derived from viruses associated with cancer. In the methods of the present invention, the immunotherapeutic agent and the compound selected from formulae (I), (II), (III), (IV) and (V) are administered in an amount effective to stimulate the immune response of a subject individual at a dose sufficient to generate an effective immune response without unacceptable toxicity. As will be appreciated by those skilled in the art, the magnitude of the immune response and the maintenance of that response may have various degrees of recognition as having potential therapeutic or prophylactic benefit.

[0093] The term "vasculitis" as used herein may refer to at least one of the following types of vasculitis: giant cell arteritis, Takayasu's disease, Churg-Strauss syndrome, Wegener's granulomatosis, microscopic polyangiitis, essential cryoglobulinemic vasculitis, Henoch-Schonlein purpura, Kawasaki disease, polyarteritis nodosa, antineutrophil cytoplasmic antibody vasculitis, necrotizing and crescentic glomerulonephritis.

[0094] Ranges: Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity, and should not be construed as an inflexible limitation on the scope of the invention. Thus, the description of a range should be considered to have specifically disclosed all the possible subranges and individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0095] explanation The present invention is based, in part, on the discovery that short chain fatty acids (SCFAs) function as modulators of multiple cell signaling proteins, including, but not limited to, IL-18, TLR3, IFN-γ, TNFα, TGF-β, MyD88, PI3K / Akt, JAK / STAT, Smad2 / 3, Smad4, IL-10, Notch, Hedgehog, Wnt (beta-catenin), matrix metalloproteinases 9 and 10, tissue inhibitor of metalloproteinases, nodal and NF-κB signaling. In various embodiments, the signaling proteins regulated by SCFAs themselves regulate biological pathways or processes, including, but not limited to, inflammation, immunity, proliferation, differentiation, apoptosis, tumorigenesis, DNA transcription, cytokine production, cell survival, angiogenesis, fibrosis, and cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet radiation, and the like.

[0096] In one embodiment, the present invention relates to compositions comprising at least one SCFA and methods of use for treating or preventing a medical disease or disorder characterized by elevated levels or aberrant expression of at least one of IL-18, TLR3, IFN-γ, TNFα, TGF-β, MyD88, PI3K / Akt, JAK / STAT, Smad2 / 3, Smad4 or IL-10 signaling. In one embodiment, the present invention relates to compositions comprising at least one SCFA and methods of use for treating or preventing a medical disease or disorder characterized by decreased or aberrant expression of NF-κB signaling.

[0097] composition In one embodiment, the present invention provides a composition comprising at least one short chain fatty acid (SCFA), SCFA precursor, SCFA biosynthetic precursor, derivative thereof, SCFA moiety, or combination thereof.

[0098] In one embodiment, the compositions of the present invention include a compound that includes at least one SCFA or SCFA moiety. In one embodiment, the SCFA or SCFA moiety can include, but is not limited to, acetic acid, butyric acid (BA), C3-C12 fatty acids, C3-C10 fatty acids, C3-C8 fatty acids, methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, N-acetylbutyrate (and other forms of butyrate, such as phenylbutyrate, isobutyrate, pivaloyloxymethylbutyrate, monoacetone glucose 3-butyrate), isovaleric acid, valer ... , isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-ethylhydracrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, and combinations thereof. In one embodiment, the SCFA or SCFA moiety includes compounds or structures having at least 12 carbon atoms, at least 11 carbon atoms, at least 10 carbon atoms, at least 9 carbon atoms, at least 8 carbon atoms, at least 7 carbon atoms, at least 6 carbon atoms, at least 5 carbon atoms, at least 4 carbon atoms, at least 3 carbon atoms, and at least 2 carbon atoms. In one embodiment, the SCFA or SCFA moiety comprises a compound or structure having less than 13 carbon atoms, less than 12 carbon atoms, less than 11 carbon atoms, less than 10 carbon atoms, less than 9 carbon atoms, less than 8 carbon atoms, or less than 7 carbon atoms. In one embodiment, the SCFA or SCFA moiety is not a branched fatty acid. In one embodiment, the SCFA or SCFA moiety is a branched fatty acid.

[0099] In one embodiment, the composition of the present invention comprises at least one compound comprising a precursor of an SCFA or a portion thereof, in one embodiment, the precursor or portion thereof is selected from the group including, but not limited to, plant cell wall polysaccharides, dietary non-starch polysaccharides (NSPs), lactate, succinate, formate, 1,2-propenedol, trypamine, indole, indole-3-acetate, and combinations thereof.

[0100] In one embodiment, the composition of the present invention comprises at least one compound comprising a biosynthetic precursor of an SCFA or a portion thereof, in one embodiment, the biosynthetic precursor or portion thereof is selected from the group including, but not limited to, an acetyl-CoA carboxylase inhibitor, an adenosine monophosphate kinase (AMPK) activator, vitamin D, and combinations thereof.

[0101] In one embodiment, the composition of the present invention comprises a salt of SCFA or its derivative. For example, the salt of butyric acid can be one or more of sodium butyrate, magnesium butyrate, or calcium butyrate. In one embodiment, the composition comprises one or more of magnesium butyrate and calcium butyrate.

[0102] In one embodiment, the composition of the present invention comprises a derivative of SCFA. In one embodiment, the derivative comprises at least one SCFA moiety linked to at least one further moiety. In one embodiment, the derivative comprises at least one SCFA moiety linked to at least one polyethylene glycol (PEG) moiety. In one embodiment, the at least one SCFA moiety linked to at least one PEG moiety is hydrolyzed under low pH conditions to produce at least one SCFA molecule and at least one PEG molecule.

[0103] In one embodiment, the compositions of the invention comprise a combination of SCFAs and / or derivatives thereof, hi one embodiment, the compositions are prepared in an amount of at least 10 mM, at least 20 mM, at least 30 mM, 40 mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, 100 mM, or more, of each or all of the compounds of the composition.

[0104] For example, derivatives of SCFAs having substituents on the carbon chain, such as O, S, N, methyl, ethyl, halogens, and other groups that do not interfere with the therapeutic activity of the compound, may also be used to form the compositions of the invention. In one embodiment, the compounds of the invention include at least one SCFA bound to at least one additional moiety, such as O, S, N, methyl, ethyl, halogens, and other groups that do not interfere with the therapeutic activity of the compound.

[0105] In some cases, the SCFAs of the present invention can be PEGylated. Polyethylene glycol (PEG) is widely used in biomaterials, biotechnology, and medicine, mainly because PEG is a biocompatible, non-toxic, non-immunogenic, and water-soluble polymer (Zhao and Harris, ACS Symposium Series 680:458-72, 1997). In the field of drug delivery, PEG derivatives are widely used in covalent attachment (i.e., "PEGylation") to proteins to reduce immunogenicity, proteolysis, and renal clearance, and to increase solubility (Zalipsky, Adv. Drug Del. Rev. 16:157-82, 1995). Similarly, PEG has been attached to low molecular weight, relatively hydrophobic drugs to increase solubility, reduce toxicity, and alter biodistribution. Typically, PEGylated drugs are injected as a solution. However, they can be administered orally or by another route.

[0106] A closely related application is the synthesis of cross-linked degradable PEG networks or formulations for use in drug delivery, since many of the same chemistries used to design degradable soluble drug carriers can also be used to design degradable gels (Sawhney et al., Macromolecules 26:581-87, 1993). It is also known that interpolymer complexes can be formed by mixing solutions of two complementary polymers. Such complexes are generally stabilized by electrostatic interactions (polyanion-polycation) and / or hydrogen bonds (polyacid-polybase) between the polymers involved, and / or hydrophobic interactions between the polymers in an aqueous environment (Krupers et al., Eur. Polym J. 32:785-790, 1996). For example, when solutions of polyacrylic acid (PAAc) and polyethylene oxide (PEO) are mixed under appropriate conditions, complexes based primarily on hydrogen bonds are formed. Dissociation of these complexes at physiological conditions has been used to deliver the free drug (i.e., non-PEGylated). Additionally, complementary polymer conjugates have been formed from both homopolymers and copolymers.

[0107] In one embodiment, the compositions of the present invention include precursors of SCFAs, alone or in combination with one or more SCFAs, including but not limited to formate, lactate, succinate, 1,2-propendol, trypamine, indole, and indole-3-acetate.

[0108] In one embodiment, the compositions of the invention include precursors of SCFA biosynthesis, alone or in combination with one or more SCFAs, including but not limited to formate, lactate, succinate, acetyl-CoA carboxylase inhibitors, adenosine monophosphate kinase (AMPK) activators, and vitamin D.

[0109] SCFAs stimulate regulatory T (Treg) cell function, which explains some of their anti-inflammatory properties. Given that inhibitors of acetyl-CoA carboxylase also promote Treg cell function, in one embodiment, the composition includes an inhibitor of acetyl-CoA carboxylase, including but not limited to biotin or its natural or chemically synthesized analogs (which are acetyl-CoA carboxylase inhibitors), alone or in combination with one or more other SCFAs, to stimulate Treg function.

[0110] In various embodiments, a compound comprising at least one SCFA or a compound comprising an SCFA moiety of the present invention may be combined with one or more compounds, such as one or more additional therapeutic agents for a particular disease or disorder. In one embodiment, one or more SCFAs of the present invention may be in the same composition as one or more additional therapeutic agents. In various embodiments, the composition may include at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more than ten additional therapeutic agents. Exemplary additional therapeutic agents and / or compounds that may be included in the compositions of the present invention are discussed in detail elsewhere herein.

[0111] method The present invention provides a method of treating or preventing a mammalian disease in a subject in need thereof by administering to said subject a therapeutically effective amount of a composition of the present invention.

[0112] General examples of target diseases for which the compositions are useful for treating (reducing or preventing adverse effects of) include autoimmune diseases, allergic diseases, infectious diseases, and rejection reactions in organ transplants, including inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, sprue, autoimmune arthritis, rheumatoid arthritis, type I diabetes, multiple sclerosis, graft-versus-host rejection following bone marrow transplantation, osteoarthritis, juvenile chronic arthritis, Lyme disease arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, insulin-dependent diabetes mellitus, thyroiditis, asthma, psoriasis, scleroderma dermatitis, and the like. scleroderma), atopic dermatitis, graft-versus-host rejection, acute or chronic immune disorders associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki disease, Graves' disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch-Scholein purpura, microscopic vasculitis in the kidney, uveitis, septic shock, toxic shock syndrome, septic syndrome, cachexia, acquired immune deficiency syndrome, acute transverse myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke, primary biliary cirrhosis, hemolytic anemia, polyglandular deficiency syndrome type I and polyglandular deficiency syndrome type II, Schmidt's syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, chlamydial infection, Yersinia simii Monera infection-related arthropathy, spondyloarthropathy, atherosclerosis / arteriosclerosis, allergic colitis, atopic allergies, food allergies (peanut allergy, nut allergy, egg allergy, milk allergy, soy allergy, wheat allergy, seafood allergy, shellfish allergy, sesame allergy, etc.), autoimmune blistering diseases, pemphigus vulgaris, pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune hemolytic anemia, Coombs test positive hemolytic anemia, acquired pernicious anemia, juvenile pernicious anemia, myositis / Royal Free disease, chronic mucocutaneous candidiasis, giant cell arteritis, acquired immune deficiency syndrome, acquired immune deficiency-related disease, common variable immunodeficiency (common variable hypogammaglobulinemia), dilated cardiomyopathy, fibrotic lung disease, idiopathic fibrosing alveolitis, postinflammatory interstitial pneumonia, interstitial pneumonia, connective tissue disease-associated interstitial lung disease, mixed connective tissue-associated lung disease,Systemic sclerosis-associated interstitial lung disease, rheumatoid arthritis-associated interstitial lung disease, systemic lupus erythematosus-associated lung disease, dermatomyositis / polymyositis-associated lung disease, Sjogren's disease-associated lung disease, ankylosing spondylitis-associated lung disease, vasculitic diffuse lung disease, hemosiderosis-associated lung disease, drug-induced interstitial lung disease, radiation fibrosis, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrate lung disease, post-infectious interstitial pneumonia, gouty Arthritis, Autoimmune Hypoglycemia, Type B Insulin Resistance due to Acanthosis Nigricans, Hypoparathyroidism, Acute Immunologic Disorders Associated with Organ Transplants, Chronic Immunologic Disorders Associated with Organ Transplants, Osteoarthritis, Primary Sclerosing Cholangitis, Idiopathic Leukopenia, Autoimmune Neutropenia, Renal Disease NOS, Glomerulonephritis, Microscopic Vasculitis in the Kidneys, Discoid Lupus Erythematosus, Idiopathic Male Infertility or NOS, Sperm Autoimmunity, Multiple Sclerosis (All) subtypes), insulin-dependent diabetes mellitus, sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, Goodpasture's syndrome, pulmonary manifestations of polyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis, Takayasu's disease / arteritis, autoimmune thrombocytopenia, idiopathic thrombocytopenia, autoimmune thyroid disease, hyperthyroidism, goiter, autoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxedema, lens-induced uveitis, primary vasculitis, vitiligo, allergic rhinitis (pollen allergy), anaphylaxis, pet allergy, latex allergy, drug allergy, allergic rhinitis conjunctivitis, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic gastroenteritis, cutaneous lupus erythematosus, eosinophilic esophagitis, hypereosinophilic syndrome, eosinophilic gastroenteritis, and diarrhea.

[0113] In one embodiment, the invention provides a method for the treatment or prevention of at least one disease or disorder in a subject, comprising administering to the subject at least one composition comprising a compound comprising a SCFA or a SCFA moiety, optionally in combination with at least one additional agent or therapy.

[0114] In some embodiments, the administered compositions of the invention may increase the number of disease-free days in a subject, may reduce the severity of a disease or disorder, may reduce the risk of developing a disease or disorder, may reduce the risk of recurrence of a disease or disorder, or a combination thereof. The administered compositions of the invention may increase the number of disease-free days in a subject by 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% or more compared to a subject not receiving treatment. The administered compositions of the invention may reduce the severity of a disease or disorder in a subject by 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% or more compared to an untreated subject. The administered compositions of the invention can reduce a subject's risk of developing a disease or disorder by 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% or more compared to an untreated subject. The administered compositions of the invention can reduce the risk of recurrence of a disease or disorder in a subject by 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60% or more compared to a subject not receiving treatment.

[0115] In some embodiments, the diseases and disorders that can be treated, prevented or improved include, but are not limited to, inflammatory diseases and various cancer diseases. In some embodiments, the inflammatory diseases and disorders that can be treated or improved include, but are not limited to, asthma, arthritis, allergic rhinitis, psoriasis, atopic dermatitis, inflammatory bowel disease, Crohn's disease, allergic or autoimmune diseases or disorders associated with C-section delivery of newborns, uveitis, and vasculitis. In some embodiments, the cancer diseases and disorders that can be treated or improved include, but are not limited to, leukemia and lymphoma.

[0116] Exemplary methods of treating diseases and disorders are provided below.

[0117] skin disorders The present invention is based in part on the discovery that SCFAs are effective in treating skin disorders. In one embodiment, the combination of at least one SCFA with at least one other skin disorder treatment can be effective as a therapeutic approach for treating skin disorders.

[0118] In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or alleviating a skin disease or disorder by administering to a subject in need thereof a composition comprising SCFAs, as disclosed herein, optionally in combination with at least one additional agent or therapy. Skin diseases and disorders that may be treated using the methods of the present invention include, but are not limited to, psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, plaque psoriasis, seborrheic psoriasis, erythrodermic psoriasis, nail psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE) rash, scleroderma (systemic sclerosis), diabetes-related skin conditions, rheumatoid arthritis and associated skin rashes (rheumatic vasculitis), melanoma, vitiligo, eczema (atopic dermatitis), dyshidrotic eczema, rosacea, urticaria, impetigo, cellulitis, contact dermatitis, stomatitis, acne, lichen planus, actinic keratosis, ichthyosis vulgaris, dermatomyositis, and pemphigoid. In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or alleviating a skin disease or disorder comprising administering to a subject in need thereof a composition comprising SCFAs as disclosed herein.

[0119] In one embodiment, the subject suffering from the skin disorder is a human. In one embodiment, the subject suffering from the skin disorder is a non-human animal.

[0120] In one embodiment, the present invention relates to a composition comprising at least one SCFA and at least one second compound for use as a therapeutic agent for the treatment of skin disorders.In one embodiment, the SCFA comprises one or more of formic acid, acetic acid, propionic acid, isobutyric acid, butyric acid, tributyrin, N-acetylbutyrate (and other forms of butyrate), isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, and dodecanoic acid.In one embodiment, the second compound comprises one or more of PDE4 inhibitors, anti-inflammatory compounds, disease-modifying antirheumatic drugs (DMARDs), immunosuppressants, biologics, and Cox-2 inhibitors.

[0121] In one embodiment, a composition for use in a method of treating a skin disorder comprises 900 mg of butyrate, 100 mg of propionate, 10 mg of apremilast, 10 mg of magnesium, and 50 IU of vitamin D3.

[0122] In one embodiment, an exemplary method for treating vasculitis comprises administering a daily oral dose of at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 g, at least 2 g, at least 3 g, at least 4 g, at least 5 g, at least 6 g, or more than 6 g of at least one SCFA at least once a day, at least twice a day, at least three times a day, or more than three times a day, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or more than 6 months.

[0123] In one embodiment, an exemplary daily oral dosage for use in the method of treating a skin disorder includes 3600 mg butyrate, 400 mg propionate, 40 mg magnesium, and 200 IU vitamin D3. In one embodiment, an exemplary daily oral dosage for use in the method of treating a skin disorder includes 900-1800 mg butyrate, 100-200 mg propionate, 10-20 mg magnesium, and 50-100 IU vitamin D3 administered 1-4 times per day. In one embodiment, the composition is administered 1-4 times per day for at least 1 week, at least 2 weeks, at least 3 weeks, or more than 3 weeks.

[0124] In one embodiment, an exemplary dosage for use in the method of treating a skin disorder includes 1-2 g butyrate, 100 mg propionate, 10-15 mg Otezla, 10-20 mg magnesium, and 80-100 IU vitamin D3.

[0125] In one embodiment, the composition comprising at least one SCFA is an enteric coated time- and sustained-release capsule.

[0126] In one embodiment, the method for treating skin disorders comprises administering an oral formulation of SCFA in combination with a topical ointment.Exemplary topical ointments for use in treating skin disorders may include 40% clobetasol (0.05%) cream, 20% calcipotriene (vitamin D, 0.005%) cream, 20% vitamin E (0.5%) cream, and 20% salicylic acid (10%) cream.Alternative exemplary topical ointments for use in treating skin disorders may include 40% clobetasol (0.05%) cream, 20% calcipotriene (vitamin D, 0.005%) cream, 20% vitamin E (0.5%) cream, and 20% zinc cream.In one embodiment, zinc may be used in combination with salicylic acid in a topical ointment.

[0127] eye disease In one embodiment, the present invention relates to a composition comprising SCFAs for use as a therapeutic agent for the treatment of an ocular disease or disorder. In one embodiment, the ocular disease or disorder is inflammatory. In one embodiment, the inflammatory ocular disease or disorder is uveitis. In one embodiment, the composition comprises one or more SCFAs. In one embodiment, the SCFAs include, but are not limited to, at least one of formic acid, acetic acid, propionic acid, isobutyric acid, butyric acid, tributyrin, N-acetylbutyrate (and other forms of butyrate), isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, and dodecanoic acid. In one embodiment, the composition comprises one or more magnesium salts and calcium salts of one or more of the compounds disclosed herein.

[0128] In one embodiment, the invention includes a formulated composition comprising a SCFA or a compound comprising an SCFA moiety, hi one embodiment, the composition includes an oral pharmaceutical or food composition comprising a SCFA or a compound comprising an SCFA moiety.

[0129] In one embodiment, the present invention relates to a method of treating an ocular disease or disorder, comprising administering to a subject a composition comprising SCFAs. In one embodiment, the ocular disease or disorder is inflammatory. In one embodiment, the inflammatory ocular disorder is uveitis. In one embodiment, the composition is administered orally. In one embodiment, the composition is administered topically (e.g., in a cream). In one embodiment, the subject suffering from the ocular disorder is a human. In one embodiment, the subject suffering from the ocular disease is a non-human animal.

[0130] In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or alleviating a disease associated with an ocular disease or disorder by administering a composition comprising SCFAs, as disclosed herein, optionally in combination with at least one additional agent or therapy, to a subject in need thereof. Ocular diseases and disorders that may be treated using the methods of the present invention include, but are not limited to, uveitis, macular degeneration, age-related macular degeneration (AMD), post-surgical inflammation (e.g., cataract surgery), ocular Behcet's disease, Sjogren's syndrome-related diseases or disorders (e.g., dry eye), blepharitis-related diseases or disorders (e.g., rosacea), and other diseases discussed in detail elsewhere herein. In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or alleviating a disease associated with an ocular disease or disorder, comprising administering a composition comprising an SCFA or a compound comprising an SCFA moiety, as disclosed herein, to a subject in need thereof. The present invention is based in part on the discovery that SCFAs can be effective as a therapeutic approach for the treatment of ocular diseases or disorders, including inflammatory ocular diseases or disorders.

[0131] In one embodiment, an exemplary method for treating or preventing an ocular disease or disorder comprises administering a daily oral dose of at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 g, at least 2 g, at least 3 g, at least 4 g, at least 5 g, at least 6 g, or more than 6 g of a composition comprising at least one SCFA at least once a day, at least twice a day, at least three times a day, or more than three times a day for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or more than 6 months.

[0132] In one embodiment, the composition comprising at least one SCFA is an enteric coated time-release capsule. In one embodiment, an exemplary daily oral dose is 4-5 g butyrate and 1.5-2 g propionate in an enteric coated time-release capsule, twice daily.

[0133] In one embodiment, an exemplary method for treating or preventing an ocular disease or disorder comprises administering to the patient a concentration of at least 100 nM, at least 200 nM, at least 300 nM, at least 400 nM, at least 500 nM, at least 600 nM, at least 700 nM, at least 800 nM, at least 900 nM, at least 1 μM, at least 2 μM, at least 3 μM, at least 4 μM, at least 5 μM, at least 6 μM, at least 7 μM, at least 8 μM, at least 9 μM, at least 10 μM, at least 15 μM, at least 20 μM, The present invention includes administering a daily topical dose of a composition comprising at least one SCFA, at least 25 μM, at least 30 μM, at least 35 μM, at least 40 μM, at least 45 μM, at least 50 μM, or more than 50 μM, at least once a day, at least twice a day, at least three times a day, or more than three times a day, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or more than 6 months.

[0134] In one embodiment, the composition comprising at least one SCFA is an eye drop formulation. In one embodiment, an exemplary eye drop formulation containing 20-30 μM butyrate and 10-20 μM propionate can be administered at least twice daily in combination with a lubricant.

[0135] In one embodiment, eye drops should be administered four times daily (in case of disease flares), and twice daily for up to several months, in combination with oral administration of SCFAs.

[0136] In one embodiment, a method for the treatment or prevention of an ocular disease or disorder includes administering a combination of SCFAs and an antibiotic and / or a steroid. For example, for infectious uveitis: eye drops (or eye injections) containing antibiotics / steroids (doses prescribed by a physician) for the first 3-5 days, then eye drops containing a mixture of SCFAs (20-30 μM) and antibiotics / steroids (half the prescribed dose) for the next 2-3 weeks, then continue with eye drops containing only SCFAs (20-30 μM).

[0137] In one embodiment, a method for treating or preventing an ocular disease or disorder comprises administering a combination of compositions comprising at least one SCFA. For example, in one embodiment, the method comprises a combination of at least one SCFA formulated for oral administration and at least one SCFA formulated for use as an eye drop.

[0138] Allergy, Autoimmunity and Asthma The present invention contemplates the treatment or prevention of allergies, autoimmune diseases and asthma. The present invention is based, in part, on the discovery that SCFAs are effective as a therapeutic approach for the treatment and prevention of allergic, autoimmune and / or asthmatic diseases or disorders.

[0139] In one embodiment, the autoimmune and / or allergic disease or disorder is Addison's disease, agammaglobulinemia, allergic rhinitis, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), asthma, autoimmune inner ear disease (AIED), axonal and neuronal neuropathy (AMAN), Behcet's disease, bullous pemphigoid, Castleman's disease (CD), celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss, cicatricial pemphigoid / Benign mucous membrane pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, food allergy, gastroenteritis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, pontine Thyroiditis, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid of gestationis (PG), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, inclusion body myositis (IBM), inflammatory bowel disease, interstitial cystitis (IC), juvenile arthritis, juvenile rheumatism, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignoconjunctivitis, linear immunoglobulin A disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCD) TD), Mooren's ulcer, Mucha-Habermann disease, multiple sclerosis (MS), myasthenia gravis, myositis, narcolepsy, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococci), paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Paley-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome (polyneuropathy, organomegaly,Endocrine disorders, monoclonal, gammopathy, skin changes), polyarteritis nodosa, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progesterone dermatitis, psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, plaque psoriasis, seborrheic psoriasis, erythrodermic psoriasis, nail psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis (RA), sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, seborrheic At least one of the following conditions is considered to be present: child & testicular autoimmunity, stiff-body syndrome (SPS), subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, and Wegener's granulomatosis with polyangiitis (GPA).

[0140] In one embodiment, the allergic disease includes, but is not limited to, hay fever, food allergy, atopic dermatitis, allergic asthma, anaphylaxis, etc. Symptoms may include red eyes, itchy rash, runny nose, shortness of breath, or inflammation. Exemplary allergic diseases include, but are not limited to, food allergies (e.g., milk, soy, egg, wheat, peanut, tree nuts, fish, shellfish), latex allergy, allergic rhinitis, asthma, atopic eczema, anaphylaxis, insect venom, drug allergy, and any combination thereof. The prevalence of allergic diseases has increased worldwide over the past two decades.

[0141] In one embodiment, the present invention is useful for preventing autoimmune and / or allergic diseases or disorders in newborns delivered by C-section. Thus, the present invention in one aspect encompasses administration of SCFAs to subjects, including pregnant women, mothers, and newborns, as an effective method of reducing the risk of developing an autoimmune and / or allergic disease or disorder in a newborn, and may also be effective in treating an autoimmune and / or allergic disease or disorder in a newborn.

[0142] In one embodiment, the present invention relates to a composition comprising SCFAs for use as a therapeutic agent for the treatment and prevention of autoimmune and / or allergic diseases or disorders in newborns delivered by C-section. In one embodiment, the composition comprises one or more SCFAs. In one embodiment, the composition comprises one or more salts of one or more SCFAs. In one embodiment, the composition comprises one or more biologically active derivatives of one or more SCFAs. In one embodiment, the composition comprises one or more precursors of one or more SCFAs. In one embodiment, the composition comprises one or more combinations of SCFAs, salts thereof, biologically active derivatives thereof, or precursors thereof. In one embodiment, the composition comprises one or more combinations of SCFAs, salts thereof, biologically active derivatives thereof, or precursors thereof in combination with at least one other compound. In one embodiment, the composition comprises one or more of formic acid, acetic acid, propionic acid, isobutyric acid, butyric acid, tributyrin, N-acetylbutyrate (and other forms of butyrate), isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, and dodecanoic acid. In one embodiment, the composition is in the form of a capsule (enteric coated, time release) that can be used by women in the late stages of pregnancy. In another embodiment, the composition is in the form of a buffered solution of SCFAs that can be added to infant formula, expressed breast milk, baby food, etc.

[0143] In one embodiment, the present invention relates to a method of treating or preventing an autoimmune and / or allergic disease or disorder in a newborn delivered by C-section, comprising administering a composition comprising SCFAs to one or more subjects. In one embodiment, the step of administering the composition occurs before the birth of the newborn, and the composition is administered to the pregnant woman. In one embodiment, the pregnant woman is near term (about the 8th or 9th month of pregnancy). In one embodiment, the SCFAs are administered orally to the pregnant woman for a period of 2 months or less. In one embodiment, the SCFAs are administered to the pregnant woman at a dose of 6 tablets per day for one week, followed by 3 tablets per day until the C-section is performed. In one embodiment, the dose of a single tablet is 600 mg of one or more SCFAs or salts thereof. In one embodiment, salts of one or more SCFAs are used, where the salts are sodium, magnesium, and / or calcium salts of one or more SCFAs. In one embodiment, the step of administering the composition occurs after the birth of the newborn, and where the composition is administered to the mother, the newborn, or both the mother and the newborn. In one embodiment, the SCFAs are administered to the newborn in the form of a mixture with food or drink, hi one embodiment, the SCFAs are administered to the newborn in the form of an infant formula or dietary supplement for at least the first 18-24 months of life.

[0144] In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or alleviating an autoimmune and / or allergic disease or disorder associated with C-section delivery of a newborn by administering to a subject in need thereof a composition comprising a compound comprising an SCFA or SCFA moiety as disclosed herein, optionally in combination with at least one additional agent or therapy. In one embodiment, the subject is a pregnant woman. In one embodiment, the subject is a fetus. In one embodiment, the subject is a mother. In one embodiment, the subject is a newborn. Autoimmune and / or allergic diseases or disorders that may be treated using the methods of the present invention include, but are not limited to, the autoimmune and / or allergic diseases or disorders described elsewhere herein. In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or alleviating a disease associated with an autoimmune and / or allergic disease or disorder comprising administering to a subject in need thereof a composition comprising a compound comprising an SCFA or SCFA moiety as disclosed herein.

[0145] In one embodiment, the subject at risk of developing or already developing an autoimmune or allergic disease or disorder is a human, hi one embodiment, the subject is a non-human animal.

[0146] In one embodiment, an exemplary method for treating or preventing an autoimmune and / or allergic disease or disorder comprises administering a daily oral dose of at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 g, at least 2 g, at least 3 g, at least 4 g, at least 5 g, at least 6 g, or more than 6 g of a composition comprising at least one SCFA at least once a day, at least twice a day, at least three times a day, or more than three times a day for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or more than 6 months.

[0147] In one embodiment, the composition comprising at least one SCFA is an enteric coated extended release capsule.

[0148] In one embodiment, the composition may be administered to a mother who is breastfeeding a newborn delivered, for example, by C-section. In such an embodiment, a typical daily oral dose for a healthy mother would be 1-2 g of butyrate and 0.5-1 g of propionate and acetate in an enteric coated sustained release capsule three times a day for the first month, then half that dose (e.g., 0.5-1 g of butyrate and 0.25-0.5 g of propionate and acetate) for an additional period of at least 1 month, at least 2 months, at least 3 months, or more than 3 months.

[0149] In one embodiment, the composition may be administered, for example, to a newborn delivered by C-section. In such an embodiment, an exemplary daily oral dose is at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, or more than 1 g of at least one SCFA at least once a day, at least twice a day, at least three times a day, at least four times a day, at least five times a day, at least six times a day, at least seven times a day, or more than seven times a day. Such an embodiment may be formulated, for example, as an additive to a nutritional formula, such as infant formula, for administration to a newborn delivered by C-section. In such embodiments, exemplary daily oral doses for administration to a newborn delivered by C-section include 80-100 mg of butyrate, 20-30 mg of acetate and propionate for the first month after delivery, followed by 100-120 mg of butyrate and 30-40 mg of acetate and propionate for the following 3-5 months.

[0150] vasculitis In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or alleviating a vasculitic disease or disorder by administering a composition comprising a compound comprising an SCFA or an SCFA moiety, as disclosed herein, optionally in combination with at least one additional agent or therapy, to a subject in need thereof. Vasculitic diseases and disorders that may be treated using the methods of the present invention include, but are not limited to, lymphangitis, polymyalgia rheumatica, Takayasu's arteritis, temporal arteritis, Buerger's disease, Kawasaki disease, polyarteritis nodosa, Behcet's syndrome, eosinophilic granulomatosis with polyangiitis, cutaneous vasculitis, Henoch-Schonlein purpura, microscopic polyannulomatosis, cutaneous small vessel vasculitis, granulomatosis with polyangiitis, Behcet's disease, and giant cell arteritis. In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or alleviating a disease associated with vasculitis comprising administering to a subject in need thereof a composition comprising a compound comprising a SCFA or a SCFA moiety, as disclosed herein.

[0151] In various embodiments, compounds containing one or more SCFAs or SCFA moieties may be used in combination with one or more corticosteroid drugs, such as prednisone or methylprednisolone (Medrol), for the treatment of vasculitis. In other embodiments, compounds containing one or more SCFAs or SCFA moieties may be used in combination with one or more cytotoxic or immunosuppressive drugs that reduce the function of immune system cells that cause inflammation. These include azathioprine (Azasan, Imuran), methotrexate (Trexall, Rheumatrex), and cyclophosphamide. In other embodiments, compounds containing one or more SCFAs or SCFA moieties may be used in combination with rituximab (Rituxan) for the treatment of some types of vasculitis.

[0152] In one embodiment, an exemplary method for treating vasculitis comprises administering a daily oral dose of at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 g, at least 2 g, at least 3 g, at least 4 g, at least 5 g, at least 6 g, or more than 6 g of at least one SCFA at least once a day, at least twice a day, at least three times a day, or more than three times a day, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or more than 6 months.

[0153] In one embodiment, the composition comprising at least one SCFA is an enteric coated extended release capsule.

[0154] In one embodiment, an exemplary method for treating vasculitis includes administering a daily oral dose of 5 g to 6 g of butyrate in an enteric coated, sustained release capsule at least three times a day for one month, followed by a daily oral dose of 3 g to 4 g of butyrate in an enteric coated, sustained release capsule at least twice a day for at least two months. In one embodiment, higher doses can be used for treating disease flares, including but not limited to stress-induced disease flares.

[0155] In one embodiment, the method includes administering a composition comprising SCFAs in combination with other steroids and / or chemotherapeutic agents. In such an embodiment, the dosage levels of the other steroids and / or chemotherapeutic agents may be reduced compared to the dosages recommended or administered for a subject undergoing treatment with steroids and / or chemotherapeutic agents alone.

[0156] Lymphoma In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or alleviating a lymphoma disease or disorder by administering a composition comprising a compound comprising an SCFA or SCFA moiety as disclosed herein, optionally in combination with at least one additional drug or therapy, to a subject in need thereof. Lymphoma diseases and disorders that may be treated using the methods of the present invention include, but are not limited to, activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue lymphoma (MALT), Hodgkin's lymphoma (HL), and primary mediastinal B-cell lymphoma (PMBL). In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or alleviating a disease associated with lymphoma, or preventing tumor recurrence, comprising administering a composition comprising a compound comprising an SCFA or SCFA moiety as disclosed herein, to a subject in need thereof.

[0157] In various embodiments, one or more SCFAs or compounds containing SCFA moieties may be used in combination with one or more other lymphoma treatment therapies. In various embodiments, the one or more other lymphoma treatment therapies include radiation therapy and / or rituximab (an anti-CD20 antibody). In various embodiments, the compositions of the present invention are administered before, during, or after another treatment for lymphoma. In various embodiments, the other treatment for lymphoma includes one or more chemotherapeutic agents, antiproliferative agents, antitumor agents, anti-neoplastic agents, anti-angiogenic agents, and / or other anti-cancer agents disclosed elsewhere herein.

[0158] In one embodiment, the method includes administering a composition comprising SCFAs in combination with other anti-lymphoma or anti-tumor agents, including chemotherapeutic agents, cytotoxic / antineoplastic agents, and anti-angiogenic agents. In such embodiments, the dosage level of the other anti-lymphoma or anti-tumor agent may be reduced compared to the dosage recommended or administered for a subject receiving treatment with the other anti-lymphoma or anti-tumor agent alone.

[0159] leukemia In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or alleviating a leukemia disease or disorder by administering a composition comprising a compound comprising an SCFA or an SCFA moiety, as disclosed herein, to a subject in need thereof, optionally in combination with at least one additional agent or therapy. Leukemia diseases and disorders that may be treated using the methods of the present invention include, but are not limited to, myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocytosis (ET), idiopathic / myelofibrosis (MF), acute myeloid leukemia (AML), childhood acute lymphoblastic leukemia (ALL), and blood cancers. In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or alleviating a disease associated with leukemia, or for treating or preventing relapse or the development of a primary tumor of at least one type of leukemia, or for preventing the evolution of an MPN into a leukemia, comprising administering a composition comprising an SCFA or a compound comprising an SCFA moiety to a subject in need thereof. In one embodiment, the at least one SCFA or compound comprising an SCFA moiety is administered before, during, or after administration of at least one additional agent or therapy for the treatment or prevention of leukemia. In certain embodiments, it is administered after a treatment phase as part of a strategy for preventing recurrence of leukemia or preventing the development of a primary tumor. In various embodiments, the composition of the present invention is administered before, during, or after another treatment for leukemia. In various embodiments, the other treatment for leukemia includes one or more chemotherapeutic agents, antiproliferative agents, antitumor agents, antineoplastic agents, antiangiogenic agents, and / or other anticancer agents disclosed elsewhere herein.

[0160] In one embodiment, the treatment includes two stages. The first stage, called induction, may include chemotherapy, for example, treatment with arabinosylcytosine (ara-C) and daunomycin, optionally in combination with cladribine (leustatin, 2-CdA). If remission is achieved, the induction is considered successful. The second stage, called consolidation, includes long-term high-dose ara-C. Alternatively, allogeneic or autologous stem cell transplantation may be used. In one embodiment, the SCFA therapeutic compound of the present invention is administered to the subject before, during, and / or after the induction. In another embodiment, the SCFA therapeutic compound of the present invention is administered to the subject before, during, and / or after the consolidation. In one embodiment, the SCFA therapeutic compound of the present invention is administered to the subject before, during, and / or after the induction and before, during, and / or after the consolidation.

[0161] In various embodiments, the compositions of the invention are administered as part of a method to prevent leukemia relapse or to treat or prevent the development of primary tumors. In one embodiment, at least one leukemia is dependent on constitutive activation of JAK / STAT signaling. In one embodiment, at least one leukemia is BCR / ABL negative. In one embodiment, the treatment method delays or prevents leukemia relapse or recurrence or prevents the development of primary tumors. In one embodiment, the treatment method reduces the toxicity profile of standard treatments initiated at diagnosis, thereby improving long-term quality of life.

[0162] In one embodiment, the method includes administering a composition comprising SCFAs in combination with other anti-leukemia or anti-tumor agents, including chemotherapeutic agents, cytotoxic / antineoplastic agents, and anti-angiogenic agents. In such embodiments, the dosage level of the other anti-leukemia or anti-tumor agent may be reduced compared to the dosage recommended or administered for a subject receiving treatment with the other anti-leukemia or anti-tumor agent alone.

[0163] immunotherapy In one embodiment, the invention provides a method for stimulating, eliciting or enhancing an immune response in a subject (individual) comprising administering to the subject an immunotherapeutic agent in combination with a composition comprising a SCFA or a compound comprising an SCFA moiety. In one embodiment, the subject may be at risk of having a disease, have been diagnosed with a disease, have previously been treated for a disease, or have been contemporaneously treated for a disease using a treatment method (e.g., a treatment method that does not involve the use of a composition of the invention as described herein).

[0164] The present invention is based in part on the discovery that administration of at least one short chain fatty acid (SCFA) can be effective as a therapeutic approach for treating or preventing adverse effects associated with cancer immunotherapy.The therapeutic effect of treatment using a composition comprising at least one SCFA is expected to treat or prevent undesirable adverse effects associated with cancer immunotherapy without significantly interfering with the benefits of immunotherapy.Thus, in one embodiment, the present invention relates to a composition comprising at least one SCFA for use as a therapeutic agent for treating or preventing adverse effects associated with cancer immunotherapy.

[0165] In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or reducing adverse effects associated with cancer immunotherapy by administering to a subject in need thereof a composition comprising a compound comprising an SCFA or SCFA moiety, as disclosed herein, optionally in combination with at least one additional agent or therapy. Adverse effects associated with cancer immunotherapy that may be treated using the methods of the present invention include, but are not limited to, cytokine release syndrome (CRS), neurotoxicity, on-target / off-tumor recognition, anaphylaxis, graft-versus-host disease (GVHD), off-target antigen recognition, and macrophage activation syndrome (MAS). In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or reducing a disease associated with adverse effects associated with cancer immunotherapy, comprising administering to a subject in need thereof a composition comprising at least one SCFA or compound comprising an SCFA moiety, as disclosed herein. In one embodiment, the adverse effects include a combination of adverse effects.

[0166] In one embodiment, the subject suffering from side effects associated with cancer immunotherapy is a human. In one embodiment, the subject suffering from side effects associated with cancer immunotherapy is a non-human animal.

[0167] In one embodiment, to stimulate an immune response, a subject is administered (i) a compound comprising at least one SCFA or SCFA moiety, and (ii) at least one immunotherapeutic agent. Typically, the administration of the compound comprising at least one SCFA or SCFA moiety and the immunotherapeutic agent will be in the form of a vaccine or administered in a vaccine regimen. The compound comprising at least one SCFA or SCFA moiety and the immunotherapeutic agent can be administered to the subject at about the same time, or can be administered separately and / or sequentially.

[0168] Immunotherapeutic agents that may be administered according to the methods of the present invention include, but are not limited to, one or more cancer antigens, one or more antigens derived from viruses associated with cancer, and anti-cancer antibodies.

[0169] A cancer antigen can be (a) a cell surface antigen that can be found on a malignant cell, (b) an antigen that can be found within a malignant cell, or (c) a mediator of tumor cell proliferation. The term "cancer antigen" refers to (i) a tumor-specific antigen, (ii) a tumor-associated antigen, (iii) a cell expressing a tumor-specific antigen, (iv) a cell expressing a tumor-associated antigen, (v) an embryonic antigen on a tumor, (vi) an autologous tumor cell, (vii) a tumor-specific membrane antigen, (viii) a tumor-associated membrane antigen, (ix) a growth factor receptor, (x) a growth factor ligand, and (xi) an antigen or antigen-presenting cell or substance associated with any other type of cancer.

[0170] The cancer antigen can be a cell, a protein, a peptide, a fusion protein, DNA encoding a peptide or a protein, RNA encoding a peptide or a protein, a glycoprotein, a lipoprotein, a phosphorylated protein, a carbohydrate, a lipopolysaccharide, a lipid, a chemically bonded combination of two or more thereof, a fusion or a mixture of two or more thereof. In another embodiment, the cancer antigen is a peptide comprising about 6 to about 24 amino acids; about 8 to about 20 amino acids; about 8 to about 12 amino acids; about 8 to about 10 amino acids; or about 12 to about 20 amino acids. In one embodiment, the cancer antigen is a peptide having an MHC class I binding motif or an MHC class II binding motif. In another embodiment, the cancer antigen comprises a peptide corresponding to one or more cytotoxic T lymphocyte (CTL) epitopes.

[0171] In one embodiment, the present invention provides a method for treating, inhibiting, preventing, or alleviating adverse effects associated with cancer immunotherapy by administering to a subject in need thereof a composition comprising a compound comprising a SCFA or a SCFA moiety, optionally in combination with at least one immunotherapeutic agent, as disclosed herein.

[0172] In one embodiment, the immunotherapy is a chimeric antigen receptor T cell (CAR-T) therapy. In some embodiments, the compositions of the present invention are administered before, during, or after CAR-T therapy for the treatment of cancer, for the treatment or prevention of at least one adverse effect associated with CAR-T therapy. Specific adverse effects treatable and / or preventable by the compositions of the present invention include, but are not limited to, cytokine release syndrome (CRS), neurotoxicity, on-target / off-tumor recognition, anaphylaxis, graft-versus-host disease (GVHD), off-target antigen recognition, and macrophage activation syndrome (MAS). Existing or developing treatments or preventions of these adverse effects include pharmacological immunosuppression (i.e., IL-6R blockade, lymphodepleting chemotherapy with agents such as systemic corticosteroids such as dexamethasone, monoclonal antibodies, cyclophosphamide, etc.), suicide or ablation genes (i.e., killing of CAR-T cells), and targeted activation (i.e., conditional activation of CAR-T cells with a drug or another agent). Thus, in one embodiment, the treatment composition of the present invention is combined with at least one other strategy to reduce, prevent, treat, or ameliorate one or more adverse effects associated with cancer immunotherapy. In one embodiment, the present invention provides a composition for treating or preventing the onset of adverse effects associated with cancer immunotherapy. In one embodiment, the composition comprises at least one SCFA or a compound comprising an SCFA moiety. In one embodiment, the immunotherapy comprises CAR-T therapy. In another embodiment, the immunotherapy comprises a therapy comprising at least one other anti-cancer composition. In some embodiments, the composition of the present invention is administered before, during, or after chemotherapy for the treatment of cancer.

[0173] In one embodiment, a composition comprising at least one SCFA is administered in parallel with chemotherapy: several days prior to CAR-T cell infusion (SCFAs only), and up to several weeks after CAR-T cell infusion (SCFAs in combination with lower levels of the chemotherapeutic agent compared to subjects receiving chemotherapy alone).

[0174] In one embodiment, an exemplary daily oral dose for use in the methods of immunotherapy is a daily oral dose of at least 2 g, at least 3 g, at least 4 g, at least 5 g, at least 6 g, or more than 6 g of at least one SCFA at least twice a day, at least three times a day, or more than three times a day, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or more than 6 months.

[0175] In one embodiment, an exemplary daily oral dose for use in the immunotherapy method is a daily oral dose of 5-6 g butyrate and 2-3 g propionate. In one embodiment, the composition comprising at least one SCFA is an enteric coated sustained release capsule. In one embodiment, the composition is administered three times daily.

[0176] Combination with additional drugs The present invention is also directed to methods of treating or preventing the above-mentioned diseases or disorders in combination with one or more additional agents.

[0177] The combination may be in a single formulation or may be administered separately in sequence (first a composition comprising a molecule comprising at least one SCFA or SCFA moiety, then a composition comprising an additional agent, or first a composition comprising an additional agent and then a molecule comprising at least one SCFA or SCFA moiety). In some embodiments, the molecule comprising at least one SCFA or SCFA moiety is administered within about 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 20 hours, 22 hours, 24 hours, 26 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 minutes, 60 minutes, 62 minutes, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 70 hours, 71 hours, 72 hours, 73 hours, The subject may be administered 8 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks prior to administration.In other embodiments, the composition comprising at least one additional agent is administered within about 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 20 hours after the composition comprising at least one SCFA or molecule comprising an SCFA moiety is administered to the subject. , 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks prior to administration to the subject.

[0178] In one embodiment, the present invention provides the general concept of administering at least one of these agents or a biologically active derivative thereof in combination with at least one short chain fatty acid (SCFA) or a biologically active derivative or precursor thereof as a therapy to treat or prevent a disease or disorder in a subject in need thereof. In one embodiment, a composition of the present invention comprises at least one of these agents or a biologically active derivative thereof, and at least one SCFA or a biologically active derivative or precursor thereof.

[0179] Exemplary therapeutic agents that may be included in or administered in combination with the compositions of the invention are provided.

[0180] Checkpoint inhibitors In one embodiment, the method includes administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with one or more immune checkpoint inhibitors. As used herein, "checkpoint inhibitors" include inhibitors or molecules that block immune checkpoints as generally understood in the field of cancer immunotherapy. Generally, checkpoint inhibitors are antibodies that block immune checkpoint proteins. Immune checkpoint proteins include, but are not limited to, PD1, PDL1, PDL2, CTLA-4, LAG3, TIM3, B7-H3, BTLA, VISTA, CD40, CEACAM1, CD80, CD86, OX40, CD27, GITR, DNAM-1, TIGIT, TMIGD2, and DC-SIGN. Some examples of known checkpoint inhibitors include, but are not limited to, ipilimumab, pembrolizumab, nivolumab, pidilizumab, atezolizumab, avelumab, dolbuvalumab, and others. In one embodiment, the composition may comprise at least one SCFA, or a molecule comprising an SCFA moiety, in combination with an antibody against a checkpoint protein.

[0181] In one embodiment, the combination of at least one SCFA, or a molecule comprising an SCFA moiety, and a checkpoint inhibitor induces the immune system more efficiently than a checkpoint inhibitor alone, and this more efficient immune response provides enhanced efficacy in the treatment and / or prevention of a particular disease or disorder.

[0182] In some embodiments, the immune response may be increased by about 0.5-fold to about 15-fold, about 0.5-fold to about 10-fold, or about 0.5-fold to about 8-fold. Alternatively, the immune response in a subject administered a combination of at least one SCFA, or a molecule comprising an SCFA moiety, and a checkpoint inhibitor may be increased by at least about 0.5-fold, at least about 1.0-fold, at least about 1.5-fold, at least about 2.0-fold, at least about 2.5-fold, at least about 3.0-fold, at least about 3.5-fold, at least about 4.0-fold, at least about 4.5-fold, at least about 5.0-fold, at least about 5.5-fold, at least about 6.0-fold, at least about 6.5 ... The increase may be 5-fold, at least about 7.0-fold, at least about 7.5-fold, at least about 8.0-fold, at least about 8.5-fold, at least about 9.0-fold, at least about 9.5-fold, at least about 10.0-fold, at least about 10.5-fold, at least about 11.0-fold, at least about 11.5-fold, at least about 12.0-fold, at least about 12.5-fold, at least about 13.0-fold, at least about 13.5-fold, at least about 14.0-fold, at least about 14.5-fold, or at least about 15.0-fold.

[0183] In yet other alternative embodiments, the immune response in a subject administered a combination of at least one SCFA, or a molecule comprising an SCFA moiety, and a checkpoint inhibitor may be increased by about 50% to about 1500%, about 50% to about 1000%, or about 50% to about 800%. In other embodiments, the immune response in a subject administered a combination of at least one SCFA, or a molecule comprising an SCFA moiety, and a checkpoint inhibitor may be increased by at least about 50%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 650%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, at least about 1200%, at least about 1250%, at least about 1300%, at least about 1350%, at least about 1450%, or at least about 1500%.

[0184] Anti-inflammatory agents In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with one or more anti-inflammatory agents. Exemplary anti-inflammatory agents that can be used in combination with the compositions of the invention include, but are not limited to, diclofenac (e.g., Arthrotec®), diflunisal (e.g., Dolobid®), etodolac (e.g., Lodine®), fenoprofen (e.g., Nalfon®), ibuprofen (e.g., Advil®, Motrin®, etc.), indomethacin (e.g., Arthrexin®), ketoprofen (e.g., Oruvail®), ketorolac (e.g., Toradol®), fosfomycin tromethamine (e.g., Monural®), meclofenamate (e.g., Meclomen®), nabumetone (e.g., Relafen®), naproxen (e.g., Anaprox®, etc.), Nonsteroidal anti-inflammatory drugs (NSAIDs) such as oxaprozin (e.g., Daypro®), piroxicam (e.g., Feldene®), sulindac (e.g., Clinoril®), tolmetin (e.g., Tolectin®, and others), flavenoids (e.g., luteolin, fisetin, and apigenin), steroids, antihistamines, loratadine, theophylline, doxantrazole, quercetin, 8-bromocyclic AMP, disodium cromoglycate, beclomethasone dipropionate, budesonide, budesonide / formoterol, fluticasone, fluticasone inhalation powder, fluticasone / salmeterol, mometasone, mometasone / formoterol, cromolyn, omalizumab, inhaled short- or long-acting beta2-agonists, leukotriene modifiers, and theophylline. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and additionally one or more anti-inflammatory agents.In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with a composition comprising one or more anti-inflammatory agents.

[0185] PDE4 Inhibitors In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with one or more phosphodiesterase 4 (PDE4) inhibitors. A non-limiting selection of PDE4 inhibitors is provided in US Patent Publication No. 2002 / 0111495, which is incorporated herein by reference. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and additionally one or more PDE4 inhibitors. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with one or more PDE4 inhibitors.

[0186] Disease-modifying antirheumatic drugs (DMARDs) In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with one or more disease-modifying antirheumatic drugs (DMARDs), or an immunosuppressant may be included in the composition of the present invention. DMARDs are known in the art and include, but are not limited to, methotrexate (Rheumatrex®), sulfasalazine (Azulfidine®), mycophenolate mofetil (CellCept®), and cyclosporine (Sandimmune®, or Neroal®). In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and additionally one or more DMARDs. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with one or more DMARDs.

[0187] Biologic agents In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with one or more biological agents. Exemplary biological agents contemplated by the present invention include, but are not limited to, etanercept (Enbrel®), infliximab (Remicade®), apremilast (Otezla®), and adalimumab (Humira®). In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and additionally one or more biological agents. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with one or more biological agents.

[0188] Cox-2 Inhibitors In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with one or more Cox-2 inhibitors. Cox-2 inhibitors include, but are not limited to, celecoxib (Celebrex®), valdecoxib (Bextra®), and meloxicam (Mobic®). In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and additionally one or more Cox-2 inhibitors. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with one or more Cox-2 inhibitors.

[0189] Magnesium, Vitamin D3, and Vitamin E In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and additionally one or more of magnesium, vitamin D3, and vitamin E (d-α-tocopherol acetate). Magnesium is a cofactor for over 300 enzymes that regulate a variety of biochemical reactions, including blood glucose regulation, detoxification, and others. Vitamin D3 deficiency is common in patients with immune disorders. Vitamin E has unique antioxidant properties. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and additionally one or more of magnesium, vitamin D3, and vitamin E. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with a composition comprising one or more of magnesium, vitamin D3, and vitamin E.

[0190] Other drugsIn one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and additionally one or more additional therapeutic agents. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with a composition comprising one or more additional therapeutic agents. Additional therapeutic agents contemplated for administration by the methods of the present invention include, but are not limited to, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide, methylprednisolone acetate, parenteral gold, oral gold, indomethacin, hydroxychloroquine, hydroxychloroquine sulfate, sulindac, prednisone, betamethasone dipropionate augmentation, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, pyroxene, tetracycline ... Cicam, diclofenac sodium, ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac, sodium / misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate, hydrocodone bitartrate / apap, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, small molecule inhibitor of KDR (ABT-123) agents, small molecule inhibitors of Tie-2, clobetasol propionate, triamcinolone acetonide, halobetasol propionate, tazarotene, fluocinonide, betamethasone dipropionate potentiator, fluocinolone, acetonide, acitretin, tar shampoo, betamethasone valerate, mometasone furoate, ketoconazole, pramoxine / fluocinolone, hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobeta propionate emollients (emoll), fluticasone propionate, azithromycin, hydrocortisone, moisturizers, folic acid, desonide, coal tar, diflorasone diacetate, folic acid, lactic acid, methoxsalen, methylprednisolone acetate, prednisone, sunscreen, salicylic acid, halcinonide, anthralin, clocortolone pivalate, coal extract, coal tar / salicylic acid, coal tar / salicylic acid / sulfur, desoximetasone, diazepam,Emollients, pimecrolimus emollients, fluocinonide / emollients, mineral oil / castor oil / sodium lactate (na lact), mineral oil / peanut oil, petroleum / isopropyl myristate, psoralens, salicylic acid, soap / tribromosalan, thimerosal / boric acid, celecoxib, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, alemtuzumab, dronabinol, Unimed, daclizumab, mitoxantrone, xaliproden hydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol, a-immunokine NNSO3, AB R-215062, AnergiX.MS, chemokine receptor antagonist, BBR-2778, Caraguarin, CPI-1189, LEM (liposome encapsulated mitoxantrone), THC.CBD (cannabinoid agonist) MBP-8298, Mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone allotrap 1258 (RDP-1258), sTNF-R1, CDP571 (humanized monoclonal anti-TNF-α IgG4 antibody), CDP870 (humanized monoclonal anti-TNF-α antibody fragment), anti-TNF dAb (Peptech), CNTO148 (golimumab; Medarex and Centocor, see WO 02 / 12502), and adalimumab (Humira® Abbott Laboratories, human anti-TNF mAb, described as D2E7 in U.S. Pat. No. 6,090,382). Additional TNF antibodies that can be used in the present invention include those described in U.S. Pat. Nos. 6,593,458; 6,498,237; 6,451,983; and 6,448,380, each of which is incorporated herein by reference, talampanel, teriflunomide, TGF-beta 2, tiplimotide, VLA-4 antagonists (e.g., TR-14035, VLA4 Ultrahaler, Antegran-ELAN / Biogen), interferon gamma antagonists, IL-4 agonists, the humanized IL-6 antibody tocilizumab, steroids (e.g., dexamethasone, prednisone, prednisolone, triamcinolone acetonide,Fluorometholone, and difluprednate), rapamycin, lampalizumab, fluocinolone acetotanide, macuCLEAR eye drops, bone marrow CD34 stem cells, other stem cells, ranibizumab, brimonidine, LFG316, ORACEA®, emixustat hydrochloride, sirolimus, copaxone, other eye drops, AL-78898A, and eculizumab.

[0191] Interleukin IL-17 inhibitors Interleukin IL-17 has been shown to stimulate TNFα production. Anti-IL-17 agents include, but are not limited to, brodalumab, ixekizumab, and secukinumab. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and additionally one or more inhibitors of IL-17. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with a composition comprising one or more inhibitors of IL-17.

[0192] IFN-γ inhibitors A key Th1-type cytokine involved in the pathogenesis of inflammatory diseases is IFN-γ, which inhibits keratinocyte apoptosis by stimulating the expression of the anti-apoptotic protein Bcl-x. This contributes to the progression of inflammatory diseases. Thus, in one embodiment, the method of the present invention may comprise administering a composition of the present invention in combination with one or more IFN-γ inhibitors. In one embodiment, the IFN-γ inhibitor may be at least one of an anti-IFN-γ antibody, a soluble IFN-γ receptor, and combinations thereof. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and additionally one or more IFN-γ inhibitors. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with one or more IFN-γ inhibitors.

[0193] VEGF inhibitors Vascular endothelial growth factor (VEGF) is involved in the pathological angiogenesis observed in inflammatory diseases characterized by increased expression of VEGF at the mRNA and protein levels (by epidermal keratinocytes) and VEGF receptors (by tortuous microvessels in the upper dermis) (Man et al., 2008, J Cell Mol Med., 12(2):649-60; Marina et al., 2015, Clujul Med, 88(3):247-52). Thus, in one embodiment, the method of the present invention may comprise administering the composition of the present invention in combination with at least one VEGF inhibitor. In one embodiment, the VEGF inhibitor is an antibody, e.g., a monoclonal antibody. In one embodiment, the VEGF inhibitor is at least one of bevacizumab, sunitinib, sorafenib, pazopanib, brivanib alaninate, cediranib, vandetanib, motesanib, linifinib, axitinib, and aflibercept.In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and additionally one or more VEGF inhibitors.In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with a composition comprising one or more VEGF inhibitors.

[0194] HDAC inhibitors Butyrate is one of the most potent histone deacetylase (HDAC) inhibitors. HDAC inhibition is a potent inhibitor of T cell proliferation and activation of naive T cells. CD4The present invention can stimulate differentiation into a subset of cells, Treg cells, which express the transcription factor FoxP3, which is important for Treg expression. Treg cells are involved in maintaining self-tolerance by suppressing the activation and proliferation of autoreactive lymphocytes, and therefore play an important role in preventing autoimmunity. Thus, the present invention provides a number of compositions that can promote Treg and / or cells and / or pathways associated with FoxP3, at least in part through HDAC inhibition. Thus, in one embodiment, the composition of the present invention comprises at least one compound that promotes the differentiation of naive T cells into Treg cells.

[0195] Thus, in one embodiment, the method of the present invention may comprise administering the composition of the present invention in combination with one or more HDAC inhibitors.Exemplary HDAC inhibitors include, but are not limited to, TSA, SAHA, CBHA, LAQ-824, PDX-101, LBH-589, ITF2357, PCI-24781, FK-228, valproic acid, phenyl butyrate, butyrate, AN-9, MS-275, MGCD0103 (Dokmanovic, M. et al., 2007, 5(10):981-989).In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and additionally one or more HDAC inhibitors.In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with a composition comprising one or more HDAC inhibitors.

[0196] AMPK activator Adenosine monophosphate kinase (AMPK) promotes the expression of the transcription factor FoxP3, which in turn stimulates the differentiation and function of Treg cells. In one embodiment, the method of the present invention may include administering the composition of the present invention in combination with one or more natural AMPK activators, including, but not limited to, rose hips (from Rosa canina) and Jiaogulan extract (from Gynostemma pentaphyllum) or other natural AMPK activators. Exemplary AMPK activators from natural products are described in Uddin et al., 2013, Natural Product Sciences, 19(1):1-7, which is incorporated herein by reference.

[0197] IDO inhibitors In one embodiment, the method of the present invention may include administering the composition of the present invention in combination with one or more IDO inhibitors.IDO inhibitors, including but not limited to 1-methyl-DL-tryptophan; p-(3-benzofuranyl)-DL-alanine; p-[3-benzo(b)thienyl]-DL-alanine; and 6-nitro-L-tryptophan, have been used to modulate T cell-mediated immunity by altering the local extracellular concentration of tryptophan and tryptophan metabolites (WO 99 / 29310).Compounds with IDO inhibitory activity are further reported in WO 2004 / 094409, the contents of both of which are incorporated herein in their entirety.

[0198] In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and additionally one or more IDO inhibitors. In one embodiment, the method comprises administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with a composition comprising one or more IDO inhibitors.

[0199] Drugs for the treatment of diabetes or diabetes-related conditions In one embodiment, the methods of the invention may include administering a composition of the invention in combination with one or more agents for the treatment of diabetes or a diabetes-related condition. The use of other agents (e.g., insulin) and diet (low sugar) may be used in combination with the SCFAs or compounds containing an SCFA moiety of the invention to enhance their therapeutic effect. Antidiabetic compounds that may be combined with the SCFAs or compounds containing an SCFA moiety of the present invention include, but are not limited to, short-acting insulins (e.g., regular insulin), fast-acting insulins (e.g., insulin aspart, insulin glulisine, and insulin lispro), intermediate-acting insulins (e.g., insulin isophane), long-acting insulins (e.g., insulin degludec, insulin detemir, insulin glargine, and insulin glargine), combination insulins (e.g., 70 / 30 (insulin aspart protamine-insulin aspart), 75 / 25 (insulin lispro protamine-insulin lispro), 50 / 50 (insulin lispro protamine-insulin lispro), 70 / 30 (human insulin NPH-human insulin regular), 70 / 30 (human insulin NPH-human insulin regular), and (insulin degludec-insulin aspart)), and the amylinomimetic drug pramlintide.

[0200] Chemotherapeutic agents In one embodiment, the methods of the invention may include administering a composition of the invention in combination with one or more chemotherapeutic agents, including, but not limited to, ara-C, daunomycin, cladribine (leustatin, 2-CdA), cytotoxic agents (e.g., 5-fluorouracil, cisplatin, carboplatin, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, oxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP, cyclophosphamide, estramucine phosphate estrogen, erythropoietin ... tertamine, altretamine, hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplatin, cisplatin, interferon alpha-2a recombinant, paclitaxel, teniposide, and streptozocin), cytotoxic alkylating agents (e.g., busulfan, chlorambucil, cyclophosphamide, melphalan, or ethylesulfonic acid acid), alkylating agents (e.g., asaril, AZQ, BCNU, busulfan, bisulfan, carboxyphthalatoplatinum, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cis-platinum, clomesone, cyanomorpholinodoxorubicin, cyclodisone, cyclophosphamide, dianhydrogalactitol, fluorodopan, hepsulfame, hycanthone, ifosphamide, melphalan, methyl-CCNU, mitomycin C, mitozolam ide), nitrogen mustards, PCNU, piperazine, piperazinedione, pipobroman, porfiromycin, spirohydantoin mustard, streptozotocin, teroxylon, tetraplatin, thiotepa, triethylenemelamine, uracil nitrogen mustard, and Yoshi-864), antimitotics (e.g., allocolchicine, halichondrin M, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel derivatives, paclitaxel, thiocolchicine, trityl cysteine, vinblastine sulfate, and vincristine sulfate),Plant alkaloids (e.g., actinomycin D, bleomycin, L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate, mithramycin, mitomycin, daunorubicin, VP-16-213, VM-26, navelbine, and taxotere), biological agents (e.g., alpha interferon, BCG, G-CSF, GM-CSF, and interleukin-2), topoisomerase I inhibitors (e.g., camptothecin, camptothecin derivatives, and morpholinodoxorubicin), topoisomerase II inhibitors (e.g., mitoxantron, amonafide, m- AMSA, anthrapyrazole derivatives, pyrazoloacridine, bisantrene HCL, daunorubicin, deoxydoxorubicin, menogaril, N,N-dibenzyl daunomycin, oxanthrazole, rubidazone, VM-26 and VP-16) and synthetic substances (e.g., hydroxyurea, procarbazine, o,p'-DDD, dacarbazine, CCNU, BCNU, cis-diaminedichloroplatinum, mitoxantrone, CBDCA, levamisole, hexamethylmelamine, all-trans retinoic acid, gliadel and porfimer sodium). In some embodiments, the compositions of the present invention are administered before, during or after the administration of at least one anti-proliferative agent for the treatment of cancer. Anti-proliferative agents are compounds that reduce the proliferation of cells. Antiproliferative agents include, but are not limited to, alkylating agents, antimetabolites, enzymes, biological response modifiers, miscellaneous agents, hormones and antagonists, androgen inhibitors (e.g., flutamide and leuprolide acetate), antiestrogens (e.g., tamoxifen citrate and its analogs, toremifene, droloxifene, and roloxifene). Further examples of specific antiproliferative agents include, but are not limited to, levamisole, gallium nitrate, granisetron, sargramostim strontium-89 chloride, filgrastim, pilocarpine, dexrazoxane, and ondansetron.

[0201] The compositions of the present invention can be administered alone or in combination with other anti-tumor agents, including cytotoxic / antineoplastic agents and anti-angiogenic agents. Cytotoxic / antineoplastic agents are defined as agents that attack and kill cancer cells. Some cytotoxic / antineoplastic agents are alkylating agents that alkylate genetic material in tumor cells, such as cisplatin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, verstine, uracil mustard, chlomaphazin, and dacabazine. Other cytotoxic / antineoplastic agents are tumor cell antimetabolites, such as cytosine arabinoside, fluorouracil, methotrexate, mercaptopuirine, azathioprime, and procarbazine. Other cytotoxic / antineoplastic agents are antibiotics, such as doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin. There are numerous liposomal formulations of these compounds available commercially. Additionally, other cytotoxic / antineoplastic agents are mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine, and etoposide. Other cytotoxic / antineoplastic agents include taxol and its derivatives, L-asparaginase, antitumor antibodies, dacarbazine, azacitidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.

[0202] Antiangiogenic agents are well known to those skilled in the art. Antiangiogenic agents suitable for combination with the compositions of the present disclosure include anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers and antisense oligonucleotides. Other known angiogenesis inhibitors include angiostatin, endostatin, interferon, interleukin 1 (including α and β), interleukin 12, retinoic acid and tissue inhibitors of metalloproteinase-1 and -2. (TIMP-1 and -2). Small molecules that contain topoisomerase, such as razoxane, a topoisomerase II inhibitor with antiangiogenic activity, can also be used.

[0203] Other anti-cancer drugs that may be used in combination with the compositions of the present invention include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; visnafide dimesylate; bizelesin; bleomycin sulfate; brequinar. carbamazepine;bropirimine;busulfan;cactinomycin;calsterone;caracemide;carbetimer;carboplatin;carmustine;carubicin hydrochloride;carzelesin;cedefingol;chlorambucil;ciloremycin;cisplatin;cladribine;crisnatol mesylate;cyclophosphamide;cytarabine;dacarbazine;dactinomycin;daunorubicin hydrochloride;decitabine;dexorumaplatin;desaguanine;desaguanine mesylate;diazicon;docetaxel;doxorubicin;doxorubicin hydrochloride;droloxifene ;Droloxifene citrate;Dromostanolone propionate;Duazomycin;Edatrexate;Eflornithine hydrochloride;Elsamitrucin;Enloplatin;Empromate;Epipropizine;Epirubicin hydrochloride;Elbrozole;Esorubicin hydrochloride;Estramustine;Estramustine phosphate sodium;Etanidazole;Etoposide;Etoposide phosphate;Etoprine;Fadrozole hydrochloride;Fazarabine;Fenretinide;Floxuridine;Fludarabine phosphate;Fluorouracil;Fluorocitabine (fluoro citabine;foskidone;fostriecin sodium;gemcitabine;gemcitabine hydrochloride;hydroxyurea;idarubicin hydrochloride;ifosfamide;irmofosine;interleukin II (including recombinant interleukin II or rIL2);interferon alpha-2a;interferon alpha-2b;interferon alpha-n1;interferon alpha-n3;interferon beta-Ia;interferon gamma-Ib;iproplatin;irinotecan hydrochloride;lanreotide acetate;letrozole;leuprolide acetate;liarozole hydrochloride;Lometrexol sodium; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocalcine; Mitochromine; Mitogillin; Mitomarcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Noga ramycin;ormaplatin;oxisuran;paclitaxel;peguasparagase;periomycin;pentamustine;peplomycin sulfate;perfosfamide;pipobroman;piposulfan;piroxantrone hydrochloride;plicamycin;promestane;porfimer sodium;porfiromycin;prednimustine;procarbazine hydrochloride;puromycin;puromycin hydrochloride;pirazofurin;ribopurin;logretimide;safingol;safingol hydrochloride;cetamide Mustine;Simtrazene;Sparfosate sodium;Sparsomycin;Spirogermanium hydrochloride;Spiromustine;Spiroplatin;Streptonigrin;Streptozocin;Sulofenur;Tallysomycin;Tecogalan sodium;Tegafur;Teroxantrone hydrochloride;Temoporfin;Teniposide;Teroxylon;Testolactone;Thiamiprine;Thioguanine;Thiotepa;Tiazofurin;Tirapazamine;Toremifene citrate;Trestorone acetate;Triciribine phosphate; Trimetrexate; Trimetrexate glucuronide; Triptorelin; Tubrozole hydrochloride; Uracil mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine sulfate; Vincristine sulfate; Vindesine; Vindesine sulfate; Binepidine sulfate; Vinglisinate sulfate; Vinleurosine sulfate; Vinorelbine tartrate; Vinlocidine sulfate; Vinzolidine sulfate; Vorozole; Zeniplatin; Zinostatin; Zorubicin hydrochloride. Other anticancer drugs include, but are not limited to, 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; Abiraterone; Aclarubicin; Acylfulvene; Adecipenol; Adzelesin; Aldesleukin; ALL-TK antagonists;Altretamine;Ambamustine;Amidox;Amifostine;Aminolevulinic acid;Amrubicin;Amsacrine;Anagrelide;Anastrozole;Andrographolide;Angiogenesis inhibitors;Antagonist D;Antagonist G;Antarelix;Anti-dorsal morphogenetic protein-1;Anti-androgens (prostate cancer);Anti-estrogens;Antineoplastics;Antisense oligonucleotides;Aphidicolin glycine salt;Apoptosis gene modulators;Apoptosis regulators;Apurinic acid;ara-CDP-DL-PTBA;Arginine deamid Enzymes;Aslaculin;Atamestane;Atrimustine;Axinastatin 1;Axinastatin 2;Axinastatin 3;Azasetron;Azatoxins;Azatyrosine;Baccatin III derivatives;Balanol;Batimastat;BCR / ABL antagonists;Benzochlorins;Benzoylstaurosporines;β-lactam derivatives;β-arretin;Betaclamycin B;Betulinic acid;bFGF inhibitors;Bicalutamide;Bisantrene;Bisaziridinylspermine;Bisnafide;Bistratin A;Bizelesin;Brefrath;Bropirimine;Budotitanium;B Thionine sulfoximine;Calcipotriol;Calfostin C;Camptothecin derivatives;Canarypox IL-2;Capecitabine;Carboxamido-amino-triazoles;Carboxamidotriazoles;CaRestM3;CARN700;Cartilage-derived inhibitors;Carzelesin;Casein kinase inhibitors (ICOS);Castanospermine;Cecropin B;Cetrorelix;Chlorin;Chloroquinoxaline sulfonamides;Cicaprost;cis-Porphyrins;Cladribine;Clomiphene analogs;Clotrimazole;Colismycin A;Colismycin mycin B;combretastatin A4;combretastatin analogs;conagenin;crambesidin 816;crisnatol;cryptophycin 8;cryptophycin A derivatives;curacin A;cyclopentaquinone;cycloplatam;sipemycin;cytarabine ocfosfate;cytolytic factors;cytostatin;dacliximab;decitabine;dehydrodidemnin B;deslorelin;dexamethasone;dexifosfamide;dexrazoxane;dexverapamil;Diazicon;Didemnin B;Didox;Diethylnorspermine;Dihydro-5-azacytidine;9-dihydrotaxol;Dioxamycin;Diphenylspiromustine;Docetaxel;Docosanol;Dolasetron;Doxifluridine;Droloxifene;Dronabinol;Duocarmycin SA;Ebselen;Ecomustine;Edelfosine;Edrecolomab;Eflornithine;Elemene;Emiteful;Epirubicin;Epristeril ;Estramustine analogs;Estrogen agonists;Estrogen antagonists;Etanidazole;Etoposide phosphate;Exemestane;Fadrozole;Fazarabine;Fenretinide;Filgrastim;Finasteride;Flavopiridol;Flezelastine;Fluasterone;Fludarabine;Fluorodaunorunicin hydrochloride;Forfenimex;Formestane;Fostriecin;Fotemustine;Gadolinium texaf cyclosporine;gallium nitrate;gallocitabine;ganirelix;gelatinase inhibitors;gemcitabine;glutathione inhibitors;hepsulfame;heregulin;hexamethylene bisacetamide;hypericin;ibandronate;idarubicin;idoxifene;idramantone;ilmofosine;ilomastat;imidazoacridone;imiquimod;immunostimulating peptides;insulin-like growth factor-1 receptor inhibitors;interferon agonists;interferon Feron;Interleukin;Iobenguane;Iododoxorubicin;4-ipomeanol;Iropract;Irosogladine;Isobengazole;Isohomohalichondrin B;Itasetron;Jasplakinolide;Kahalalide F;Lamellarin-N triacetate;Lanreotide;Leinamycin;Lenograstim;Lentinan sulfate;Leptolstatin;Letrozole;Leukemia inhibitory factor;Leukocyte alpha interferon;Leuprolide + estrogen + progesterone;Leuprorelin;Levamisole;Liarozole;Linear polyamine analogs;Lipophilic disaccharide peptides;Lipophilic platinum compounds;Lissoclinamide 7;lobaplatin; lombricin; lometrexol; lonidamine; rosoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maytansine; mannostatin A; marimastat; massoprocol; maspin; matrilysine inhibitors; matrix metalloproteinase inhibitors; menogaril; mervalone; meterelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; millimostim; mismatched double-stranded RNA; mitoguazone; mi Traktol;Mitomycin analogs;Mitonafide;Mitotoxin fibroblast growth factor-saporin;Mitoxantrone;Mofalotene;Molgramostim;Monoclonal antibodies, human chorionic gonadotrophin;Monophosphoryl lipid A+myobacterium cell wall sk;Mopidamol;Multidrug resistance gene inhibitors;Multiple tumor suppressor 1-based therapy;Mustard anticancer drugs;Mycaperoxide B;Mycobacterial cell wall extract;Miliaporone;N-acetyldinarine;N-substituted benzamides;Naphtha arelin; nagrestip; naloxone + pentazocine; napavin; napavin; naphterpine; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidants; nitrullyn; O6-benzylguanine; octreotide; oxenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxalate Saliplatin;Oxaunomycin;Paclitaxel;Paclitaxel analogues;Paclitaxel derivatives;Palauamine;Palmitoyl rhizoxin;Pamidronic acid;Panaxytriol;Panomyphen;Parabactin;Pazeliptin;Pegaspargase;Perdecin;Pentosan polysulfate sodium;Pentostatin;Pentrozole;Perflubron;Perphosphamide;Perillyl alcohol;Phenazinomycin;Phenyl acetate;Phosphatase inhibitors;Picibanil;Pilocarpine hydrochloride;Pirarubicin;Piritrexim;Placetin A;Placetin B;Plasminogen activator inhibitors;Platinum complexes;Platinum compounds;Platinum-triamine complexes;Porfimer sodium;Porfiromycin;Prednisone;Propyl bis-acridone;Prostaglandin J2;Proteasome; RA inhibitors;Protein A-based immunomodulators;Protein kinase C inhibitors;Protein kinase C inhibitors (microalgae);Protein tyrosine phosphatase inhibitors;Purine nucleoside phosphorylase inhibitors;Purpurins;Pyrazoloacridines;Pyridoxylated hemoglobin polyoxyethylene conjugates;Raf antagonists;Raltitrexed;Ramosetron;Ras farnesyl protein transferase inhibitors;Ras inhibitors;Ras-GAP inhibitors;Demethylated reterliptin;Rhenium etidronate Re 186 (rhenium Re 186 etidronate;rhizoxin;ribozyme;RII retinamide;logretimide;rohitukin;romurtide;roquinimex;rubiginone B1;ruboxil;safingol;sintopine;SarCNU;sarcophytol A;sargramostim;Sdi1 mimetic;semustine;senescence derived inhibitor 1;sense oligonucleotide;signal transduction inhibitor;signal transduction modulator;single chain antigen binding protein;sizofiran;sobzoxane;sodium borocaptate borocaptate;Sodium phenylacetate;Sorberol;Somatomedin binding protein;Sonermin;Sparfosic acid;Spicamycin D;Spiromustine;Splenopentin;Spongistatin 1;Squalamine;Stem cell inhibitors;Stem cell division inhibitors;Stypiamide;Stromelysin inhibitors;Sulfinosine;Superactive vasoactive intestinal peptide antagonists;Suradista;Suramin;Swainsonine;Synthetic glycosaminoglycans;Talimustine;Tamoxifen methiodide;Tauromustine;Tazarotene;Tecogalanna Thorium;Tegafur;Terlapyrylium;Telomerase inhibitors;Temoporfin;Temozolomide;Teniposide;Tetrachlorodecaoxide;Tetrazomine;Taliblastine;Thiocoraline;Thrombopoietin;Thrombopoietin mimetics;Thymalfasin;Thymopoietin receptor agonists;Thymotrin;Thyroid-stimulating hormone;Ethyl etiopurinse;Tirapazamine;Titanocene dichloride;Topsentin;Toremifene;Pluripotent stem cell factor;Translation inhibitors;Tretinoin;Triacetyluridine;Triciribine;Trimetrexate;Triptorelin;Tropisetron;Examples include turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitors, urokinase receptor antagonists, vapreotide, variolin B, vector systems, red blood cell gene therapy, veraresol, veramine, verudin, verteporfin, vinorelbine, vinxaltine, vitaxin, vorozole, zanoteron, zeniplatin, zilascorub, and zinostatin stimalamer. In one embodiment, the anticancer drug is 5-fluorouracil, taxol, or leucovorin.

[0204] Antiviral agents The present invention contemplates compositions comprising at least one SCFA or compound comprising an SCFA moiety as described herein in combination with an antiviral agent, including, but not limited to, inhibitors of viral uncoating (e.g., amantadine and rimantidine), reverse transcriptase inhibitors (e.g., acyclovir, zidovudine, and lamivudine), agents that target integrase, agents that block the attachment of transcription factors to viral DNA, agents that affect translation (e.g., antisense molecules) (e.g., fomivirsen), agents that modulate translation / ribozyme function, protease inhibitors, viral assembly modulators (e.g., rifampicin; antiretroviral agents such as nucleoside analog reverse transcriptase inhibitors (e.g., azidothymidine (AZT), ddl, ddC, 3TC, d4T); non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, nevirapine); nucleotide analog reverse transcriptase inhibitors; and agents that prevent the release of viral particles (e.g., zanamivir and oseltamivir), abacavir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir , atripla, boceprevirertet, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, phosphonet, ganciclovir, ibasitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, various interferons (e.g., peginterferon alfa- 2a), lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nexavir, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, ritonavir, pyramidine, saquinavir, stavudine, telaprevir, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zalcitabine.

[0205] Anthelmintics The present invention contemplates a composition comprising at least one SCFA or compound comprising SCFA moiety as described herein in combination with an antiparasitic agent.Such agents include, but are not limited to, thiabendazole, pyrantel pamoate, mebendazole, praziquantel, niclosamide, bithionol, oxamniquine, metrifonate, ivermectin, albendazole, eflornithine, melarsoprol, pentamidine, benznidazole, nifurtimox, and nitroimidazole.Those skilled in the art will recognize other agents that may find utility in treating parasitic disorders.

[0206] Antibacterial agents The present invention contemplates compositions comprising at least one SCFA or compound comprising an SCFA moiety as described herein in combination with an agent useful for treating or preventing bacterial disorders. Antibacterial agents can be classified in a variety of ways, including based on mechanism of action, based on chemical structure, and based on spectrum of activity. Examples of antibacterial agents include those that target bacterial cell walls (e.g., cephalosporins and penicillins) or cell membranes (e.g., polymyxins) or interfere with essential bacterial enzymes (e.g., sulfonamides, rifamycins, and quinolines). Most antibacterial agents that target protein synthesis (e.g., tetracyclines and macrolides) are bacteriostatic, while agents such as aminoglycosides are bactericidal. Another means of classifying antibacterial agents is based on target specificity, with "narrow spectrum" agents targeting certain types of bacteria (e.g., gram-positive bacteria such as Streptococcus) and "broad spectrum" agents having activity against a broader range of bacteria. Those of skill in the art will recognize the types of antibacterial agents that are appropriate for use in particular bacterial infections.

[0207] Treatment One aspect of the present invention relates to a treatment regimen for treating or preventing a disease or disorder using the composition of the present invention.The administration of the composition of the present invention to a subject can be carried out using known procedures at a dosage and for a period of time effective to treat or prevent the disease or disorder of the subject.The effective amount of the therapeutic compound required to achieve a therapeutic effect can vary depending on factors such as the state of the disease or disorder of the subject, the age, sex, weight of the subject, etc.

[0208] The dosing regimen may affect what constitutes an effective amount. Furthermore, the dosage of the composition may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. A non-limiting example of an effective dose range for the therapeutic compounds of the present invention is about 1 to about 5,000 mg / kg body weight / day. An effective dose may be 1 μg to 10 mg active ingredient / kg body weight / hour, and may be 20 μg to 10 mg ingredient / kg body weight / hour. The therapeutic compound may be administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days. The number of doses for effective treatment may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10.

[0209] One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0210] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to provide an effective amount of the active ingredient to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.

[0211] In particular, the selected dosage level will depend on a variety of factors, including the activity of the particular compound used, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and similar factors well known in the medical arts.

[0212] A medical practitioner, e.g., a physician or veterinarian, having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start the dosage of the compound of the invention used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0213] The composition of the present invention for administration may be administered in the following dosage amounts: about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about 40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg to about 7,500 mg, about 200 μg to about 7,000 mg, about 3050 μg to about 6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000 mg, about 1 mg to about 3,000 mg, about 2 mg to about 4,000 mg, about 1 mg to about 5,000 mg, about 2 mg to about 5,000 mg, about 3 mg to about 6,000 mg, about 4 mg to about 7,000 mg, about 5 mg to about 8,000 mg, about 6 mg to about 9,000 mg, about 7 mg to about 9,000 mg, about 8 mg to about 10,000 mg, about 9 mg to about 12,000 mg, about 15 mg to about 16,000 mg, about 16 mg to about 18,000 mg, about 17 mg to about 19,000 mg, about 20 mg to about 22,000 mg, about 25 mg to about 26,000 mg, about 26 mg to about 28,000 mg, about 27 mg to about 30,000 mg, about 28 mg to about 32,000 mg, about 29 mg to about 40,000 mg, about 32 mg to about 42,000 mg, about 33 mg to about 44,000 mg, about 34 mg to about 46,0 The range may be from about 0 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 50 mg to about 1,000 mg, about 75 mg to about 900 mg, about 100 mg to about 800 mg, about 250 mg to about 750 mg, about 300 mg to about 600 mg, about 400 mg to about 500 mg, and all whole and partial increments therebetween.

[0214] In some embodiments, the dosage of the compound of the present invention used in the compositions described herein is less than about 1 mg to about 2,500 mg. In some embodiments, the dosage of the compound of the present invention used in the compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and all whole and partial increments therebetween.

[0215] In one embodiment, the treatment regimen comprises daily administration of the composition of the present invention. In one embodiment, the treatment regimen comprises administering short chain fatty acids at least once a day for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 7 days, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year or more. In one embodiment, the treatment regimen comprises administering short chain fatty acids three times a day for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 7 days, at least 10 days, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year or more. In one embodiment, the treatment regimen comprises administering a composition comprising short chain fatty acids, short chain fatty acid precursors, short chain fatty acid biosynthetic precursors, or combinations thereof at least once a day at the onset of the disease or disorder.

[0216] In one embodiment, the treatment regimen comprises daily oral administration of short chain fatty acid. In an exemplary embodiment, 600mg butyrate is administered three times a day (total 1800mg / day) for at least one week. In one embodiment, the treatment regimen comprises oral administration of two butyrate capsules containing 600mg butyrate three times a day (total 3600mg / day) for at least one week. In one embodiment, the treatment regimen comprises oral administration of two butyrate capsules containing 600mg butyrate three times a day (total 3600mg / day) for at least one week, followed by oral administration of two butyrate capsules containing 600mg butyrate three times a day (total 1800mg / day) for at least one week.

[0217] As described herein, administering the composition of the present invention to an individual can induce tolerance, strengthen the integrity of the intestinal barrier, and reduce inflammation in the individual. The method includes administering the composition described herein to the individual. In some embodiments, the composition includes one or more SCFAs or SCFA derivatives. The composition is administered to the individual in an amount sufficient to produce the desired effect of inducing tolerance, strengthening the intestinal barrier, and reducing inflammation. It can be administered to an individual in need of treatment, reduction of severity, or prevention of at least one disease selected from an autoimmune disease, an inflammatory disease, an allergic disease, or an infectious disease.

[0218] Whether administration of the composition induces tolerance can be determined by using as an indicator an increase or enhancement of at least one of the following: the number of regulatory T cells (Treg), the proportion of Treg in the colonic T cell population, the function of Treg, or the expression of a marker of Treg. Particular approaches are measuring counts or percentages of Foxp3 expressing Treg in a patient sample such as a biopsy or blood sample, promoting (enhancing) IL-10 expression, promoting (enhancing) CTLA4 expression, promoting (enhancing) IDO expression, or suppressing IL-4 expression as an indicator of induction of proliferation or accumulation of regulatory T cells. Whether administration of the composition enhances barrier function can be determined by using as an indicator an increase in the production of active TGF-β and / or tight junction associated proteins by intestinal epithelial cells. Whether administration of the composition reduces inflammation can be determined by using as an indicator an increase in the production of anti-inflammatory cytokines such as IL-10 and / or TGF-β, or a decrease in the production of pro-inflammatory cytokines such as IL-4.

[0219] Methods for detecting such expression include Northern blots, RT-PCR, and dot blots for detecting gene expression at the transcriptional level; ELISA, radioimmunoassays, immunoblots, immunoprecipitation, and flow cytometry for detecting gene expression at the translational level. Samples that can be used to measure such indicators include tissues and body fluids obtained from an individual, such as blood, biopsy, or fecal samples.

[0220] Pharmaceutical Compositions The present invention includes pharmaceutical compositions comprising one or more compositions of the present invention.The formulation of pharmaceutical compositions described herein can be prepared by any method known or hereafter developed in the field of pharmacology.In general, such preparation methods include combining active ingredient with carrier or one or more other accessory ingredients, and then, if necessary or desired, shaping or packaging the product into desired single or multiple dose units.

[0221] The compositions may contain additional medicinal agents, pharmaceutical agents, carriers, buffers, adjuvants, dispersing agents, diluents, etc. depending on the intended use and application.

[0222] Examples of suitable pharmaceutical carriers, excipients and / or diluents are well known in the art and include, but are not limited to, gums, starches (e.g., corn starch, pregelatinized starch), sugars (e.g., lactose, mannitol, sucrose, dextrose), cellulosic materials (e.g., microcrystalline cellulose), acrylates (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc or mixtures thereof.

[0223] Pharmaceutically acceptable carriers for liquid preparations are aqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethylene glycol and injectable organic esters, such as ethyl oleate.Examples of oils are those of animal origin, vegetable origin or synthetic origin, such as peanut oil, soybean oil, olive oil, sunflower oil, turmeric oil, fish liver oil, other marine oils, or fats derived from milk or eggs.

[0224] Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media such as phosphate buffered saline solutions, water, emulsions such as oil / water emulsions, various types of wetting agents, sterile solutions, and the like. Compositions containing such carriers can be formulated by well-known conventional methods. Suitable carriers may include any material that retains biological activity when combined with the biologically active compounds of the present invention. Preparations for parenteral administration may include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles may include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles may include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present including, for example, antimicrobials, antioxidants, chelating agents, and inert gases and the like, and in addition, the pharmaceutical composition of the invention may include a proteinaceous carrier such as, for example, serum albumin or immunoglobulin.

[0225] The pharmaceutical compositions provided herein may also be administered as controlled release compositions, i.e., compositions in which the active ingredient is released over a period of time after administration. Controlled release or sustained release compositions include formulations in lipophilic depots (e.g., fatty acids, waxes, oils). In another embodiment, the composition is an immediate release composition, i.e., compositions in which all active ingredients are released immediately after administration.

[0226] Furthermore, the pharmaceutical composition according to the present invention and described herein in various embodiments, or a composition comprising said compound, may be administered by mixing it into food, functional food, beverages, medical foods.

[0227] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for ethical administration to humans, those skilled in the art will appreciate that such compositions are generally suitable for administration to all kinds of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make the compositions suitable for administration to various animals are well understood, and an ordinary veterinary pharmacologist can design and perform such modifications, if necessary, with no more than routine experimentation. Subjects contemplated for administration of the pharmaceutical compositions of the present invention include, but are not limited to, humans and other primates, mammals, including commercially relevant mammals, such as non-human primates, cows, pigs, horses, sheep, cats and dogs, non-mammals, and other veterinary uses.

[0228] Pharmaceutical compositions useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for ophthalmic, oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, intratumoral, epidural, intracerebral, intraventricular, or another route of administration. Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunological-based preparations.

[0229] The pharmaceutical composition of the present invention can be prepared, packaged or sold in bulk, as a single unit dose, or as a plurality of single unit doses.As used herein, a "unit dose" is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient.The amount of active ingredient is generally equal to the dosage of active ingredient administered to a subject, or a convenient fraction of such a dosage, such as 1 / 2 or 1 / 3 of such a dosage.

[0230] The relative amounts of active ingredient, pharma- ceutically acceptable carrier and any additional ingredients in a pharmaceutical composition of the invention will vary depending on the identity, size and condition of the subject being treated, as well as the route by which the composition is to be administered. By way of example, the composition may contain from 0.1% to 100% (w / w) active ingredient.

[0231] In addition to the active ingredient, the pharmaceutical compositions of the present invention may further comprise one or more additional pharma- ceutical active agents.

[0232] Controlled or sustained release formulations of the pharmaceutical compositions of the invention can be made using conventional techniques.

[0233] Pharmaceutical compositions also include nutritional compositions, such as oral nutritional compositions, for oral ingestion and optionally for enteral absorption, which nutritional compositions comprise a compound of the invention. Thus, in one embodiment, the present invention relates to a nutritional supplement composition.

[0234] When the nutritional composition is formulated and administered orally, the composition can be a liquid oral nutritional supplement (e.g., an incomplete nutritional supplement) or a complete nutritional supplement. Thus, the nutritional composition can be administered in any known form, including, for example, tablets, capsules, liquids, chewables, soft gels, sachets, powders, syrups, liquid suspensions, emulsions, infant formulas, and solutions in a convenient dosage form.

[0235] A nutritional formulation includes any nutritionally complete or supplemental formulation (e.g., nutritional supplement). As used herein, "nutritionally complete" is preferably a nutritional product that contains sufficient variety and levels of macronutrients (protein, fat and carbohydrate) and sufficient micronutrients to be the sole source of nutrition for the subject to which it is administered. A patient may obtain 100% of their nutritional requirements from such a complete nutritional composition. According to one embodiment, the nutritional formulation is a supplemental formulation that provides supplemental nutrients. A "supplemental formulation" may not be nutritionally complete, but preferably contains specific nutrients that are supportive and / or address specific or additional needs of a subject in combination with, for example, physical exercise, and the beneficial effects of the present invention.

[0236] The nutritional formulation may be a generally applicable nutritional formulation, such as one adapted for a subject of a certain age, for example a formulation for children, but it may also be, for example, a formulation for elderly patients, a formulation for intensive care patients or a formulation specially adapted for patients suffering from a certain disease. Any nutritional formulation may, for example, be reconstitutable, i.e. present in a substantially dry state, for example in powder form, or ready-to-drink in the form of a liquid formulation.

[0237] A formulation of a pharmaceutical composition suitable for parenteral administration comprises the active ingredient in combination with a pharma- ceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as ampoules, or multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional components, including, but not limited to, suspending agents, stabilizing agents, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in a dry (i.e., powder or granule) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0238] The pharmaceutical composition may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. The suspension or solution may be formulated according to known techniques and may contain, in addition to the active ingredient, additional ingredients, such as dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable preparations may be prepared, for example, using a non-toxic parenterally acceptable diluent or solvent, such as water or 1,3-butanediol. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils, such as synthetic mono- or diglycerides. Other parenterally administrable preparations that are useful include those that include the compound in microcrystalline form, in liposomal preparations, or as a component of biodegradable polymer systems. Compositions for sustained release or implantation may include pharma-ceutically acceptable polymeric or hydrophobic materials, such as emulsions, ion exchange resins, poorly soluble polymers, or poorly soluble salts.

[0239] The compositions of the present invention described herein may be used as a complete food, as a food ingredient, as a dietary supplement or part of a dietary supplement, as a feed additive, and may be in liquid, semi-solid, or solid form.The compositions of the present invention described herein may also be in the form of a pharmaceutical composition.The compositions, dietary supplements, foods, baby food products, feed additives, and / or pharmaceutical compositions of the present invention may be advantageously utilized in methods for promoting the health of individuals.

[0240] As indicated above, the composition may be in liquid, semi-solid, or solid form. For example, the composition may be administered as a tablet, gel pack, capsule, gelatin capsule, flavored drink, powder that can be reconstituted into such drink, cooking oil, salad oil or dressing, sauce, syrup, mayonnaise, margarine, etc. Furthermore, the food products, dietary supplements, etc. of the present invention include, but are not limited to, dairy products, infant foods, infant formulas, beverages, bars, powders, food toppings, drinks, cereals, ice cream, candies, snack mixes, baked foods, and fried foods. The beverages of the present invention include, but are not limited to, energy drinks, nutritional drinks, smoothies, sports drinks, orange juice, and other fruit drinks. The bars of the present invention include, but are not limited to, meal replacements, nutritional bars, snack bars, energy bars, extruded bars, etc. The dairy products of the present invention include, but are not limited to, yogurt, yogurt drinks, cheese, and milk.

[0241] The food or dietary supplement of the present invention may further comprise herbs, herbal extracts, fungal extracts, enzymes, fiber sources, minerals, and vitamins. The microalgal oil and microalgal biomass of the present invention may be used in the compositions of the present invention for both therapeutic and non-therapeutic uses. Thus, the compositions, food and animal feed additives of the present invention may be used for therapeutic or non-therapeutic purposes.

[0242] Compositions intended for oral administration can be prepared according to any known method for the manufacture of dietary supplements or pharmaceutical preparations, and such compositions can contain at least one additive selected from the group consisting of taste-improving substances such as sweeteners or flavorings, stabilizers, emulsifiers, colorants and preservatives, in order to provide a nutritionally or pharma-ceutical palatable preparation. Vitamins, minerals and trace elements from physiologically acceptable sources can also be included in the compositions of the present invention.

[0243] The pharmaceutical composition of the present invention comprises a therapeutically effective amount of the composition of the present invention. The composition may further comprise a prescription or non-prescription drug. The combination may advantageously produce one or more of the following effects: (1) additive and / or synergistic effects; (2) reduction of side effects and / or adverse effects associated with the use of the prescription drug in the absence of the formulation; and / or (3) the ability to reduce the dosage of the prescription drug compared to the amount of the prescription drug required in the absence of the formulation.

[0244] The active agents of the present invention can be prepared in the form of their pharmaceutically acceptable salts. As understood by those skilled in the art, pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. As defined herein, "pharmaceutically acceptable salts" include derivatives of the disclosed SCFAs or compounds containing SCFA moieties, where the parent compound is modified by making non-toxic salts of its carboxylate group, and further refers to pharmaceutically acceptable hydrates and solvates of such compounds. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the carboxylic acid group of SCFAs. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and those derived from acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxylmaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) nSalts prepared from organic acids such as -COOH (n is 0-4) are included. Further lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985). In some embodiments, the SCFA can be present as an ester of the carboxylic acid of the SCFA with a branched or unbranched alkyl alcohol having 1 to 6 carbon atoms. For example, the SCFA can be present as an ethyl ester, propyl ester, butyl ester, isopropyl ester, t-butyl ester, pentyl ester, or hexyl ester.

[0245] The active agent can be formulated for administration according to known pharmaceutical techniques. See, for example, Remington, The Science And Practice of Pharmacy (9th Ed. 1995). In preparing a pharmaceutical composition according to the invention, the active agent (including its physiologically acceptable salts) is typically mixed with, inter alia, an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and not deleterious to the subject. The carrier can be solid or liquid, or both, and can be formulated with the active agent as a unit dose formulation, e.g., a tablet, which can contain 0.01% or 0.5% to 95% or 99%, or any value between 0.01% and 99%, by weight of the active agent. One or more active agents can be incorporated into the compositions of the invention, which can be prepared by any well-known technique of pharmacy, including mixing the ingredients, optionally with one or more accessory ingredients. Moreover, as noted herein above, the carrier can be free of preservatives.

[0246] In some embodiments, the active agent is present in an amount ranging from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10% by weight of the composition to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 10 In some embodiments, the active agent comprises from about 0.05% to greater than about 99% by weight of the composition.

[0247] Pharmaceutical compositions according to embodiments of the invention will generally be formulated for oral or topical (i.e., to the skin, eyes and mucosal surfaces) administration, by the most appropriate route in any given case, depending on the nature and severity of the condition being treated and the nature of the particular active agent being used.

[0248] Topical preparations The pharmaceutical compositions containing the compositions and compounds of the present invention may be administered topically, and therefore may be formulated in a form suitable for topical administration, i.e., as a pH-balanced cream preparation. An obstacle to topical administration of pharmaceuticals is the stratum corneum of the epidermis. The stratum corneum is a highly resistant layer composed of proteins, cholesterol, sphingolipids, free fatty acids, and various other lipids, and contains keratinized cells and living cells. One of the factors that limits the penetration rate (flux) of compounds through the stratum corneum is the amount of active that can be loaded or applied to the skin surface. The more active that is applied per unit area of ​​skin, the greater the concentration gradient between the skin surface and the lower layers of the skin, resulting in a greater diffusion force of the active through the skin. Thus, a formulation containing a higher concentration of active, all other things being equal, is more likely to penetrate the active through the skin, penetrates more active, and penetrates at a more consistent rate, than a formulation with a lower concentration.

[0249] Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid formulations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments, pastes, and solutions or suspensions. Furthermore, formulations suitable for topical administration can be in the form of creams and liquids, including, for example, syrups, suspensions or emulsions, inhalants, sprays, mousses, oils, gels, solids, and the like. Topically administrable formulations contain, for example, about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further include one or more additional ingredients as described herein.

[0250] Penetration enhancers may be used. These materials increase the rate of penetration of drugs into the skin. Typical enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide, etc. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkane carboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone.

[0251] One acceptable vehicle for topical delivery of some compositions of the invention may contain liposomes, the composition of which and their use are known in the art (see, e.g., U.S. Pat. No. 6,323,219).

[0252] In another embodiment, the topically active pharmaceutical composition may be optionally combined with other ingredients, such as adjuvants, antioxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifiers, thickening agents, buffers, preservatives, etc. In another embodiment, a penetration or penetration enhancer is included in the composition and is effective to improve the transdermal penetration of the active ingredient into and through the stratum corneum relative to a composition lacking the penetration enhancer. Various penetration enhancers are known to those skilled in the art, including oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkane carboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone. In another aspect, the composition may further include a hydrotropic agent, which functions to increase the disorder in the structure of the stratum corneum, thus increasing the transport across the stratum corneum. Various hydrotropic agents are known to those skilled in the art, such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate.

[0253] Topically active pharmaceutical compositions should be applied in an amount effective to affect the desired change. As used herein, "effective amount" shall mean an amount sufficient to cover the area of ​​the skin surface where the change is desired. In various embodiments, the active compound may be present in an amount of about 0.0001% to about 15% by weight of the composition, about 0.0005% to about 5% of the composition, or about 0.001% to about 1% of the composition. Such compounds may be of synthetic or natural origin.

[0254] Oral Formulations The pharmaceutical compositions of the present invention and the compounds can be administered orally, and therefore can be formulated in a form suitable for oral administration, i.e., as solid or liquid preparations.Suitable solid oral formulations include tablets, capsules, pills, granules, pellets, etc.Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils, etc.When formulated in capsule form, the compositions of the present invention include a hard gelling capsule in addition to the active compound and inert carrier or diluent.In one embodiment, the formulation for oral administration is an enteric coated sustained release capsule.

[0255] Formulations suitable for oral administration can be provided in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; such as powders or granules; such as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. Such formulations can be prepared by any suitable pharmaceutical method, including bringing into association the active compound with a suitable carrier, which may include one or more accessory ingredients as described above. In general, the formulations of the present invention are prepared by uniformly and intimately mixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, molding the resulting mixture. For example, a tablet can be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, and / or surfactant / dispersant. Molded tablets can be made by molding the powdered compound moistened with an inert liquid binder in a suitable machine.

[0256] Formulations for other routes of administration The compositions of the present invention and pharmaceutical compositions containing the compounds may further be administered intranasally, i.e., by inhalation, and thus may be formulated in a form suitable for intranasal administration, i.e., as an aerosol or liquid preparation.

[0257] The compositions of the present invention may also be formulated, for example, for parenteral administration. A formulation of a pharmaceutical composition suitable for parenteral administration comprises the active ingredient combined with a pharma- ceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as ampoules, or multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional components, including, but not limited to, suspending agents, stabilizing agents, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in a dry (i.e., powder or granule) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0258] The pharmaceutical composition may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. The suspension or solution may be formulated according to known techniques and may contain, in addition to the active ingredient, additional ingredients, such as dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable preparations may be prepared, for example, using a non-toxic parenterally acceptable diluent or solvent, such as water or 1,3-butanediol. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils, such as synthetic mono- or diglycerides. Other parenterally administrable formulations that are useful include those that contain the active ingredient in microcrystalline form, in liposomal preparations, or as components of biodegradable polymer systems. Compositions for sustained release or implantation may include pharma-ceutically acceptable polymeric or hydrophobic materials, such as emulsions, ion exchange resins, poorly soluble polymers, or poorly soluble salts.

[0259] The formulation is prepared using a pharma- ceutically acceptable "carrier" composed of materials deemed safe and effective, and may be administered to an individual without causing undesired biological side effects or undesired interactions. A "carrier" is any component present in a pharmaceutical formulation other than the active ingredient or ingredients. The term "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers, and coating compositions. A "carrier" also includes any component of a coating composition, which may include plasticizers, pigments, colorants, stabilizers, and lubricants. Delayed release dosage formulations may be prepared as described in references such as "Pharmaceutical dosage form tablets", eds. Liberman et.al. (New York, Marcel Dekker, Inc., 1989), "Remington--The science and practice of pharmacy", 20th ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000, and "Pharmaceutical dosage forms and drug delivery systems", 6th Edition, Ansel et.al., (Media, Pa.: Williams and Wilkins, 1995), which provide information on carriers, materials, equipment, and processes for preparing tablets and capsules, as well as delayed release dosage forms of tablets, capsules, and granules.

[0260] Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalates, acrylic acid polymers and copolymers, and methacrylic resins commercially available under the trade name Eudragit® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.

[0261] Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, lubricants, stabilizers, pore formers, and surfactants.

[0262] Optional pharma- ceutically acceptable excipients present in drug-containing tablets, beads, granules, or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also called "fillers," are typically required to increase the bulk of solid dosage forms to provide a practical size for tablet compression or bead and granule formation. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pregelatinized starch, silicon dioxide, titanium dioxide, magnesium aluminum silicate, and powdered sugar.

[0263] Binders are used to impart cohesiveness to solid dosage forms, thus ensuring that the tablets or beads or granules remain intact after formation of the dosage form. Examples of suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, celluloses (including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose) and veegum, and synthetic polymers such as acrylic and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid and polyvinylpyrrolidone.

[0264] Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.

[0265] Disintegrants are used to facilitate the disintegration or "break-up" of the dosage form after administration and commonly include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clay, cellulose, arginine, gums, or cross-linked polymers such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp).

[0266] Stabilizers are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions.

[0267] The surfactant may be anionic, cationic, amphoteric or nonionic surfactant. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium long chain alkyl and alkylaryl sulfonates such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-beta-alanine, sodium N-lauryl-beta-iminodipropionate, myristamphoacetate, lauryl betaine, and lauryl sulfobetaine.

[0268] If desired, the tablets, granules, or particles of beads may contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, and preservatives.

[0269] As will be appreciated by those skilled in the art, and as described in the relevant documents and literature, many methods are available for preparing drug-containing tablets, beads, granules or particles that provide various drug release profiles, including, but not limited to, coating the drug or drug-containing composition with a suitable coating material (typically but not necessarily incorporating a polymeric material), increasing the drug particle size, placing the drug within a matrix, and forming a complex of the drug with a suitable complexing agent.

[0270] The delayed release dosage units may be coated with a delayed release polymer coating using conventional techniques, such as conventional coating pans, airless spray techniques, fluidized bed coating equipment (with or without a Wurster insert), etc. Detailed information regarding materials, equipment, and processes for preparing tablets and delayed release dosage forms can be found in Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6 th Ed. (Media, Pa.: Williams & Wilkins, 1995).

[0271] An exemplary method for preparing a sustained release tablet is by compressing a drug-containing mixture, for example, a mixture of granules prepared using a direct blend, wet granulation, or dry granulation process. A sustained release tablet may also be molded rather than compressed, starting with a wet material containing a suitable water-soluble lubricant. However, tablets are manufactured using compression rather than molding. A method for forming a sustained release drug-containing mixture is to directly mix drug particles with one or more excipients, such as diluents (or fillers), binders, disintegrants, lubricants, glidants, and colorants. As an alternative to direct blending, a wet granulation or dry granulation process may be used to prepare the drug-containing mixture. Beads containing an active agent may also be prepared by any one of many conventional techniques, typically starting from a dispersion. For example, a typical method for preparing drug-containing beads involves dispersing or dissolving an active agent in a coating suspension or solution containing pharmaceutical excipients, such as polyvinylpyrrolidone, methylcellulose, talc, metal stearates, silicon dioxide, plasticizers, and the like. The mixture is used to coat bead cores such as sugar spheres (or so-called "nonpareils") having a size of approximately 60-20 mesh.

[0272] An alternative procedure for preparing drug beads is by mixing the drug with one or more pharma- ceutically acceptable excipients such as microcrystalline cellulose, lactose, cellulose, polyvinylpyrrolidone, talc, magnesium stearate, disintegrants, etc., extruding the mixture, spheronizing the extrudate, drying, and optionally coating to form immediate release beads.

[0273] Delayed release formulations are made by coating a solid dosage form with a film of a polymer that is insoluble in the acidic environment of the stomach and soluble in the neutral environment of the small intestine. Delayed release dosage units can be prepared, for example, by coating a drug or drug-containing composition with a selected coating material. The drug-containing composition can be, for example, a tablet for incorporation into a capsule, a tablet for use as the inner core of a "coated core" dosage form, or a plurality of drug-containing beads, particles, or granules for incorporation into a tablet or capsule. Exemplary coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and / or enzymatically degradable polymers, which may be conventional "enteric" polymers. Enteric polymers, as understood by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly the colon.Examples of suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, and sodium carboxymethyl cellulose; Acrylic acid polymers and copolymers formed from ethyl, methyl and / or ethyl methacrylate, as well as acrylic acid polymers and copolymers sold under the trade names Eudragit® (Rohm), including Eudragit® L30D-55 and L100-55 (soluble at pH 5.5 and above), Eudragit® L-100 (soluble at pH 6.0 and above), Eudragit® S (soluble at pH 7.0 and above as a result of a high degree of esterification), and Eudragits® NE, RL and RS (water-insoluble polymers with different degrees of permeability and swelling). Other methacrylic resins available from Pharma; Westerstadt, Germany; vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azopolymers, pectin, chitosan, amylose, and guar gum; zein and shellac. Combinations of different coating materials may be used. Multi-layer coatings using different polymers may also be applied.

[0274] The coating composition may include conventional additives such as plasticizers, pigments, colorants, stabilizers, and lubricants. Plasticizers are usually present to reduce the brittleness of the coating and generally represent about 10% to 50% by weight of the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, castor oil, and acetylated monoglycerides. Stabilizers are used to stabilize the particles in the dispersion. Typical stabilizers are nonionic emulsifiers such as sorbitan esters, polysorbates, and polyvinylpyrrolidone. Glidants are recommended to reduce the sticking effect during film formation and drying and generally represent about 25% to 100% by weight of the polymer weight in the coating solution. One effective lubricant is talc. Other lubricants such as magnesium stearate and glycerol monostearate may also be used. Pigments such as titanium dioxide may also be used. Small amounts of anti-foaming agents such as silicones (e.g., simethicone) may also be added to the coating composition.

[0275] The particles can be prepared entirely from the therapeutic agent or from a combination of the therapeutic agent and a surfactant. The particles can be made of a variety of materials. Both inorganic and organic materials can be used. For example, ceramics may be used. Aerodynamically light particles can be formed using polymeric materials and non-polymeric materials such as fatty acids. Other suitable materials include, but are not limited to, gelatin, polyethylene glycol, trehalose, and dextran. Particles can be designed and manufactured with degradation and release times ranging from seconds to months, based on factors such as the particle material.

[0276] In addition to the therapeutic or diagnostic agent (or possibly other desired molecules for delivery), the particles may contain excipients, such as sugars, such as lactose, proteins, such as albumin, and / or surfactants.

[0277] Enteric Capsules: As used herein, "gastric resistant natural polymer" refers to a natural polymer or mixture of natural polymers that is insoluble in the acidic pH of the stomach. As used herein, "film-forming natural polymer" refers to a polymer that is useful for surface coatings that undergo film formation, spraying, brushing, or applied by various industrial processes. In most film-forming processes, a relatively low viscosity liquid coating is applied to a solid substrate and cured to become a solid high molecular weight polymer-based adhesive film that has the properties desired by the user. In most common applications, this film has a thickness of 0.5 to 500 micrometers (0.0005 to 0.5 millimeters, or 0.00002 to 0.02 inches).

[0278] As used herein, "gelling agent" refers to a material that undergoes a high degree of cross-linking or association when hydrated and dispersed in a dispersion medium or when dissolved in a dispersion medium. This cross-linking or association of the dispersed phase changes the viscosity of the dispersion medium. The movement of the dispersion medium is restricted by the dispersed phase, increasing the viscosity.

[0279] Described herein is a gastro-resistant film-forming composition that contains (1) a gastro-resistant natural polymer; (2) a film-forming natural polymer; and, optionally, (3) a gelling agent. Exemplary gastro-resistant natural polymers include, but are not limited to, pectins and pectin-like polymers, which are typically composed primarily of galacturonic acid and galacturonic acid methyl ester units that form linear polysaccharide chains. Typically, these polysaccharides are rich in galacturonic acid, rhamnose, arabinose, and galactose, such as polygalacturonan, rhamnogalacturonan, and some arabinans, galactans, and arabinogalactans. They are usually classified according to the degree of esterification. In high (methyl) ester ("HM") pectins, a relatively large proportion of the carboxyl groups occur as methyl esters, with the remaining carboxylic acid groups in the form of free acids or as their ammonium, potassium, calcium, or sodium salts. Useful properties may vary depending on the degree of esterification and the degree of polymerization. Pectins in which less than 50% of the carboxylic acid units occur as methyl esters are usually referred to as low (methyl) ester or LM-pectins. Generally, low ester pectins are obtained from high ester pectins by treatment with mildly acidic or alkaline conditions. When ammonia is used in an alkaline deesterification process, amidated pectins are obtained from high ester pectins. In this type of pectin, some of the remaining carboxylic acid groups have been converted to acid amides. The useful properties of amidated pectins may vary depending on the ratio of ester and amide units and the degree of polymerization. In one embodiment, the gastro-resistant natural polymer is pectin. The gastro-resistant natural polymer is present in an amount of less than about 5% by weight of the composition, for example, about 2 to about 4% by weight of the composition.

[0280] Exemplary film-forming natural polymers include, but are not limited to, gelatin and gelatin-like polymers. In an exemplary embodiment, the film-forming natural polymer is gelatin. Many other gelatin-like polymers are commercially available. The film-forming natural polymer is present in an amount of about 20% to about 40% by weight of the composition, for example, about 25% to about 40% by weight of the composition.

[0281] The composition may optionally contain a gelling agent. Exemplary gelling agents include Ca 2+ and Mg 2+ Sources of these ions include inorganic calcium and magnesium salts, and calcium gelatin. The gelling agent is present in an amount of less than about 2% by weight of the composition, for example, less than about 1% by weight of the composition.

[0282] One or more plasticizers may be added to the composition to facilitate the film-forming process. Suitable plasticizers include glycerin, sorbitol, sorbitan, maltitol, glycerol, polyethylene glycol, polyalcohols having 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate, and combinations thereof. The concentration of the one or more plasticizers is about 8% to about 30% by weight of the composition. In one embodiment, the plasticizer is glycerin and / or sorbitol.

[0283] The film-forming compositions can be used to prepare soft or hard shell gelatin capsules that can encapsulate a liquid or semi-solid fill material or a solid tablet (Softlet®) containing the active agent and one or more pharma- ceutically acceptable excipients. Alternatively, the compositions can be administered as a liquid with the active agent dissolved or dispersed in the composition.

[0284] The film-forming composition can be used to prepare soft or hard capsules using techniques well known in the art. For example, soft capsules are typically produced using a rotary die encapsulation process. The fill formulation is fed into the encapsulation machine by gravity.

[0285] The capsule shell may comprise one or more plasticizers selected from the group consisting of glycerin, sorbitol, sorbitan, maltitol, glycerol, polyethylene glycol, polyalcohols having 3 to 6 carbon atoms, citric acid, citrate esters, triethyl citrate, and combinations thereof.

[0286] In addition to plasticizers, the capsule shell may contain other suitable shell additives, such as opacifiers, colorants, humectants, preservatives, flavors, buffer salts, and acids.

[0287] If the encapsulated active agent is light sensitive, an opacifying agent is used to opacify the capsule shell. Suitable opacifying agents include titanium dioxide, zinc oxide, calcium carbonate, and combinations thereof.

[0288] Colorants can be used for marketing and product identification / differentiation purposes. Suitable colorants include synthetic and natural dyes and combinations thereof.

[0289] Humectants can be used to reduce the water activity of the softgel. Suitable humectants include glycerin and sorbitol, which are often components of plasticizer compositions. Properly stored dry softgels have low water activity, so the greatest microbial risk comes from molds and yeasts. For this reason, preservatives can be incorporated into the capsule shell. Suitable preservatives include alkyl esters of p-hydroxybenzoic acid, such as methyl, ethyl, propyl, butyl, and heptyl (collectively known as "parabens"), or combinations thereof.

[0290] Flavoring agents can be used to mask unpleasant odors and tastes of fill formulations.Suitable flavoring agents include synthetic flavoring agents and natural flavoring agents.The use of flavoring agents can be problematic due to the presence of aldehydes that can crosslink gelatin.As a result, buffer salts and acids can be used in combination with flavoring agents that contain aldehydes to inhibit gelatin crosslinking.

[0291] Soft or hard capsules can be used to deliver a variety of pharma- ceutically active agents. Suitable agents include small molecules, proteins, nucleic acids, carbohydrates, lipids, and whole organisms.

[0292] The fill formulation may be prepared using a pharma- ceutically acceptable "carrier" that is composed of a material that is deemed safe and effective, and can be administered to an individual without causing undesirable biological side effects or undesirable interactions. A carrier is any component present in a pharmaceutical formulation other than the active ingredient or ingredients. As generally used herein, "carrier" includes, but is not limited to, surfactants, humectants, plasticizers, crystallization inhibitors, wetting agents, bulk fillers, solubilizers, bioavailability enhancers, pH adjusters, and combinations thereof.

[0293] Alternatively, the composition can be administered as a liquid in which the active agent is dissolved (e.g., a solution) or dispersed (e.g., a suspension) in the composition. Suitable active agents are described above. The solution or suspension can be prepared using one or more pharma- ceutically acceptable excipients. Suitable excipients include, but are not limited to, surfactants, humectants, plasticizers, crystallization inhibitors, wetting agents, bulk fillers, solubilizers, bioavailability enhancers, pH adjusters, flavoring agents, and combinations thereof.

[0294] Mucoadhesive Particles and Methods of Manufacture: In general, adhesion of polymers to tissues can be achieved by (i) physical or mechanical bonds, (ii) primary or covalent chemical bonds, and / or (iii) secondary chemical bonds (e.g., ionic). Physical or mechanical bonds can result from deposition and inclusion of adhesive materials in mucus crevices or mucosal folds. Secondary chemical bonds that contribute to bioadhesive properties consist of dispersion interactions (e.g., van der Waals interactions) and stronger specific interactions including hydrogen bonds. Hydrophilic functional groups involved in the formation of hydrogen bonds are hydroxyl groups (-OH) and carboxyl groups (-COOH).

[0295] The adhesive polymeric microspheres have been selected based on the physical and chemical bonds that are formed as a function of their chemical composition and physical properties, such as surface area, as described in detail below. These microspheres have a viscosity of 11 mN / cm 2These microspheres are characterized by adhesion to mucosa exceeding 100 μm. Sizes of these microspheres range from nanoparticles to 1 millimeter in diameter. Adhesion is a function of polymer composition, biomatrix, particle morphology, particle geometry (e.g., diameter), and surface modification.

[0296] Classes of polymers useful for forming bioadhesive microspheres: Suitable polymers that can be used to form bioadhesive microspheres include soluble and insoluble, biodegradable and non-biodegradable polymers. These can be natural or synthetic hydrogels or thermoplastics, homopolymers, copolymers or blends. However, the key feature is that the polymer must generate a bioadhesive interaction of 110 N / m2 (11 mN / cm2) to 100,000 N / m2 when applied to the mucosal surface of the rat intestine.

[0297] In order for bioadhesive particles to embed themselves in, or be phagocytosed by, the mucus lining the gastrointestinal tract, the radius of the individual particles must be similar in thickness to the native mucus layer. The thickness of the gastric mucosa layer has been shown to typically vary from 5 to 200 μm in rats and from 10 to 400 μm in humans. However, in some cases, the thickness can reach as much as 1000 μm in humans, as described in Spiro, RG, "Glycoproteins," Annual Review of Biochemistry, 39, 599-638, 1970; Labat-Robert, J. & Decaeus, C., "Glycoproteins du Mucus Gastrique: Structure, Function, et Pathologie," Pathologie et Biologie (Paris), 24, 241, 1979; Allen, A., Hutton, DA, Pearson, JP, & Sellers, LA, "Mucus Glycoprotein Structure, Gel Formation and Gastrointestinal Mucus Function" in Mucus and Mucosa, Ciba Foundation Symposium 109 (eds. J. Nugent & M. O'Connor), pp. 137 (London: Pitman, 1984). In the past, two classes of polymers appeared to exhibit useful bioadhesive properties: hydrophilic polymers and hydrogels. Within the large class of hydrophilic polymers, polymers containing carboxyl groups (e.g., poly[acrylic acid]) exhibit the best bioadhesive properties. One might speculate that polymers with the highest concentration of carboxyl groups would be the preferred materials for bioadhesion to soft tissue. In other studies, the most promising polymers were sodium alginate, carboxymethylcellulose, hydroxymethylcellulose, and methylcellulose. Some of these materials are water soluble, others are hydrogels.

[0298] Rapidly bioerodible polymers such as poly[lactide-co-glycolide], polyanhydrides, and polyorthoesters, whose carboxyl groups become exposed on the outer surface as their smooth surfaces erode, are excellent candidates for bioadhesive drug delivery systems. Furthermore, polymers containing labile bonds such as polyanhydrides and polyesters are well known for their hydrolytic reactivity. Their hydrolysis rates generally change with simple changes in the polymer backbone.

[0299] Representative natural polymers include proteins such as zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, polysaccharides such as cellulose, dextran, polyhyaluronic acid, polymers of acrylic and methacrylic acid esters, and alginic acid. Representative synthetic polymers include polyphosphazines, poly(vinyl alcohols), polyamides, polycarbonates, polyalkylenes, polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidones, polyglycolides, polysiloxanes, polyurethanes, and copolymers thereof. Synthetically modified natural polymers include alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and nitrocelluloses. Other polymers of interest include, but are not limited to, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethylcellulose, cellulose triacetate, sodium cellulose sulfate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl acetate), polyvinyl chloride, polystyrene, polyvinylpyrrolidone, and polyvinylphenol. Representative bioerodible polymers include polylactide, polyglycolide and copolymers thereof, poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), poly[lactide-co-glycolide], polyanhydrides, polyorthoesters, blends and copolymers thereof.

[0300] The pharma- ceutically acceptable compound of the present invention is typically administered to a subject in a daily dosing regimen. For an adult subject, this may be, for example, an oral dose of 0.1 grams to 15 grams of a compound comprising at least one SCFA or SCFA moiety. In a further embodiment, the oral dose of a compound comprising at least one SCFA or SCFA moiety may be 0.5 grams to 10 grams. In yet a further embodiment, the oral dose of a compound comprising at least one SCFA or SCFA moiety may be 0.5 grams to 6 grams.

[0301] Pharmaceutical compositions can be administered 1, 2, 3, 4 or more times per day. Thus, in certain embodiments, compositions formulated for topical administration, for example, can be administered multiple times each day.

[0302] In one embodiment, a composition comprising a 1:1 (w / w) ratio of a first and a second SCFA is contemplated, where the first SCFA may be present at 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 grams. In other embodiments, the ratio of the first and second SCFA may be 2:1, 3:1, 4:1, 5:1; 6:1, 7:1, 8:1, 9:1, or 10:1 (w / w), where the first SCFA may be present at 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 grams. Of course, the ratio of the first and second SCFA administered may be different from that disclosed herein above.For example, any amount of the first SCFA, including 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 grams of the first SCFA, may be administered with any amount of the second SCFA, including 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 grams of the second SCFA.These amounts of any supplements may be mixed in one composition or may be separate compositions.

[0303] kit The invention also includes kits comprising compounds useful in the methods of the invention and instructional materials, e.g., describing how to administer the compositions of the invention as described elsewhere herein, hi one embodiment, the kit comprises a composition of the invention. EXAMPLES

[0304] The present invention will be described in more detail with reference to the following examples.These examples are provided for illustrative purposes only and are not intended to be limiting unless otherwise specified.Therefore, the present invention should not be interpreted as being limited to the following examples in any way, but rather should be interpreted as embracing any and all variations that become evident as a result of the teachings provided herein.

[0305] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and use the present invention and practice the methods set forth in the claims. Thus, the following examples are not to be construed as limiting in any way the remainder of the disclosure.

[0306] Example 1: Treatment of skin disorders with short chain fatty acids Psoriasis is a chronic autoinflammatory disease that causes raised, red, scaly patches on the skin. It typically affects the outside of the elbows, knees, or scalp, but can appear anywhere. Some people report that psoriasis is itchy, burning, and stinging. Psoriasis is associated with other serious health conditions, such as diabetes, heart disease, and depression.

[0307] Current treatments for psoriasis include topical (creams, ointments, and phototherapy) and systemic (oral and injectable) therapies. Topical creams and ointments include corticosteroids (overuse can cause skin thinning and resistance), retinoids, anthralin (normalize skin cell growth) and vitamin D analogues (treatment with retinoids, anthralin or vitamin D analogues can irritate the skin), calcineurin inhibitors (interfere with T-cell activation and continued use is associated with an increased risk of skin cancer and lymphoma), as well as non-prescription moisturizers and salicylic acid.

[0308] Phototherapy (UV light) involves the use of ultraviolet A (UVA) or ultraviolet B (UVB) light alone or in combination with medications. Short-term side effects include nausea, headache, burning sensation, and itching. Long-term side effects include dry, wrinkly skin, freckling, and an increased risk of skin cancer, including melanoma.

[0309] Currently available systemic psoriasis treatments include the use of retinoids (side effects can include inflammation of the lips, hair loss, and severe birth defects; women must avoid pregnancy for at least three years after taking the drug); chemotherapy drugs such as methotrexate and cyclosporine (which can cause several severe side effects, including liver damage, reduced production of red and white blood cells and platelets, and increased risk of infections and cancer); and immunomodulatory drugs or biologics (which have a strong effect on the immune system and can tolerate life-threatening infections). The side effects and high toxicity of currently available treatments make them undesirable for many patients suffering from psoriasis.

[0310] SCFAs have never been used to treat any form of psoriasis. The main advantage of this approach is that it has little or no toxicity compared to other currently available treatments. SCFAs were administered orally up to three times a day for three weeks. The dosing schedule was one or two 600 mg butyrate tablets three times a day for seven days to four weeks, followed by one 600 mg butyrate tablet three times a day for several weeks to months. These treatments used sodium, magnesium, or calcium salts of butyric acid. When treatment was discontinued, the psoriatic skin lesions reappeared. When treatment was resumed, the lesions disappeared again. Pre- and post-treatment results of four individuals taking butyrate are shown in Figures 2-5. Individuals with psoriasis who took butyrate capsules orally for three to four weeks showed significant improvement or complete resolution of skin lesions.

[0311] For example, clinical trials can evaluate different combinations and dosing schedules of selected SCFAs in healthy individuals (Phase 1) and patients with psoriasis (Phase II).

[0312] For example, the toxicity of single or combination SCFAs will be evaluated in dose escalation studies to identify the level of toxicity and the tissues or organs affected. Pharmacokinetic (PK) studies will be performed in mice to optimize oral dosage for further preclinical testing. In the latter category, it will be important to determine whether the molecules thought to mediate psoriasis pathogenesis in previous mouse studies are the same pathways inhibited in mice treated with SCFAs. This study will use two mouse models of psoriasis. These preclinical studies will also be validated by previous human studies showing that the proinflammatory molecules targeted by SCFAs in mice with psoriasis are the same ones thought to mediate psoriasis in humans. This study will determine whether oral administration of SCFAs will resolve psoriatic lesions in mice. This will be as is the case in humans taking butyric acid orally. To optimize the dosage of the cream containing SCFAs, the cream will be applied to some lesions and not others in mice with psoriasis. If only the treated lesions are cured, the effect of SCFAs is local, whereas if application to some lesions results in the curing of all lesions, the effect of SCFAs may be mediated by systemic distribution. Depending on the results, parallel clinical trials will be performed in patients.

[0313] The materials and methods used in the experiments are described below.

[0314] Materials and Methods SCFA SCFAs consisting of sodium butyrate, magnesium butyrate, and calcium butyrate were purchased commercially and manufactured by BodyBio.

[0315] Treatment with SCFAs In all cases, no additional drugs for the treatment of psoriasis were used during the butyrate regimen.

[0316] Subjects with moderate to severe psoriasis were given 600 mg of butyrate orally three times daily for at least two weeks. Subjects with severe psoriasis were given 1200 mg of butyrate orally three times daily for three weeks, followed by 600 mg of butyrate orally three times daily for an extended period. Lesions were evaluated before and after treatment.

[0317] Next, the results of the experiment are described.

[0318] Figure 1 shows the signaling pathways affected by SCFAs. Among the proteins included in the figure, IL-18, TLR3, IFN-γ, TNFα, TGF-β, MyD88, PI3K / Akt, JAK / STAT, Smad2 / 3, Smad4, and IL-10 were found to be downregulated by SCFA treatment. The levels of IL-6, TRIF, PKR, TRAF2, TAK1, and TRAF6 were not evaluated in this study.

[0319] Figure 2 shows the results of a psoriasis patient receiving a butyrate treatment regimen. The treatment regimen used was one 600mg butyrate tablet three times a day for 16 days. The images show the patient's left elbow before and after treatment, the patient's right elbow before and after treatment, and the reappearance of psoriasis on the patient's left elbow after the patient has stopped the butyrate treatment regimen for 20 days.

[0320] Figure 3 shows the results of another psoriasis patient receiving a butyrate treatment regimen. The treatment regimen used was two 600 mg butyrate tablets three times a day for 10 days, followed by one butyrate tablet three times a day for three weeks.

[0321] Figure 4 shows the results of a third psoriasis patient undergoing a butyrate treatment regimen. The treatment regimen used was two 600 mg butyrate tablets three times a day for seven days, followed by one 600 mg butyrate tablet three times a day for 24 days. Images are of the patient's left elbow before and after treatment. The patient consumed high doses of alcohol during the treatment period.

[0322] FIG. 5 shows the results of a fourth patient with severe psoriasis over approximately 50% of the skin undergoing a butyrate treatment regimen. The patient began a regimen of two 600 mg butyrate tablets three times a day for four weeks, followed by one 600 mg butyrate tablet three times a day for several months. Significant improvement was noted, and no side effects were noted during the long-term treatment. To ensure that the positive effects observed were due to treatment with our formulation, the patient was asked to discontinue the regimen. The psoriasis recurred in approximately 20-25 days (before photo). The patient began a regimen of two 600 mg butyrate tablets three times a day for ten days, followed by one 600 mg butyrate tablet three times a day for three weeks, and the psoriasis disappeared (after photo). The images are of the patient's left hip before and after treatment with the second treatment regimen, the patient's right hip before and after treatment with the second treatment regimen, and the patient's coccyx before and after treatment with the second treatment regimen.

[0323] Figure 6 shows the results of a patient with plaque psoriasis. The initial treatment regimen used was two 600 mg butyrate tablets three times a day for 20 days, then the regimen was reduced to one 600 mg butyrate tablet three times a day for 25 days. Significant improvement was observed 3-5 months after the patient stopped the treatment. The patient was not taking any medications before (at least 3 months), during and after the treatment (at least 2 months).

[0324] [Table 1]

[0325] Example 2: Combination Treatment of Skin Disorders with Short Chain Fatty Acids This example is based in part on the discovery that administering at least one SCFA in combination with at least one second compound is an effective approach for treating skin diseases and disorders, including psoriasis.Without being bound by theory, it is expected that the combination of at least one SCFA and at least one second compound provides effective treatment of skin disorders.Additional compounds contemplated for use include PDE4 inhibitors, anti-inflammatory compounds, disease-modifying antirheumatic drugs (DMARDs), immunosuppressants, biological agents, Cox-2 inhibitors, apremilast or combinations thereof, and / or other agents.Non-limiting examples of these and other compounds useful in the present invention are provided above.

[0326] Recommended action: Combination treatment with Apremilast: Daily oral dose is 1-2 g butyrate, 100 mg propionate, 10-15 mg apremilast, 10-20 mg magnesium, 80-100 IU vitamin D3, 50-100 IU vitamin E (d-alpha-tocopherol acetate).

[0327] Psoriasis of the palms and feet responds poorly to treatment (these parts of the body are constantly "blocked" by daily activities). The impact of psoriasis of the hands and feet on the patient's quality of life is extremely high (the patient cannot comfortably wear shoes or use their hands).

[0328] In such cases of psoriasis, the combination with a topical ointment is important. The daily oral dose of the SCFA preparation is: 2 / 5 parts clobetasol (0.05%), 1 / 5 part calcipotriene (vitamin D, 0.005%), 1 / 5 part salicylic acid (10%), 1 / 5 part Vitamin E (0.5%) It should be used in conjunction with the application of an ointment consisting of:

[0329] All these components are used (separately) as local treatments.

[0330] Example 3: Use of Short Chain Fatty Acids in the Treatment of Ocular Diseases and Disorders The onset of uveitis is often sudden, and the treatment and prognosis of various uveitis diseases vary greatly. Delay in treatment can cause serious complications (exfoliation, blindness). It is important to use strong drugs at the beginning to stop the progression of the disease. To maintain the achieved therapeutic effect (especially the reduction of inflammation), SCFAs can be used (oral and / or in the form of eye drops). This eliminates the negative side effects (including glaucoma, cataracts) that are usually observed after long-term treatment with biologics and steroids (in the case of chronic or autoimmune uveitis). SCFAs can also be used in mixtures with antibiotics (as eye drops) and / or steroids (administered in reduced doses).

[0331] The clinical trials will evaluate different combinations and dosing schedules of SCFAs in healthy individuals (Phase 1) and in patients with uveitis (Phase II). Because some cases of uveitis are associated with bacterial or viral infections, the formulations may also contain appropriate antibiotic or antiviral compounds along with the SCFAs, respectively.

[0332] Further studies include testing single or combinations of SCFAs in dose escalation studies to assess toxicity and what form that toxicity takes (i.e., which tissues or organs are affected). Pharmacokinetic (PK) studies may be performed in mice to understand the oral dose that should be used for further preclinical studies. It will be important to confirm whether the molecules thought to mediate the pathogenesis of uveitis in previous animal studies are now the same pathways that are inhibited in animal models treated with SCFAs.

[0333] In this study, two mouse models of uveitis are used. In one model, experimental autoimmune uveitis (EAU) is induced by immunization with retinal antigens S-ag and IRBP bound to complete Freund's adjuvant (CFA) and a B. pertussis toxin boost. The second model uses IRBP161-180 peptide-specific transgenic T cell receptors on a B10.RIII background, which results in the development of spontaneous uveitis. These preclinical studies are also validated by prior human studies showing that the proinflammatory molecules targeted by SCFAs in mice with uveitis are the same molecules thought to mediate uveitis in humans. This study confirms that oral administration of SCFAs resolves uveitis lesions in mice.

[0334] Dry eye occurs when the quantity and / or quality of tears are not sufficient to keep the eye surface lubricated. Tears are made up of oil, water, mucus, and over 1500 proteins that protect the eye. Tears play an important role in focusing light, which can affect vision in dry eye disease. Factors that may contribute to dry eye include medications (antihistamines, antidepressants, oral contraceptives, Parkinson's medications, high blood pressure, etc.), aging, rosacea, autoimmune disorders (Sjogren's syndrome, lupus, scleroderma, etc.), vitamin A deficiency, etc.

[0335] As a result, the outer (lipid layer) produced by the meibomian glands, the middle (aqueous layer) produced by the lacrimal glands, and the inner (mucin layer) produced by the goblet cells were impaired.

[0336] The frequent use of artificial tears or other lubricating eye drops is the primary treatment for dry eye, although when dry eye is associated with inflammation, cyclosporine A, corticosteroids, tacrolimus, tetracycline derivatives, etc. have been used (such treatments have demonstrated measurable clinical improvement). In such cases, butyrate treatment may be useful.

[0337] Behçet's disease (BD) is an autoimmune reaction in which blood vessels, including those in the eye, become inflamed (ocular BD). Inflammation of the inside of the eye occurs in more than half of people with BD and can cause blurred vision, pain, and redness. Other symptoms of the disease include blood clots, and inflammation of the central nervous system and digestive tract. Some people can become blind or severely disabled. Corticosteroids and drugs that suppress the immune system may be prescribed to reduce inflammation.

[0338] The development of the disease is mainly linked to genetic factors (human leukocyte antigen (HLA)-B51 antigen), but molecular mechanisms involve increased neutrophil motility, increased production of TNF-α and IL-17, and decreased production of IL-10, all controlled by SCFAs. Anti-TNF-α therapy was shown to suppress effector T cell differentiation in BD patients with uveitis. Because butyrate suppresses TNF-α, treatment with SCFAs (oral) may provide protection from inflammation in BD.

[0339] Inflammation after cataract surgery may persist. Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat inflammation (prophylactic or postoperative), but there are no established guidelines for the treatment of inflammation induced by cataract surgery. Long-term use of corticosteroids has raised safety concerns, especially with regard to increased intraocular pressure. Surgical trauma induces the arachidonic acid cascade (converted to prostaglandins (PGs) by activated COX-1 and COX-2 enzymes), and PGs are the most important inflammatory mediators in this disease. Butyrate has been shown to inhibit COX-2 expression and PG production, and can therefore be used (in eye drops) for treatment.

[0340] Based on animal data, oral doses of SCFAs must be high to have a therapeutic effect.

[0341] Recommended action: The daily oral dose is 4-5 g of butyrate and 1.5-2 g of propionate in an enteric-coated sustained-release capsule, given twice daily.

[0342] Eye drops containing both 20-30 μM butyrate and 10-20 μM propionate can also be used (since the plasma concentrations of these SCFAs are up to approximately 30 μM).

[0343] In the case of dry eyes, eye drops should be administered twice daily consecutively in combination with a lubricant.

[0344] In other eye diseases, eye drops should be administered four times a day (in case of disease flares), and twice a day for up to several months, in combination with oral administration of SCFAs.

[0345] The SCFAs can be used in mixtures with antibiotics and / or steroids.

[0346] For example, for infectious uveitis: use eye drops (or eye injections) containing antibiotics / steroids (doses prescribed by doctor) for the first 3-5 days, then eye drops containing a mixture of SCFAs (20-30 μM) and antibiotics / steroids (half the prescribed dose) for the next 2-3 weeks, then continue with eye drops containing only SCFAs (20-30 μM). Based on the type and severity of the disease, oral SCFAs may also be administered, alone or in combination with antibiotics. This may promote healing and minimize side effects.

[0347] Treatment of Individuals with Uveitis Using SCFAs The experiment was designed to treat subjects with infectious uveitis. In some cases, butyrate is administered to the subjects. After completing butyrate therapy, the subjects experience a significant reduction in inflammation.

[0348] Example 4: Use of Short Chain Fatty Acids in the Treatment of Macular Degeneration Age-related macular degeneration (AMD) causes damage to the macula (a small area in the center of the retina). In the dry form of AMD, lipid aggregates (drusen) accumulate in the retina. The later stages of dry AMD (geographic atrophy) are characterized by degeneration of the retinal pigment epithelial cells and the overlying light-sensing retinal photoreceptors. "There is no cure for dry AMD." The Age-Related Eye Disease Study (AREDS) found that daily intake of high doses of vitamins (vitamins E and C) and minerals (zinc oxide) can slow the progression of the disease. In wet AMD, choroidal neovascularization occurs (new immature blood vessels grow from the underlying choroid toward the outer retina). These vessels leak fluid and cause scarring of the macula. The major factor contributing to neovascularization is vascular endothelial growth factor (VEGF). The most widely used antiangiogenic FDA approved therapies (intraocular injections) include pegaptanib, Lucentis, and VEGF-TRAP-Eye (Ambati J, Fowler BJ. Mechanisms of age-related macular degeneration. Neuron, 2012; 75(1): 26-39), which improve or stabilize vision in the majority of patients. Butyrate has been found to inhibit angiogenesis in vitro and in vivo and to reduce the expression of proangiogenic factors including hypoxia-inducible factor (HIF-1a) and VEGF (Canani B, Di Costanzo M, Leone L. The epigenetic effects of butyrate: potential therapeutic implications for clinical practice. Clinical Epigenetics, 2012; 4(1): 4). Therefore, butyrate can be used for AMD treatment (eye drops).

[0349] Clinical trials can evaluate different combinations and dosing schedules of selected SCFAs in healthy individuals (phase 1) and then in patients with adult macular degeneration (AMD) (phase II). Some studies have shown that consuming a Mediterranean diet can slightly improve advanced AMD, so some human trials may combine this diet with SCFAs to look for additive or synergistic effects. However, human trials can take more than two years to obtain statistically significant results.

[0350] Further studies may include testing single or combinations of SCFAs (+ / - dietary antioxidants) in dose escalation studies to look for toxicity and what form that toxicity takes (i.e., which tissues or organs are affected). Pharmacokinetic (PK) studies may also be performed in mice to understand the oral dose that should be used for further preclinical studies. In the latter category, it may be important to see whether molecules thought to mediate the pathogenesis of macular degeneration in previous animal studies are now the same pathways that are inhibited in animal models treated with SCFAs.

[0351] Two mouse models of AMD can be used in this study. In one model of dry AMD, a novel mouse model of immune-mediated retinal degeneration was induced by immunization with carboxyethylpyrrole (CEP)-modified albumin (CEP-MSA). CEP-albumin adducts were generated in retinal photoreceptors in response to oxidative stress. Patients with AMD also have circulating CEP autoantibodies. In another model, CCL2 / CX3CR1 KO mice have defects in migration (and recruitment) of macrophages / retinal microglia and develop degenerative changes characteristic of some AMD lesions within 4–6 weeks of age. Here, the tissue response to oxidative stress is nonfunctional (repair versus continued inflammation). Given that SCFAs block oxidative stress, block angiogenesis (by downregulating VEGF and PDGF expression) and downregulate the inflammatory response, SCFAs may be effective in preventing and / or reversing AMD. Such preclinical studies can also be validated by previous human studies showing that the proinflammatory molecules targeted by SCFAs in mice with AMD are the same as those associated with AMD in humans. This study can confirm that oral administration of SCFAs resolves AMD lesions in mice.

[0352] Recommended action: The daily oral dose is 4-5 g of butyrate and 1.5-2 g of propionate in an enteric-coated sustained-release capsule, given twice daily.

[0353] Eye drops containing both 20-30 μM butyrate and 10-20 μM propionate can also be used (since the plasma concentrations of these SCFAs are up to about 30 μM). The eye drops should be administered four times a day (in case of disease flares) and twice a day for up to several months in combination with oral administration of SCFAs.

[0354] The SCFAs can be used in mixtures with antibiotics and / or steroids.

[0355] Example 5: Treatment and prevention of autoimmune and allergic diseases in newborns delivered by C-section with short-chain fatty acids Infants born by Caesarean section (C-section) experience an increased risk of type 1 diabetes (Cardwell et al., 2008, Diabetologia, 51(5):726-35) and asthma (Thavagnanam et al., 2008, Clin Exp Allergy, 38(4):629-33). These infants (full term or premature) acquire a gut microbiota that is characteristic of the maternal skin, not the birth canal. This makes the newborn more susceptible to the development of allergic and autoimmune diseases and disorders, such as allergic rhinitis, gastroenteritis, inflammatory bowel disease, asthma, juvenile rheumatoid arthritis, food allergies, obesity, and type 1 diabetes. Between 1996 and 2005, the number of C-sections in the United States increased by about 50%, reaching 30.2%, which is far above the optimal limit of 10-15% recommended by the WHO. Other countries with rates above 20% include Canada, the UK, Mexico, and Brazil, suggesting that an increasing number of infants are at risk for allergic and autoimmune diseases. The C-section rate for second births after a first child has been delivered by C-section is approximately 90%. Currently, there is no standard treatment for these and other allergic / autoimmune diseases that may appear after a C-section delivery. Some clinics attempt to partially restore the mother's deficient microbes to infants born by C-section by swabbing those infants with the mother's vaginal fluid within two minutes of birth. However, this practice is controversial. There is even evidence that this approach may inadvertently expose infants to the mother's diseases.

[0356] The experiment is designed to evaluate the effectiveness of using SCFAs to prevent, delay or enhance the onset of at least one autoimmune and / or allergic disease or disorder in a subject.As discussed herein, infants delivered by C-section experience an increased risk of developing autoimmune and allergic disease and disorder, and the number and frequency of C-sections are increasing.Therefore, the experiment is designed to deliver SCFAs to pregnant women or newborns delivered by C-section to prevent at least one autoimmune and / or allergic disease or disorder as disclosed herein.

[0357] One or more SCFAs of the present invention can be orally administered up to three times a day for two months. The administration schedule can be 6 tablets (600 mg / tablet) per day for one week, followed by 3 tablets (600 mg / tablet) per day until a C-section is performed. Sodium, magnesium, or calcium salts of SCFAs can be used in these treatments. Alternatively, if SCFAs are not being given to a pregnant woman planning a C-section, SCFAs can be mixed into the food or drink provided to the infant.

[0358] In some embodiments, experiments have been designed to develop SCFAs as supplements or dietary supplements. Alternatively, SCFAs can be repackaged as enteric coated capsules providing a sustained release product for the mother or added as a supplement to infant formula or food for at least the first 6-12 months or 18-24 months of life. Clinical trials can evaluate different combinations and dosing schedules of selected SCFAs in healthy individuals (Phase I), followed by women delivering by C-section and infants born to women by C-section (Phase II).

[0359] Further experiments were designed to include testing single or combination SCFAs in dose escalation studies to determine toxicity and what form that toxicity takes (i.e., which tissues or organs are affected). Pharmacokinetic (PK) studies could also be performed in mice to figure out what oral doses should be used for further preclinical testing. In the latter category, it is important to confirm whether the molecules thought to mediate the pathogenesis of the relevant allergy or autoimmune disease in prior mouse studies are the same pathways that are inhibited in mice treated with SCFAs. In this study, an appropriate mouse model could be used. These preclinical studies could also be validated by prior human studies showing that the proinflammatory molecules targeted by SCFAs in the mouse model are the same ones thought to mediate the corresponding human disease. This study could determine whether oral administration of SCFAs resolves the relevant disease or disorder (e.g., lesions) in mice. Parallel clinical trials could be performed among women scheduled for C-section delivery in late pregnancy and neonates delivered by C-section delivery.

[0360] The main advantages of this approach are that it has little or no toxicity compared to other currently available treatments and at the same time helps to re-establish intestinal homeostasis.

[0361] Babies born by C-section do not usually receive any routine intervention. However, Similac Pro-Advance and Similac Pro-Sensitive have human milk oligosaccharides, which are prebiotics found in most breast milk. This embodiment contemplates the combination of one or more SCFAs with one or more of these products.

[0362] Recommended action: For breast-fed infants: The daily oral dosage for healthy mothers is 1 to 2 g butyrate and 0.5 to 1 g propionate and acetate in an enteric-coated sustained-release capsule three times a day for the first month, then half that dose for the following 3 months.

[0363] In the paper (Xu J, Chen X, Yu S, et al. Effects of Early Intervention with Sodium Butyrate (SB) on Gut Microbiota and the Expression of Inflammatory Cytokines in Neonatal Piglets. PLoS One, 2016; 11 (9): e0162461), early intervention with sodium butyrate modulated ileal inflammatory cytokines in neonatal piglets with low impact on gut microbial structure, which suggests that oral administration of SB may have a beneficial role in the health of neonatal piglets (1 and 7 days old). The oral dose was about 10 ml at 150 mmol / L (pigs consumed 10 ml of sodium butyrate at about 150 mmol / L, which is equivalent to about 165 mg). For formula supplementation, the recommended treatment regimen uses incremental doses: start at low concentrations (80-100 mg butyrate, 20-30 mg acetate and propionate in the first month), then increase the dose to 100-120 mg butyrate and 30-40 mg acetate and propionate for the next 3-5 months.

[0364] Example 6: Use of short chain fatty acids in the treatment of vasculitis Vasculitis is a rare autoimmune disease involving inflammation of blood vessels, arteries, veins, or capillaries and can affect people of any age. Vasculitis may also be associated with certain blood cancers (leukemia and lymphoma). Different types of vasculitis are classified according to the size and location of the affected blood vessels. Common vasculitis treatments include corticosteroids and cytotoxic drugs. Some molecular mechanisms of vasculitis pathogenesis have been reviewed in our patent application. The GPR-109a pathway has also been shown to play an important role (Chai JT, Digby JE, Choudhury RP. GPR109A and vascular inflammation. Curr. Atheroscler. Rep. 2013;15(5):325). Activation of the GPR-109a receptor downregulates NF-κB, and many selective GPR109A agonists have been developed by Merck, GSK, and other companies. This receptor is activated by butyrate (EC50 approx. 1.5 mM) and niacin.

[0365] Clinical trials will evaluate different combinations and administration schedules of selected SCFAs in healthy individuals (phase 1) and then in patients with vasculitis (phase II). At this point, cyclophosphamide or glucocorticoids are most frequently used for treatment, but methotrexate, azathioprine, and mycophenolate have also been used. The problem is that these are highly toxic therapeutic approaches that limit their application in patients. More specific biological therapies using monoclonal antibodies against TNFβ, IL-1, or IL-6 require evaluation. Considering that the inflammatory process in most forms of vasculitis, atherogenesis, and aneurysms share many features, interventions with SCFAs are likely to show broader application in re-establishing homeostasis between these various disease states.

[0366] Further studies include testing single or combination SCFAs in dose escalation studies to look for toxicity and what form that toxicity takes (i.e., which tissues or organs are affected). Pharmacokinetic (PK) studies must be performed in mice to understand the oral dose that should be used for further preclinical studies. In the latter category, it will be important to confirm whether the molecules thought to mediate the pathogenesis of vasculitis in animal studies are the same targets / pathways that are now inhibited in animal models treated with SCFAs.

[0367] In this study, two mouse models of ANCA-associated vasculitis can be used because they are fairly well characterized. In one model, MPO knockout mice (MPO- / - mice) are immunized with MPO. These animals are then irradiated and reconstituted with syngeneic wild-type bone marrow. Antibody-producing plasma cells are relatively radioresistant, so circulating anti-MPO levels are maintained. The bone marrow reconstitutes neutrophils, which become available for binding of anti-MPO. Mice then develop crescentic glomerulonephritis and urinary abnormalities by 8 weeks after bone marrow transplantation. Without being bound to a particular theory, given that MPO-expressing neutrophils are also a target in human vasculitis, and that SCFAs downregulate MPO expression by blocking macrophage NF-kB activity (thereby blocking secretion of factors by macrophages that activate neutrophils), it is proposed that administration of SCFAs can block the development of vasculitis in this animal model.

[0368] Another model involves immunizing wild-type C57BL / 6 mice with human or mouse MPO, which leads to the induction of both humoral and cellular responses against MPO. While this alone does not result in disease, passive transfer of polyclonal glomerulus-bound antibodies leads to the accumulation of neutrophils in the glomeruli. The MPO of these neutrophils is then targeted by antigen-specific CD4+ T cells, leading to the autoimmune glomerulonephritis seen in approximately 50% of patients with ANCA vasculitis. Other animal models can be utilized as needed. Without being bound to a particular theory, it is hypothesized that administration of SCFAs can block or ameliorate the development of autoimmune glomerulonephritis, given that SCFAs promote the differentiation of T cells into a Treg phenotype.

[0369] Such preclinical studies can also be validated by previous human studies in the literature showing that the proinflammatory molecules targeted by SCFAs in mice with vasculitis are the same as those associated with vasculitis in humans. This work will allow us to determine whether oral administration of SCFAs resolves vasculitis in mice.

[0370] The model outlined in this example may not cover all aspects of vasculitis pathogenesis, and for many forms of vasculitis, there are no available animal models. For example, for ANCA vasculitis, there is no reproducible model of granulomatous PR3-ANCA. However, the model used can establish proof of principle for whether SCFA should be incorporated into human clinical trials for vasculitis.

[0371] Recommended action: The daily oral dose is 5-6 g butyrate in an enteric-coated sustained-release capsule three times a day for the first month, then 3-4 g butyrate twice a day for several months. In case of relapse, higher doses should be used.

[0372] Butyrate may be used in combination with reduced doses of steroids and chemotherapy agents.

[0373] Example 7: Use of Short Chain Fatty Acids to Treat Selected Lymphomas Since this example is an idea based on the properties of SCFAs, combining the difficulty of achieving long-term remission and preventing relapse of selected lymphomas, it may be useful to test this approach in 1-2 preclinical models of each selected lymphoma to establish proof of principle for human trials. The invention itself simply involves oral administration of SCFAs at the time of diagnosis, alone or in combination with standard treatment therapy. Furthermore, in mouse models, treatment before the onset of lymphoma can establish whether SCFAs can delay or block tumor onset. Considering that these cancers in humans are often accompanied by multiple genetic abnormalities that may be present before the clinical stage of the disease, and that some of these tumors may have associated genetic predispositions, this suggests that SCFAs may be (at least) useful in preventing relapse / relapse.

[0374] SCFAs are: (1) As used herein, SCFAs are NF- K To block B activity, NF- K For selected lymphomas that depend on constitutive activation of B, it may be used, alone or in combination with standard of care treatments, (2) to delay or prevent lymphoma recurrence / relapse, (3) to reduce the toxicity profile of standard of care treatments, thereby improving long-term quality of life, (4) to allow intervention in high-risk patients before lymphoma emerges, and (5) to target lymphomas with SCFA histone deacetylase (HDAC) inhibitory activity that is not part of other therapeutic approaches, actual or in development. These features would help extend the invention to better treat patients with high tumor burden.

[0375] Recommended action: The daily oral dose is 4 to 5 g of butyrate in an enteric-coated sustained-release capsule, three times daily.

[0376] Treatment with butyrate may be combined with reduced doses of steroids and chemotherapy agents.

[0377] Example 8: Use of Short Chain Fatty Acids to Treat Leukemia Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF), all of which can evolve into acute myeloid leukemia (AML). MPNs are characterized by constitutive activation of the myeloproliferative leukemia (MPL) oncogene and signaling molecule, JAK2 (usually by mutation). STAT-1, -3, and -5, MAPK, ERK, and AKT / PI3K all support the cytokine-independent growth of PV, ET, and MF. The tumor suppressor and epigenetic modifier ten-eleven translocation 2 (TET2) is also frequently mutated in these cells, suggesting that activation of JAK2 and inactivation of TET2 are drivers of AML. They block differentiation and promote self-renewal. Ph-MPNs are relatively rare, with 90-120 cases per 100,000. A variety of tyrosine kinase inhibitors (TKIs) have been developed to block JAK / STAT overactivation, but they are not curative in many patients and are associated with significant toxicity.

[0378] Butyrate has been shown to block the nuclear translocation of STAT1 and block the activation of JAK2. In addition, butyrate and propionate are HDAC inhibitors. Since increased HDAC activity inhibits retinoic acid (RA)-induced differentiation, it is expected that butyrate / propionate + retinoic acid may prevent the progression and / or recurrence of MPN.

[0379] Pediatric ALL is also characterized by constitutive activation of the JAK / STAT pathway, which is inhibited by butyrate. Moreover, butyrate activates p53, which is otherwise downregulated in ALL. Furthermore, the valproic acid SCFA inhibits TGFbeta1 and PI3K signaling in ALL, all of which suggests that SCFA intervention may be effective in this setting. This is particularly important in pediatric and adult ALL, as minimal residual disease after initial chemotherapy is common and relapse times are characteristically short.

[0380] Since this example is based on the properties of SCFAs, combining the difficulty of achieving long-term remission and preventing relapse of AML and other leukemias, it may be useful to test this approach in 1-2 preclinical models of each selected leukemia to establish proof of principle for human trials. The invention itself involves the administration of one or more SCFA therapeutic compounds at the time of diagnosis, alone or in combination with standard treatment therapy. Furthermore, in mouse models, it can be established that SCFAs can delay or block tumor progression with treatment initiated at the time of diagnosis. Considering that these cancers in humans are often accompanied by multiple genetic abnormalities that may be present before the clinical stage of the disease, and that some of these tumors may have an associated genetic predisposition, this suggests that SCFAs may be (at least) useful in preventing relapse / relapse.

[0381] The experiments involve introducing AML or ALL cell lines (or banked primary cells from patients with the same disease) into immunodeficient mice (NOD / SCID) and administering SCFA treatment or placebo for various periods of time. Periodic blood samples are analyzed for minimal residual disease by PCR amplification of gene rearrangements known to be common in AML or ALL in clinical samples or associated with the particular cell line used for injection. If commercially available transgenic mice carrying the major genetic lesions characteristic of AML or ALL are available, experiments can be designed to test whether SCFAs can alter disease pathogenesis.

[0382] SCFAs can be used (1) alone or in combination with standard of care treatments for selected leukemias that depend on constitutive activation of JAK / STAT (AML and ALL) since SCFAs as used herein block JAK / STAT activity, (2) to delay or prevent leukemia relapse / recurrence, and (3) to reduce the toxicity profile of standard of care treatments initiated at diagnosis, thereby improving long-term quality of life. These features would help extend the present invention to better treat patients with high tumor burden.

[0383] Currently, treatment involves two phases. The first phase, called induction, often involves chemotherapy with ara-C and daunomycin, which reduces the white blood cell count and destroys the bone marrow. A third drug, cladribine (leustatin, 2-CdA), may also be administered. If remission is achieved, induction is considered successful. However, induction leaves patients susceptible to potentially fatal infections for up to several weeks, during which time they remain hospitalized. The second phase, called consolidation, involves long-term high-dose ara-C. Alternatively, allogeneic or autologous stem cell transplantation can be considered, but consolidation is associated with an increased risk of death.

[0384] Constitutively activated HDACs have been observed in many types of leukemia, and thus synthetic HDAC inhibitors have been proposed as an intervention strategy. However, although valproate and phenylbutyrate have been evaluated for selected lymphomas, none have entered human clinical trials. In acute myeloid leukemia (APL), a variant of AML, inhibition of HDAC1 / 2 promotes differentiation and apoptosis. However, treatment of pre-leukemic cells with the same HDAC inhibitors promotes cell proliferation, suggesting that SCFAs may help block tumor recurrence but cannot prevent tumor development. A potential advantage of using a mixture of SCFAs including butyrate and propionate for AML recurrence is that they would be effective without discernible side effects. Because SCFA-associated HDAC inhibitory activity is reversible, this example offers a potentially sound way of balancing efficacy while reducing the risk of toxicity or other adverse effects common in other therapeutic approaches. This may be especially true in the context of addressing tumor recurrence / relapse, where combination therapy may prove to be the best option.

[0385] Recommended action: The daily oral dose is 4 to 5 g of butyrate in an enteric-coated sustained-release capsule, three times daily.

[0386] Treatment with butyrate may be combined with reduced doses of steroids and chemotherapy agents.

[0387] Example 9: Use of short chain fatty acids in treating or preventing adverse effects associated with CAR-T therapy Given the goals of cancer immunotherapy and the known immunomodulatory functions of SCFAs, there is a high likelihood that this example will work in preclinical models. SCFAs can be taken orally, are non-toxic, and have no problems crossing both the intestinal epithelium and the blood-brain barrier, a combination of benefits not available in other approaches. Because immune modulation by SCFAs is reversible, this example offers a sound way to balance efficacy while reducing the risk of adverse effects of CAR-T and other cancer immunotherapeutic approaches.

[0388] For example, in one aspect, the present invention (1) ameliorates the cytokine storm seen in some patients administered CAR-T, (2) provides neuroprotection to patients experiencing these adverse effects, (3) immunomodulates CAR-T cell activity without the use of cytotoxic chemotherapy or systemic corticosteroids, (4) also has anti-tumor properties due to SCFA histone deacetylase (HDAC) inhibitory activity in both liquid and solid tumors where the Warburg effect shunts SCFAs to the nucleus, and (5) inhibits NF-α, where SCFAs directly stimulate the production of IL-6, TNFα, and IFNγ, all of which are commonly elevated in cytokine release syndrome (CRS). K B, providing a broadly anti-inflammatory, adjunctive therapy. SCFAs also downregulate the production of TNFα and IL-6 from macrophages, thereby potentially ameliorating macrophage activation syndrome, which is also a documented adverse effect of CAR-T therapy. This would help extend the invention to better treat patients with high tumor burden.

[0389] Two CD19-targeted CAR-T therapies have been approved by the FDA for the treatment of children with acute lymphoblastic leukemia and adults with aggressive lymphoma.

[0390] Cytokine release storm (CRS) is considered to be an "on-target" side effect, meaning that T cells are active. However, it can lead to dangerously high fevers and a rapid drop in blood pressure. All patients experiencing severe CRS had particularly high levels of the cytokine IL-6 (secreted by T cells and macrophages in response to inflammation). Tocilizumab (which blocks IL-6 activity) became the standard therapy to manage CRS. This approach worked and solved the problem for the majority of patients. However, patients treated with tocilizumab were at high risk of developing serious infections that could lead to hospitalization or death.

[0391] Butyrate (Yuan H, Liddle FJ, Mahajan S, Frank DA. IL-6-induced survival of colorectal carcinoma cells is inhibited by butyrate through down-regulation of the IL-6 receptor. Carcinogenesis. 2004;25(11):2247-55) and propionate (Nastasi C, Fredholm S, Willerslev-Olsen A, et al. Butyrate and propionate inhibit antigen-specific CD8(+)T cell activation by suppressing IL-12 production by antigen-presenting cells. Sci Rep. 2017;7(1):14516) have been shown to inhibit IL-6 and can therefore be considered as co-treatment options.

[0392] SCFAs should be administered in parallel with chemotherapy: several days prior to CAR-T cell infusion (SCFAs only), and up to several weeks after CAR-T cell infusion (SCFAs in combination with significantly reduced chemotherapy drugs). The daily oral dose is 5-6 g butyrate and 2-3 g propionate in an enteric-coated sustained-release capsule, three times daily.

[0393] The disclosures of each and every patent, patent application and publication cited herein are incorporated herein by reference in their entirety. Although the present invention has been disclosed with respect to specific embodiments, it will be apparent to those skilled in the art that other embodiments and variations of the present invention may be devised without departing from the true spirit and scope of the present invention. It is intended that the appended claims be construed to include all such embodiments and equivalent variations.

Claims

1. A pharmaceutical composition for treating skin disorders, comprising a therapeutically effective amount of a compound which is a short-chain fatty acid or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is used in combination with a therapeutically effective amount of a phosphodiesterase 4 (PDE4) inhibitor.

2. 2. The pharmaceutical composition of claim 1, wherein the skin disorder is psoriasis.

3. 2. The pharmaceutical composition of claim 1, wherein the short chain fatty acid is butyric acid.

4. 4. The pharmaceutical composition of claim 3, wherein the therapeutically effective amount of the butyric acid or a pharmaceutically acceptable salt thereof is 100 mg to 6 g.

5. 2. The pharmaceutical composition of claim 1, wherein the short chain fatty acid is propionic acid.

6. 6. The pharmaceutical composition of claim 5, wherein the therapeutically effective amount of propionic acid or a pharmaceutically acceptable salt thereof is from about 25 mg to about 200 mg.

7. 2. The pharmaceutical composition of claim 1, wherein the compound is butyric acid or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition further comprises an additional short chain fatty acid or a pharmaceutically acceptable salt thereof, wherein the additional short chain fatty acid is propionic acid or a pharmaceutically acceptable salt thereof.

8. 2. The pharmaceutical composition of claim 1, wherein the PDE4 inhibitor is apremilast.

9. 9. The pharmaceutical composition of claim 8, wherein the therapeutically effective amount of the PDE4 inhibitor is from about 10 mg to about 15 mg.

10. 10. The pharmaceutical composition of claim 1, further comprising vitamin D3.

11. 10. The pharmaceutical composition of claim 1, formulated for oral administration.

12. 10. The pharmaceutical composition of claim 1, further comprising a magnesium source in an amount of about 10 mg to about 20 mg.

13. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical combination is for use in combination with said therapeutically effective amounts of a PDE4 inhibitor and vitamin D3.

14. a) a first pharmaceutical composition comprising a therapeutically effective amount of a compound that is a short chain fatty acid or a pharmaceutically acceptable salt thereof; and b) a second pharmaceutical composition comprising a therapeutically effective amount of a compound that is a phosphodiesterase 4 (PDE4) inhibitor. Kit including:

15. 15. The kit of claim 14, wherein the short chain fatty acid is butyric acid.

16. 15. The kit of claim 14, wherein the short chain fatty acid is propionic acid.

17. 15. The kit of claim 14, wherein the compound is butyric acid or a pharmaceutically acceptable salt thereof, and the first pharmaceutical composition further comprises an additional short chain fatty acid or a pharmaceutically acceptable salt thereof, wherein the additional short chain fatty acid is propionic acid or a pharmaceutically acceptable salt thereof.

18. 15. The kit of claim 14, wherein the PDE4 inhibitor is apremilast.

19. 15. The kit of claim 14, wherein the therapeutically effective amount of the PDE4 inhibitor is from about 10 mg to about 15 mg.

20. 15. The kit of claim 14, wherein the first pharmaceutical composition further comprises vitamin D3.

21. 15. The kit of claim 14, wherein the first pharmaceutical composition is formulated for oral administration.

22. 15. The kit of claim 14, wherein the first pharmaceutical composition and the second pharmaceutical composition are in unit dose form.

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