WO2021252290A2 - Compositions and methods for treating novel coronavirus sars-cov-2-mediated inflammatory conditions - Google Patents

Description

Compositions and Methods for Treating Novel Coronavirus SARS-CoV-2-mediated

Inflammatory Conditions

CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application Nos. 63/036,389 filed June 8, 2020, which is incorporated herein by reference in their entirety for all purposes.

BACKGROUND

[0002] The present embodiments relate to compositions and methods for modulating Type I and/or Type II NKT cells in the prevention and treatment of inflammatory conditions, including novel Coronavirus SARS-CoV-2 -mediated inflammatory and fibrotic conditions associated with COVID-19 disease.

BRIEF SUMMARY

[0003] The present embodiments generally relate to methods and compositions for modulating the adaptive and innate immune system to prevent and treat tissue damage associated with inflammatory conditions. For example, several embodiments described herein related to the prevention and treatment of novel Coronavirus SARS-CoV-2-mediated inflammatory conditions (COVID-19).

[0004] Several embodiments described herein relate to methods and compositions for modulating Type II and/or Type I Natural Killer T (NKT) cells in the prevention and treatment of inflammatory conditions such as COVID-19. Several embodiments described herein relate to methods and compositions for manipulating the activities of type I NKT cells and type II NKT cells, interactions between type I and type II NKT cells, and their interactions with other cells in order to treat, alleviate or prevent inflammation-associated injury to tissue and fibrosis, such as that which occurs with COVID-19.

[0005] In some aspects, embodiments herein relate to methods for the treatment and prevention of an inflammatory condition associated with Novel Coronavirus SARS-CoV-2 comprising administering to a subject one or more of the compounds substantially described and illustrated herein.

[0006] In some aspects, embodiments herein relate to methods of treating a patient with a SARS-CoV-2 infection comprising administering to a subject one or more of the compounds substantially described and illustrated herein. DETAILED DESCRIPTION

[0007] In accordance with some embodiments herein, compositions comprising an amount of NKT-2 activator sufficient to activate Type II NKT cells can be useful in alleviating or preventing any of a number of inflammatory conditions. Without being limited by any theory, it is contemplated herein that upon activation, Type II NKT cells can inhibit activation of Type I NKT cells, and thus can alleviate or prevent Type I NKT cell-mediated damage associated with inflammation. Accordingly, in some embodiments, methods of alleviating or preventing inflammatory conditions comprise administering a composition comprising an amount of NKT-2 activator, for example miltefosine or an analog of miltefosine sufficient to activate Type II NKT cells. Optionally the composition can comprise an amount of Retinoic Acid Receptor (RAR) agonist sufficient to inhibit activation of Type I NKT cells. These findings bear particular application to the treatment of inflammation and fibrosis associated with Novel Coronavirus SARS-CoV-2. Accordingly, embodiments herein provide for compositions and treatment methods for subjects afflicted with Covid-19. Such methods may mitigate or prevent damage associated with cytokine storm syndrome (CSS) or acute respiratory distress syndrome (ARDS), for example.

I. NKT cells

[0008] The liver harbors a number of specialized cells of the adaptive and innate immune system, including Kupffer cells, Natural Killer (NK) cells, Natural Killer T (NKT) cells and dendritic cells. NKT cells are unique in that they share the cell surface receptors of NK cells (e.g., NK1.1) and in addition express T cell receptors (TCR), enabling them to recognize, but not limited to, lipid antigens in the context of CD Id molecules and bridge the innate immune responses to adaptive immunity. NKT cells have the ability to regulate the activity of other cells that contribute to inflammation of tissue and the associated cellular damage. Upon activation, NKT cells rapidly secrete large quantities of IFN-gamma, IL-4, granulocyte-macrophage colony-stimulating factor, osteopontin (OPN) as well as multiple other cytokines and chemokines. Since NKT cells are capable of secreting both Thl and Th2 cytokines, it can be difficult to predict the consequences of NKT cell activation in vivo. Depending upon context, NKT cell activation triggers cascades of events that promote or suppress different immune responses. In some contexts, activation of NKT cells leads to the activation of NK cells, dendritic cells (DCs) and B cells. Aspects of NKT cells are discussed in Kumar, “NKT-cell subsets: Promoters and protectors in inflammatory liver disease” Journal of Hepatology, 2013, 59: 618-620, which is hereby incorporated by reference in its entirety. [0009] NKT cells recognize primarily lipid antigens presented in the context of the monomorphic MHC class I-like molecule, CD Id. CDld-restricted NKT cells are categorized into type I (also referred to as “type I NKT cells” or “NKT-1” cells) and type II (also referred to as “type II NKT cells” or “NKT-2” cells), which recognize different lipid antigens presented by CDld molecules. While both NKT cell subsets are predominantly NK1.1+ (mouse) or CD161+/CD56+ (human), their relative numbers are different in mice and humans: thus, while type I NKT cells predominate in mice, the type II NKT cell subset predominates in humans.

[0010] Type I, also known as invariant NKT cells, express a semi-invariant T cell receptor (TCR) characterized in mice by Val4-Jal8 and nb8.2, nb7, or b2 or in humans by Va24-JaQ and nbΐ 1, are strongly reactive with the marine sponge-derived glycolipid alpha-galactosyl ceramide (“alpha-GalCer” or “aGalCer”), and are identified by alpha-GalCer/CDld-tetramers in flow cytometry. Type I NKT cells also recognize lipid-based antigens, such as, bacterial -derived lipids and a self-glycolipid, isoglobotrihexosyl ceramide (iGb3). Type I NKT cells display memory markers and are unique in storing preformed mRNA for cytokines. Mice lacking the Jal8 gene (Jal8 mice) are deficient only in type I NKT cells.

[0011] Type II NKT cells, which are distinct from type I NKT cells, are regulatory cells that can modulate the activity of several other cell subsets, including type I NKT cells. Activation of type II NKT cells can be evaluated by assessing the in vitro proliferative response of type II NKT cells to a candidate agent, as well as by assessing CD69 expression and cytokine secretion profile by intracellular cytokine staining or real-time PCR for IFN-gamma, IL-4 or IL-13. In addition, the ability of activated type II NKT cells to anergize type I NKT cells can be evaluated by assessing the proliferative response of type I NKT cells to alpha-GalCer (a potent activator of type I NKT cells) using CFSE dilution analysis and intracellular cytokine staining of alpha-GalCer/CDld tetramer cells. Activation of NKT cells (type I or type II) in accordance with some embodiments herein can be quantified as a stimulation index, based on thymidine incorporation.

[0012] As used herein “NKT-2 activators”, including variations of this root term refer to compounds that, upon contact with type II NKT cells, induce at least one of secretion of IL-2 by type II NKT cells, proliferation of type II NKT cells, or elevated CD69 expression on the surface of type II NKT cells. Example NKT-2 activators suitable in accordance with methods, kits, and composition herein include, but are not limited to, miltefosine, miltefosine analogs (for example the compounds listed in Table 2.1 and Table 2.2), phospholipids such as a lysophophatidylcholine

(LPC)(e.g., LPC (08:0), LPC (06:0), LPC (C18:1(9Z)), LPC(C18:l(loleyl)), and/or LignA(LPC)(C24:0)), an analog of LPC, lyso platelet- activating factor (LPAF), a lysosphingomyelin (LSM), and/or an analog of LSM. Without being limited by any theory, it is contemplated that NKT-2 activators in accordance with some embodiments herein can thus activate type II NKT cells, which in turn can inhibit activation of type I NKT cells.

[0013] In some embodiments, activation of type II NKT cells comprises secretion of IL-2 by type II NKT cells, proliferation of type II NKT cells, elevated CD69 expression on the surface of type II NKT cells, any two of these, any three of these, or all four of these.

[0014] In some embodiments, inhibition of activation of type I NKT cells comprises an inhibition of proliferation of type I NKT cells, reduced accumulation of type I NKT cells, decreased CD69 expression on the surface of type I NKT cells, any two of these, or all three of these.

[0015] In some embodiments, a composition comprising an amount of NKT-2 activator, for example miltefosine or a miltefosine analog, or a phospholipid sufficient to activate type II NKT cells is provided for use in treating, ameliorating, preventing, or reducing the risk of developing COVID-19. Optionally, the composition further comprises an amount of RAR agonist, for example tazarotene sufficient to inhibit type I NKT cells. In some embodiments, the composition is administered to a subject suffering from, or at risk for developing COVID-19.

[0016] In some embodiments, a composition comprising an amount of NKT-2 activator (for example miltefosine or a miltefosine analog or a phospholipid) is provided for use in treating, ameliorating, preventing, or reducing the risk of developing COVID-19. Optionally, the composition further comprises an amount of RAR agonist (for example, tazarotene) sufficient to inhibit type I NKT cells. In some embodiments, the composition is administered to a subject suffering from, or at risk for developing COVID-19. Optionally, the composition is for oral administration.

[0017] In some embodiments, an amount of NKT-2 activator (for example miltefosine or a miltefosine analog or a phospholipid) sufficient to activate type II NKT cells is administered to a subject suffering from, or at risk for an inflammatory conditions, such as COVID-19. Optionally, an amount of RAR agonist (for example, tazarotene) sufficient to inhibit activation of type I NKT cells is administered to the subject. Optionally, the administration is oral. Optionally, an amount of miltefosine sufficient to activate type II NKT cells is further administered to the subject. In some embodiments, the NKT-2 activator and RAR agonist are administered simultaneously. In some embodiments, the NKT-2 activator and RAR agonist are administered separately. In some embodiments, the NKT-2 activator is administered first and the RAR agonist is administered subsequently. In some embodiments, the RAR agonist is administered first and the NKT-2 activator is administered subsequently. In some embodiments, alternating administrations of RAR agonist and NKT-2 activator are performed.

II. Retinoic Acid Receptor (RAR) Agonists

[0018] Several embodiments relate to the inhibition of pro-inflammatory type I NKT cell activity by tazarotene, tazarotenic acid or a mixture thereof. Tazarotene is an ethyl ester prodrug that is metabolized to the corresponding free acid, tazarotenic acid. Tazarotene has a rigid ring- locked structure that offers limited conformational flexibility compared to all-trans-retinoic acid, the natural ligand for the retinoic acid receptors (RARs). This structural change confers tazarotenic acid with specificity for the RARs and selectivity for RARP and RARy.

[0019] As described herein, RAR agonists induce inhibition in type I NKT cells. Further, tissue damage caused by type I NKT cell mediated inflammation can be prevented, reduced or mitigated by administration of an RAR agonist. The tissue can become inflamed for a variety of different reasons. For example, tissue inflammation can be caused by bacterial or viral infection (e.g. COVID-19), injury, or attack from one’s own immune system. While inflammation is normally a protective response and a required step of the healing process, prolonged or chronic inflammation can cause injury. Several embodiments described herein relate to the RAR agonist mediated modulation of the adaptive and innate immune mechanisms leading to tissue damage following, related to or caused by inflammation. Some embodiments relate to methods and compositions for RAR agonist mediated inhibition of type I NKT cell activity which modulate interactions among the components of the immune system to provide tolerance to gut-derived or metabolite-derived antigens without affecting or minimally affecting the adaptive and/or innate immune response to non-self-identified pathogens.

[0020] As RAR agonists can directly anergize Type I NKT cells, RAR agonists may be used to treat any indication in which Type I NKT cells play a pathogenic role. Some examples of diseases which can be treated by the embodiments of the present disclosure include COVID-19 and other inflammatory conditions. [0021] Some embodiments relate a method of inhibiting or preventing type I NKT cell mediated inflammation following viral infection by administering an RAR agonist. Type I NKT cells play a pathogenic role in conditions such as inflammation and respiratory infections.

[0022] Embodiments described herein relate to the inhibition of type I NKT cell activity by one or more retinoic acid receptor (RAR) agonists. Retinoic acid receptors comprise three major subtypes: RARa, RARP, and RARy, Some embodiments relate to the inhibition of type I NKT cell activity by one or more pan-active RAR agonists, precursors of such pan-active RAR agonists and mixtures thereof. As used herein, the term “pan-active RAR agonist” refers to a RAR agonist which affects (for example, activates) RARa, RARP, and RARy substantially equally or non- selectively. Some embodiments relate to the inhibition of type I NKT cell activity by one or more active RAR agonists effective to selectively, or even specifically, affect (for example, activate) at least one, and preferably both, of RARp and RARy relative to RARa, precursors of such active RAR agonists and mixtures thereof. As used in this context, the term “selectively” means that the RAR agonist precursors of the RAR agonist and mixtures thereof are more effective, preferably at least about 10 or about 100 times to about 1000 times or more as effective, to affect at least one, and preferably both, of RARp and RARy relative to RARa. Some embodiments relate to the inhibition of type I NKT cell activity by one or more subtype-selective RAR agonists, precursors of such subtype-selective RAR agonists and mixtures thereof. As used herein, the term “subtype- selective RAR agonist” refers to a RAR agonist which selectively affects, for example, activates one RAR subtype. Retinoid compounds having RARa, RARP, and RARy -selectivity are known in the art and disclosed, for example, in U.S. Pat. Nos. 6,534,544 and 6,025,388 which are hereby incorporated by reference in their entirety.

[0023] Several embodiments relate to a method of inhibiting pro-inflammatory type I NKT cell activity by administering one or more retinoic acid receptor (RAR) agonists. Examples of RAR agonists include, but are not limited to, the RAR agonists listed in Table 1.

[0024] In some embodiments, pro-inflammatory type I NKT cell activity is inhibited by one or more RAR agonists selected from the group consisting of ATRA, retinol, 9-cis-RA or 13-cis-RA, tretinoin, AM580, AC55649, CD1530 or Tazarotene. In some embodiments, pro-inflammatory type I NKT cell activity is inhibited by one or more polyolefmic retinoids, such as isoretinoin and acitretin. In some embodiments, pro-inflammatory type I NKT cell activity is inhibited by one or more RAR agonists selected from the group consisting of etretinate, acitretin and isotretinoin.

[0025] Examples of RAR agonists further include esters of cis- and trans- retinoic acids, for example, alkyl esters, such as primary, secondary or tertiary alcohols, including but not limited to: methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, hexyl, heptyl, ethylhexyl, octyl, nonyl, lauryl, oleyl, stearyl, hydroxyethyl, hydroxypropyl, benzyl, alpha-methylbenzyl, alpha-propylphenyl, amyl, iso-amyl, anisyl, cetyl, menthyl, cinnamyl, pinacol, furyl, or myristyl.

[0026] Pharmaceutically acceptable salts of RAR agonists can also be used to inhibit type I NKT cell activity. Compounds disclosed herein which possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly can react with any of a number of organic or inorganic bases, and inorganic and organic acids, to form a salt.

[0027] Examples of acids that may be used to form acid addition salts from RAR agonists with basic groups include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenyl- sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such salts include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne- 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycol ate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

[0028] Examples of bases that may be used to form base addition salts from RAR agonists with acidic groups include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy- substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2- hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert- butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy lower alkyl)- amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl) amine; N- methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.

[0029] In some embodiments, the specific amount of RAR agonist administered to a patient will vary depending upon the disease or condition being treated, as well as the age, weight and sex of the patient being treated.

[0030] In accordance with the embodiments, RAR agonist can be administered to alleviate a patient’s symptoms, or can be administered to counteract a mechanism of the disorder itself. In certain embodiments, RAR agonist may be administered as a prophylactic measure. In some embodiments multiple doses of RAR agonist are administered. It will be appreciated by those of skill in the art that these treatment purposes are often related and that treatments can be tailored for particular patients based on various factors. These factors can include the age, gender, or health of the patient, and the progression of autoimmune or immune related disease or disorder. The treatment methodology for a patient can be tailored accordingly for dosage, timing of administration, route of administration, and by concurrent or sequential administration of other therapies. In some embodiments, the patient is a human. [0031] In some embodiments, one or more RAR agonist compounds can be administered alone or in combination with another therapeutic compound. Any currently known therapeutic compound used in treatment of inflammatory conditions can be used. In some embodiments, RAR agonist can be administered in combination with hydrogen sulfide (H2S). In some embodiments RAR agonist can be administered in combination with antioxidants. In some embodiments RAR agonist can be administered in combination with, for example, corticosteroids, biologies (e.g. anti- TNF-alpha and anti-IL-6), immunomodulators (e.g. RU-486), disease modifying anti-rheumatic drugs (DMARDS, such as leflunomide), COX-2 inhibitors (celecoxib), non-steroidal antiinflammatory drugs (NS AIDS, such as naproxen), oral anti -diabetic (OAD, such as metformin or sitaglipten), GLP-1 agonists, insulin, PPAR agonists/antagonists, EGF mediators (anti-cancer agents), other agents effective to treat hepatic cancers, cell-based therapies for liver cancers; interferons (IFN) for Hepatitis C, multiple sclerosis or lupus erythematosus; and LFA-1 antagonists.

[0032] In some embodiments, pro-inflammatory type I NKT cell activity is inhibited by one or more RAR agonists selected from the group consisting of ATRA, retinol, 9-cis-RA or 13-cis-RA, tretinoin, AM580, AC55649, CD1530 or tazarotene. In some embodiments, pro-inflammatory type I NKT cell activity is inhibited by one or more polyolefmic retinoids, such as isoretinoin and acitretin. In some embodiments, pro-inflammatory type I NKT cell activity is inhibited by one or more RAR agonists selected from the group consisting of etretinate, acitretin and isotretinoin.

[0033] Several embodiments relate to the inhibition of pro-inflammatory type I NKT cell activity by tazarotene, tazarotenic acid or a mixture thereof Tazarotene is an ethyl ester prodrug that is metabolized to the corresponding free acid, tazarotenic acid. Tazarotene has a rigid ring- locked structure that offers limited conformational flexibility compared to all-trans-retinoic acid, the natural ligand for the retinoic acid receptors (RARs). This structural change confers tazarotenic acid with specificity for the RARs and selectivity for RARP and RARγ.

[0034] Examples of RAR agonists further include esters of cis- and trans- retinoic acids, for example, alkyl esters, such as primary, secondary or tertiary alcohols, including but not limited to: methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, hexyl, heptyl, ethylhexyl, octyl, nonyl, lauryl, oleyl, stearyl, hydroxyethyl, hydroxypropyl, benzyl, alpha-methylbenzyl, alpha-propylphenyl, amyl, iso-amyl, anisyl, cetyl, menthyl, cinnamyl, pinacol, furyl, or myristyl. [0035] The RAR agonist compounds described herein may be used as an active ingredient incorporated into a pharmaceutical composition. In some embodiments the pharmaceutical composition may comprise a single active ingredient. In some embodiments the pharmaceutical composition may comprise two, three, four, five or more active ingredients. All modes of administration are contemplated, for example, orally, rectally, parenterally, topically, or by intravenous, intramuscular, intrastemal or subcutaneous injection or in a form suitable by inhalation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. The active ingredients will ordinarily be formulated with one or more pharmaceutically acceptable excipients in accordance with known and established practice. Thus, the pharmaceutical composition can be formulated as a liquid, powder, elixir, injectable solution, suspension, suppository, etc.

[0036] Pharmaceutically acceptable salts of RAR agonists can also be used to inhibit type I NKT cell activity. Compounds disclosed herein which possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly can react with any of a number of organic or inorganic bases, and inorganic and organic acids, to form a salt.

[0037] Examples of acids that may be used to form acid addition salts from RAR agonists with basic groups include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenyl- sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such salts include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne- 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycol ate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

[0038] Examples of bases that may be used to form base addition salts from RAR agonists with acidic groups include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy- substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2- hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethypamine, 2-hydroxy-tert- butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy lower alkyl)- amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl) amine; N- methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.

III. CD8 Regulatory T cells

[0039] It is contemplated that a combination of administering CD8 T_reg cells and administering an NKT-2 activator in accordance with some embodiments herein can be useful for treating or preventing an inflammatory condition, for example COVID-19. In some embodiments, CD8 T_reg cells are administered to a subject who has, or is at risk of developing an inflammatory condition. An NKT-2 inhibitor can also be administered to the subject. Optionally, the NKT-2 inhibitor comprises miltefosine. Optionally, the inflammatory condition comprises at least one of: COVID- 19, inflammation-induced tissue damage, fibrosis, or a combination of two or more of these listed items.

[0040] In some embodiments, the T_reg cells administered comprise CD8αα⁺, TCRaP⁺, CD200⁺ cells. In some embodiments, the T_reg cells administered comprise CD8αα +, TCRaP+, IL-2RP⁺ (CD122). In some embodiments, the T_reg cells administered comprise CD8αα TCRaP⁺, CD200⁺, CD122⁺. Without being limited by any theory it is contemplated that each of CD8αα⁺, TCRaP⁺, CD200⁺ T_reg cells, CD8αα⁺, TCRaP⁺, CD122⁺ T_reg cells and CD8αα⁺, TCRaP⁺, CD200⁺, CD122⁺ T_reg cells also control the population of activated nb8.2⁺ CD4 T cells in vivo and can be utilized in similar ways as the CD8αα⁺, TCRaP⁺ T_reg cells described herein.

[0041] In some embodiments, the regulatory T cells are administered to the same subject from which they were obtained. In other embodiments, the regulatory T cells can be administered to a subject other than the subject from which they were obtained. In still other embodiments, the regulatory T cells can be obtained from a mammal that is not a subject. In some embodiments, the administered regulatory T cells comprise a mixture of cells obtained from at least two of: the subjects to whom the regulatory T cells are administered, a subject other than the subject to whom the regulatory T cells are administered, and a non-subject mammal.

[0042] In some embodiments, anti-CD3 coated plates with growth factors such as IL-2, IL-7 and IL-15 are used to expand the T cell population. In some embodiments, T_reg can be expanded in vitro using recombinant TCR proteins or peptides, for example p42-50 derived from the TCR nb 8.2 chain. Optionally, the the TCR nb or Va chain gene utilized by disease-specific pathogenic T cells can be determined. Then, the proteins corresponding to those TCR nb or Va chain genes can be introduced into the body to activate the appropriate T_reg cell population.

[0043] A number of different modes and methods of administration of the therapeutic T_reg cell population are suitable in accordance with embodiments described herein. In some embodiments, delivery routes include, for example, intravenous, intraperitoneal, inhalation, intramuscular, subcutaneous, nasal and oral administration or any other delivery route available in the art. Depending on the particular administration route, the dosage form may be, for example, solid, semisolid, liquid, vapor or aerosol preparation. The dosage form may include, for example, those additives, lubricants, stabilizers, buffers, coatings, and excipients available in the art of pharmaceutical formulations.

IV. ARDS and Organ Failure due to Hypoxia in COVID-19 Patients [0044] Primary drivers of death in COVID-19 patients can include organ failure due to hypoxia and Acute Respiratory Distress Syndrome (ARDS). Patients infected with SARS-CoV-2 may experience organ failure, including but not limited to renal failure, heart failure, liver damage or failure, or multi-organ failure, as a result of the lack of oxygen brought on by the infection. Additionally and/or alternatively, patients infected with SARS-CoV-2 may experience respiratory failure in the form of ARDS as a result of the infection. ARDS, or wet lung, causes fluid to collect in the air sacs of the lungs, depriving organs of oxygen, potentially to the point of organ failure as described above.

V. Definitions

[0045] As used herein, the term “alkyl” means any unbranched or branched, saturated hydrocarbon. The term “substituted alkyl” means any unbranched or branched, substituted saturated hydrocarbon. Cyclic compounds, both cyclic hydrocarbons and cyclic compounds having heteroatoms, are within the meaning of “alkyl.”

[0046] As used herein, the term “substituted” means any substitution of a hydrogen atom with a functional group.

[0047] As used herein, the term “functional group” has its common definition, and refers to chemical moieties preferably selected from the group consisting of a halogen atom, C₁ to C20 alkyl, substituted C₁ to C20 alkyl, perhalogenated alkyl, cyloalkyl, substituted cycloalkyl, aryl, substituted aryl, benzyl, heteroaryl, substituted heteroaryl, cyano, and nitro.

[0048] As used herein, the terms “halogen” and “halogen atom” refer to any one of the radiostable atoms of column VII of the Periodic Table of the Elements, preferably fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being particularly preferred.

[0049] As used herein, the term “alkenyl” means any unbranched or branched, substituted or unsubstituted, unsaturated hydrocarbon. The term “substituted alkenyl” means any unbranched or branched, substituted unsaturated hydrocarbon, substituted with one or more functional groups, with unbranched C2-C6 alkenyl secondary amines, substituted C2-C6 secondary alkenyl amines, and unbranched C2-C6 alkenyl tertiary amines being within the definition of “substituted alkyl.” Cyclic compounds, both unsaturated cyclic hydrocarbons and cyclic compounds having heteroatoms, are within the meaning of “alkenyl ”

[0050] As used herein, the term “alkoxy” refers to any unbranched, or branched, substituted or unsubstituted, saturated or unsaturated ether.

[0051]

[0052] As used herein, the term “cerebroside” refers to any lipid compound containing a sugar, and generally of the type normally found in the brain and nerve tissue.

[0053] As used herein, the term “patient” or “subject” refers to the recipient of a therapeutic treatment and includes all organisms within the kingdom animalia. In preferred embodiments, the animal is within the family of mammals, such as humans, bovine, ovine, porcine, feline, buffalo, canine, goat, equine, donkey, deer and primates. In some embodiments, the animal comprises a non-human mammal. The most preferred animal is human. Accordingly, in some embodiments, the patient or subject is a human.

[0054] As used herein, the terms “treat” “treating” and “treatment” include “prevent” “preventing” and “prevention” respectively.

[0055] As used herein the term “an effective amount” of an agent is the amount sufficient to treat, inhibit, or prevent tissue damage resulting from pro-inflammatory type 1 NKT cell activity. [0056] As used herein, “inflammatory conditions associated with Novel Coronavirus SARS- CoV-2” include for example, excessive cytokine release, also known as cytokine release syndrome. Examples include, without limitation, IL-6, TNF and IL-1. VI. Compounds

[0057] The compound of formula (I) may be in the form of pharmaceutically acceptable nontoxic salts thereof. Salts of formula (I) include acid added salts, such as salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid) or with organic acids (e.g., acetic acid, propionic acid, maleic acid, oleic acid, palmitic acid, citric acid, succinic acid, tartaric acid, fumaric acid, glutamic acid, pantothenic acid, laurylsulfonic acid, methanesulfonic acid and phthalic acid).

[0058] The compound of formula (I) may be in the form of solvates thereof (e.g., hydrates).

[0059] The compound of formula (I) can be produced by any purposive method to synthesize sulfatides. [0060] The compound of formulas (I) can also be isolated from natural products (e.g., biological organisms) and purified by column chromatography or the like.

[0061] In some embodiments, the NKT-2 activator comprises a LPC having the formula of formula I:

Formula I

wherein R is selected from the group consisting of a C₁ to C40 alkyl, a C₁ to C40 substituted alkyl, a C₁ to C40 alkenyl, a C₁ to C40 substituted alkenyl and a C₁ to C40 alkynl. Example LPCs include LPC (08:0), the structure of which is depicted below,

LPC (06:0), the structure of which is depicted below,

LPC (C18:1(9Z)), the structure of which is depicted below,

LPC (08: l(loleyl)), the structure of which is depicted below,

and Lign A (LPC (C24:0)), the structure of which is depicted below,

[0062] Additional example phospholipids contemplated as suitable NKT-2 activators include, but are not limited to, lyso platelet-activating factor (LPAF), such as LPAF (08:0), the structure of which is depicted below,

and lysosphingomyelin (LSM), the structure of which is depicted below,

[0063] In some embodiments, the NKT-2 activator comprises miltefosine. The structure of miltefosine is shown below:

[0064] In some embodiments, the NKT-2 activator comprises a miltefosine analog. As used herein, “miltefosine analog” refers broadly to structural analogs of miltefosine and functional analogs of miltefosine. Some miltefosine analogs in accordance with some embodiments herein comprise compounds of formula V: Formula V

wherein R is selected from the group consisting of a C₁ to C30 alkyl, a C₁ to C30 substituted alkyl, a C₁ to C30 alkenyl, a C₁ to C30 substituted alkenyl and a C₁ to C30 alkynl.

[0065] Example miltefosine analogs that can be used in accordance with some embodiments herein include, but are not limited to compounds listed in Table 2.1 and 2.2, below.

Table 2,1: Miltefosine analogs

[0066] In some embodiments, the miltefosine analog comprises, consists of, or consists essentially of any of the compounds shown in Table 2.1. In some embodiments, the miltefosine analog comprises, consists of, or consists essentially of a compound selected from Table 2.1. In some embodiments, the miltefosine analog comprises, consists of, or consists essentially of any of the compounds shown in Table 2.1 or Table 2.2. In some embodiments, the miltefosine analog comprises, consists of, or consists essentially of a compound selected from Table 2.1 or Table 2.2. In some embodiments, the miltefosine analog comprises, consists of, or consists essentially of any of the compounds shown in Table 2.2. In some embodiments, the miltefosine analog comprises, consists of, or consists essentially of a compound selected from Table 2.2. In some embodiments, the miltefosine analog comprises, consists of, or consists essentially of a compound of formula (V).

[0067] All modes of administration of miltefosine and miltefosine analogs are contemplated, for example, orally, rectally, parenterally, topically, or by intravenous, intramuscular, intrastemal or subcutaneous injection or in a form suitable by inhalation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. The active ingredients will ordinarily be formulated with one or more pharmaceutically acceptable excipients in accordance with known and established practice. Thus, the pharmaceutical composition can be formulated as a liquid, powder, elixir, injectable solution, suspension, suppository, etc.

[0068] Miltefosine can be suitable for oral or topical administration. As such, in some embodiments, miltefosine or a miltefosine analog is administered orally. In some embodiments, miltefosine or a miltefosine analog is administered topically. In some embodiments, miltefosine or a miltefosine analog is administered by intravenous, intramuscular, intrastemal or subcutaneous injection or in a form suitable by inhalation.

VII. Pharmaceutical compositions

[0069] The NKT-2 activators, such as miltefosine or miltefosine analogs or phospholipids, and RAR agonist compounds described herein may be used as an active ingredient incorporated into a pharmaceutical composition. In some embodiments the pharmaceutical composition may comprise a single active ingredient. In some embodiments the pharmaceutical composition may comprise two, three, four, five or more active ingredients. Any of the following NKT-2 activator compositions can be for use in treating, ameliorating, or preventing an inflammatory condition, for example, COVID-19, fibrosis, or other inflammation-induced tissue damage.

[0070] In some embodiments, the pharmaceutical composition comprises an amount of NKT-2 activator (for example miltefosine or a miltefosine analog or a phospholipid) sufficient to activate type II NKT cells. Optionally, the pharmaceutical composition further comprises an amount or RAR agonist, such as a retinoid for example tazarotene sufficient to inhibit activation of type I NKT cells.

[0071] In some embodiments, the pharmaceutical composition comprises an amount of miltefosine or a miltefosine analog sufficient to activate type II NKT cells and an amount of tazarotene sufficient to inhibit activation of type I NKT cells.

[0072] All modes of administration are contemplated, for example, orally, rectally, parenterally, topically, or by intravenous, intramuscular, intrastemal or subcutaneous injection or in a form suitable by inhalation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. The active ingredients will ordinarily be formulated with one or more pharmaceutically acceptable excipients in accordance with known and established practice. Thus, the pharmaceutical composition can be formulated as a liquid, powder, elixir, injectable solution, suspension, suppository, etc. Approaches for pharmaceutical formulations are described in detail in Remington’s Pharmaceutical Sciences, 18th Edition, A.R. Gennaro, ed., Mack Publishing Company (1995), which is hereby incorporated by reference in its entirety.

[0073] Active ingredients according to some embodiments can be formulated for administration for oral administration as tablets, hard gelatin capsules, soft gelatin capsules, comprising the active in the form of a powder, a blend with excipients, a liquid or solution, a suspension, a solid solution. Active ingredients according to some embodiments can be formulated for administration for intra oral administration (sublingual or buccal) as a solid dosage form rapidly dissolving or effervescent tablets, thin films, buccal wafers, or as a liquid or semi-solid form, such as a gel, solution, emulsion, suspension. Active ingredients according to some embodiments can be formulated for administration for injection as an aqueous or non-aqueous solution, suspension or emulsion. Oil- based solutions and suspensions comprise mixtures of natural and or synthetic oils such as soybean oil, cotton seed oil, mineral oil, sesame oil, castor oil, hydrogenated vegetable oils, beeswax. Active ingredients according to some embodiments can be formulated for administration for transdermal administration as a cream, a gel, an emulsion, an aqueous-based solution, an oil-based solution, a suspension, a film, a patch, a foam. Active ingredients according to some embodiments can be formulated for administration for intranasal administration as a powder, suspension, solution, emulsion. Active ingredients according to some embodiments can be formulated for administration for pulmonary delivery as a micronized powder. Oral administration is associated with first pass metabolism as well as induction of metabolizing enzymes. Thus dosage strength and dosing regimen of oral administered retinoic acids may be tailored for optimal effect. Alternative routes of delivery, e.g. sublingual, buccal, injection, pulmonary and transdermal, may be a preferred over oral administration. Alternative routes of administration, such as those as described, avoid first pass metabolism and GI absorption, demonstrate less enzyme induction and provide steady repeat dose pharmacokinetics.

[0074] Pharmaceutical formulations according to the present embodiments may be immediate release or modified release (e.g., sustained release, pulsatile release, controlled release, delayed release, slow release). Because it is immediately active, pharmacological amounts of orally administered Retinoid isomers may have side effects. These side effects have been a serious limitation to the use of oral retinoids in therapy. Although topically applied retinoids carry little teratogenic liability there are other toxicities associated with this route of administration that limit their use including skin irritation. A major reason for both oral and topical toxicity is that the retinoids are totally and immediately available upon administration. A process whereby a retinoid can be made available in vivo more slowly and more continuously would avoid peaks and valleys in the availability of the retinoid thereby providing an effective in vivo level of the compound over a more prolonged period of time and also avoiding or substantially reducing the toxicities that often result from the sudden availability of excessive amounts of the substance. An oil based injectable formulation of retinol, ester of retinol, and in particular a fatty ester of retinol, retinoic acid or a retinoic acid ester could be administered intra-muscularly on a weekly basis and provide a systemic slow-release delivery, according to such principles.

[0075] Some embodiments relate to a kit, which may include one or more RAR agonists, preferably as a pharmaceutical composition. In some embodiments, cis-tetracosenoyl is provided in a pharmaceutically acceptable carrier. In some embodiments, ATRA is provided in a pharmaceutically acceptable carrier. In some embodiments, tazarotene is provided in a pharmaceutically acceptable carrier. In several embodiments, hydrogen sulfide (H₂S) may optionally be provided. In several embodiments, one or more antioxidants may optionally be provided. In several embodiments, kits may further comprise suitable packaging and/or instructions for use. Kits may also comprise a means for the delivery of the one or more RAR agonists, such as an inhaler, spray dispenser (e.g., nasal spray), syringe for injection, needle, W bag or pressure pack for capsules, tables, suppositories. The one or more RAR agonists can be in a dry or lyophilized form or in a solution, particularly a sterile solution. When in a dry form, the kit may comprise a pharmaceutically acceptable diluent for preparing a liquid formulation. The kit may contain a device for administration or for dispensing the compositions, including, but not limited to, syringe, pipette, transdermal patch, or inhalant. Some embodiments relate to kits that contain sufficient dosages of the compounds or composition to provide effective treatment for an individual for an extended period, such as a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks or more.

[0076] A number of different pharmaceutical formulations are contemplated in accordance with embodiments described herein. In some embodiments, a pharmaceutical formulation comprises CD8 T_reg cells and an NKT-2 activator as described herein. In some embodiments, a pharmaceutical formulation comprises CD8 T_reg cells and miltefosine. In some embodiments, a pharmaceutical formulation comprises at least one of the following types of CD8 T_reg cells: CD8αα+ TCRaP+ T cells, CD8αα+ TCRaP± CD200⁺ T cells, CD8αα⁺ TCRaP± CD122⁺ T cells, and CD8αα⁺, TCRal³±, CD200⁺ CD122⁺ T cells, and further comprises an NKT-2 activator as described herein. In some embodiments, a pharmaceutical formulation comprises at least one of the following types of CD8 T_reg cells: CD8αα⁺ TCRaP⁺ T cells, CD8αα⁺ TCRaP⁺ CD200⁺ T cells, CD8αα⁺ TCRal³⁺ CD122⁺ T cells, and CD8αα⁺, TCRaP⁺, CD200⁺ CD122⁺ T cells, and further comprises miltefosine. In some embodiments, a first pharmaceutical formulation comprises CD8 Treg cells and a second pharmaceutical formulation comprises an NKT-2 activator as described herein.

[0077] In some embodiments, a first pharmaceutical formulation comprises CD8 T_reg cells and a second pharmaceutical formulation comprises miltefosine. In some embodiments, a first pharmaceutical formulation comprises at least one of the following types of CD 8 T_reg cells: CD8αα TCRaP⁺ T cells, CD8αα TCRaP± CD200⁺ T cells, CD8αα TCRaP± CD122⁺ T cells, and CD8αα⁺, TCRaP⁺, CD200⁺ CD122⁺ T cells and a second pharmaceutical formulation comprises an NKT-2 activator. In some embodiments, a first pharmaceutical formulation comprises at least one of the following types of CD8 T_reg cells: CD8αα⁺ TCRaP⁺ T cells, CD8αα⁺ TCRal³⁺ CD200⁺ T cells, CD8αα⁺ TCRaP⁺ CD122⁺ T cells, and CD8αα ⁺, TCRaP⁺, CD200⁺ CD122⁺ T cells and a second pharmaceutical formulation comprises miltefosine. In some embodiments, the first and second pharmaceutical formulations are administered concurrently. In some embodiments, the first and second pharmaceutical formulations are administered at different times. In some embodiments, the first pharmaceutical formulation is administered prior to the second pharmaceutical formulation. In some embodiments, the second pharmaceutical formulation is administered prior to the first pharmaceutical formulation. Optionally, any of the pharmaceutical formulations described herein can be prepared by conventional methods using the following pharmaceutically acceptable vehicles or the like: excipients such as solvents (e.g., water, physiological saline), bulking agents and filling agents (e.g., lactose, starch, crystalline cellulose, mannitol, maltose, calcium hydrogenphosphate, soft silicic acid anhydride and calcium carbonate); auxiliaries such as solubilizing agents (e.g., ethanol and polysolvates), binding agents (e.g., starch, polyvinyl pyrrolidine, hydroxypropyl cellulose, ethylcellulose, carboxymethyl cellulose and gum arabic), disintegrating agents (e.g., starch and carboxymethyl cellulose calcium), lubricating agents (e.g., magnesium stearate, talc and hydrogenated oil), stabilizing agents (e.g., lactose, mannitol, maltose, polysolvates, macrogol, and polyoxyethylene hydrogenated castor oil), isotonic agents, wetting agents, lubricating agents, dispersing agents, buffering agents and solubilizing agents; and additives such as antioxidants, preservatives, flavoring and aromatizing agents, analgesic agents, stabilizing agents, coloring agents and sweetening agents. [0078] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

EXAMPLES

Example 1: Inhibition or inactivation of iNKT cells as a novel target in the novel Coronavirus SARS-CoV-2-mediated inflammatory conditions

[0079] The coronavirus disease 2019 (COVID-19) pandemic has spread from Wuhan, China [1] to more than 180 countries and territories to date worldwide, and has led to severe morbidity and mortality in the inflicted populations. The causative agent of COVID-19 has been identified as a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [2, 3] with ~ 96% identical to other coronaviruses that had originated from bats [3, 4], Interestingly, unlike the other corona viruses, SARS and MERs, the incubation period of the COVID-19 virus is relatively longer than ranging from 7-14 days vs. 5.0-6.9 and 4.4-6.9 days, respectively [4] and the mean reproductive number (Ro) of SARS-CoV-2 has been estimated to be higher ranging from 2.20 to 3.58, indicating that each infected patient has on average been spreading the viral infection to two to three other individuals [5, 6], For infected patients, the severity of symptoms has been classified as mild, severe, and critical. This spectrum of disease symptoms widely varies, as clinical presentations in infected individuals have ranged from asymptomatic infection to severe respiratory failure, with older individuals and/or those having underlying medical conditions such as immunosuppression and metabolic disease having more severe or critical symptoms [2], Thus, asymptomatic transmission of COVID-19 poses a great challenge for the containment efforts [7],

[0080] To date, approximately 5.8 million cases globally have been identified thus far with SARS-CoV-2 infection worldwide and in the absence of any vaccine or treatment morbidity and mortality is a major issue in the World at present. At present immunological mechanism(s) by which this virus generates severe disease and death is not understood. It is clear that controlling the inflammatory response may be as important as targeting the virus itself (Tay et al 2020). Thus, recent data suggest (Reviewed in Tay et al, Nature Reviews, 2020) that there is an immunological imbalance in several critical immune populations in severe COVID-19 patients, including most abundant neutrophils lymphocyte population in lung and inflammatory cytokine storm appears to be a major pathological mechanism leading to tissue and organ damage [8] [9, 10] (Barnes, Tweet, April 2020) (Wang et al, Cell Mol Immmmunol, 2020). Among different damaging cytokines, IL- 6 seems to play a crucial pathogenic role in COVID-19 disease (Ascierto et al, 2020). Thus, IL-6 levels have been found to be higher in non-survivors in comparison to survivors (Zhou et al, Lancet, 2020, Heberman et al., NEJM, 2020). It is also becoming clear that COVID-19 pathology initially may involve only lung tissue but eventually other organs including liver, heart and bowl become inflamed. And in these vital organs fibrosis seems to play an important role in disease pathology.

[0081] Based upon the role of iNKT cells in fibrosis, neutrophil recruitments and blunting cytokine storm, including IL-6, it is clear that agents that can inactivate or inhibit this critical innate-like iNKT cell population should result in mitigation of the COVID-19 disease (Maricic et al, 2015 and 2018, Mathews 2018 and KC Lee et al 2019). Consistent with this, we have demonstrated the following two points. First, genetic deficiency of iNKT cells but not type II NKT cells leads to a lack of inflammatory neutrophil recruitments into organs; inhibition of cytokine storm, including IL-6, TNF and IL-1; inhibition of fibrosis; and other inflammatory conditions. Second, inactivation of inhibition of iNKT cells either directly using tazarotene or indirectly using a type II NKT activator, such as miltefosine, leads to inhibition of neutrophil recruitment; inflammatory cytokines, including IL-6; fibrosis; and organ damage.

[0082] Therefore, iNKT inhibitor tazarotene and/or miltefosine, either alone or in combination, presents an important avenue towards mitigating COVID-19-mediated disease establishment and progression.

Example 2: Involvement of NKT I cells in the novel Coronavirus SARS-CoV-2-mediated disease COVID-19.

[0083] Severe illness in individuals infected with SARS-CoV-2 is not solely correlated to viral load, and an excessive inflammatory response is thought to be a major cause of disease severity and death in patients with COVID-19 [1],

[0084] Almost all patients infected with SARS-CoV-2, both older and younger, present with lung involvement. Severe complications in a sub-group of patients is marked by increased neutrophils, increased serum levels of inflammatory cytokines and chemokines [2-5] and increased inflammatory monocytes and macrophages, perhaps driven by a strong innate immune response [6], SARS-CoV-2 infection may also cause T cell lymphopenia, increased FAS expression, and activation-induced cell death [7], Increased FASL expression on activated NKT I [8] may also be seen. Therefore, it is possible that NKT I mediated activation-induced cell death via FAS-FASL could be driving lymphopenia.

[0085] Neutrophils are increased in COVID-19 patients [9-11] and patients may show pulmonary disease with NKT involvement [12], NKT regulates neutrophil recruitment in liver [13, 14] and pulmonary models.

[0086] Macrophage subsets in COVID-19 patients are enriched in genes associated with tissue repair and fibrosis, such as seen in liver cirrhosis [15]. NKT I-mediated enrichment of similar populations was observed in ALD and NASH [13, 16] , IPF [17] and chronic pulmonary disease [18], High levels of IFNg, IL-6, TNFa, TGFb and CXCL10 have been seen in severe COVID-19 patients [1, 19-21], Inhibition of NKT I has been shown to reduce these cytokines and inflammasome-related genes in liver disease [13, 14, 16, 22] and pulmonary models [17, 18, 23].

[0087] Increased IP-10 has been shown in COVID-19 patients [1, 2], Pathogenic NKT I cells overexpress CXCR3 (receptor for IP- 10) in liver disease, and are correlated with severe disease [13]·

[0088] Severe COVID-19 co-morbidities or risk factors [3, 24-26] are NKT-mediated diseases, type 2 diabetes, obesity and liver disease [13, 14, 16, 27-32], pulmonary disease [17, 33-36]. COVID-19 patients may present with pulmonary fibrosis [37]. Inhibiting NKT I in multiple animal models protects from fibrosis [13, 14, 16, 17]. NKT I cells have also been implicated in promoting chronic lung disease following respiratory viral infection [18].

REFERENCES FOR EXAMPLE 1

1. Cascella, M., et al., Features, Evaluation and Treatment Coronavirus (COVID-19), in StatPearls. 2020: Treasure Island (FL).

2. He, F., Y. Deng, and W. Li, Coronavirus disease 2019: What we know? J Med Virol, 2020

3. Lu, R., et al., Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet, 2020. 395(10224): p. 565- 574.

4. Yi, Y., et al., COVID-19: what has been learned and to be learned about the novel coronavirus disease. Int J Biol Sci, 2020. 16(10): p. 1753-1766. 5. Zhuang, Z., et al., Preliminary estimation of the novel coronavirus disease (COVID-19) cases in Iran: A modelling analysis based on overseas cases and air travel data. Int J Infect Dis, 2020.

6. Zhao, S., et al., Preliminary estimation of the basic reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: A data-driven analysis in the early phase of the outbreak. Int J Infect Dis, 2020. 92: p. 214-217.

7. Du, Z., et al., Serial Interval of COVID-19 among Publicly Reported Confirmed Cases. Emerg Infect Dis, 2020. 26(6).

8. Zheng, M., et al., Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol, 2020.

9. McGonagle, D., et al., The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun Rev, 2020: p. 102537.

10. Bonow, R.O., et al., Association of Coronavirus Disease 2019 (COVID-19) With Myocardial Injury and Mortality. JAMA Cardiol, 2020.

REFERENCES FOR EXAMPLE 2

1. P, M., et al., COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression. Lancet (London, England), 2020. 395(10229).

2. C, EL, et al., Clinical Features of Patients Infected With 2019 Novel Coronavirus in Wuhan, China. Lancet (London, England), 2020. 395(10223).

3. G, C., et al., Clinical and Immunological Features of Severe and Moderate Coronavirus Disease 2019. The Journal of clinical investigation, 2020. 130(5).

4. Gong, J., et al., Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia. 2020.

5. Yang, Y., et al., Exuberant elevation of IP-10, MCP-3 and IL-lra during SARS-CoV-2 infection is associated with disease severity and fatal outcome. 2020.

6. F, Z., et al., Clinical Course and Risk Factors for Mortality of Adult Inpatients With COVID-19 in Wuhan, China: A Retrospective Cohort Study. Lancet (London, England), 2020. 395(10229). 7. chen, y., et al., The Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS- CoV-2) Directly Decimates Human Spleens and Lymph Nodes. 2020.

8. Kumar, V., NKT-cell subsets: promoters and protectors in inflammatory liver disease. J Hepatol, 2013. 59(3): p. 618-20.

9. F, W., et al., Characteristics of Peripheral Lymphocyte Subset Alteration in COVID-19 Pneumonia. The Journal of infectious diseases, 2020. 221(11).

10. FA, L.-R., Neutrophil-to-lymphocyte Ratio and lymphocyte-to-C-reactive Protein Ratio in Patients With Severe Coronavirus Disease 2019 (COVID-19): A Meta-Analysis. Journal of medical virology, 2020.

11. BJ, B., et al., Targeting Potential Drivers of COVID-19: Neutrophil Extracellular Traps. The Journal of experimental medicine, 2020. 217(6).

12. O, D., et al., The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis. Frontiers in medicine, 2018. 5.

13. Maricic, I. et al., Differential Activation of Hepatic Invariant NKT Cell Subsets Plays a Key Role in Progression of Nonalcoholic Steatohepatitis. J Immunol, 2018. 201(10): p. 3017-3035.

14. Mathews, S., et al., Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration. Cell Mol Immunol, 2016. 13(2): p. 206-16.

15. P, R., et al., Resolving the Fibrotic Niche of Human Liver Cirrhosis at Single-Cell Level. Nature, 2019. 575(7783).

16. Maricic, I, et al., Inhibition of type I natural killer T cells by retinoids or following sulfatide-mediated activation of type II natural killer T cells attenuates alcoholic liver disease in mice. Hepatology, 2015. 61(4): p. 1357-69.

17. Grabarz, F., et al., Protective role of NKT cells and macrophage M2 -driven phenotype in bleomycin-induced pulmonary fibrosis. Inflammopharmacology, 2018. 26(2): p. 491-504.

18. EY, K., et al., Persistent Activation of an Innate Immune Response Translates Respiratory Viral Infection Into Chronic Lung Disease. Nature medicine, 2008. 14(6). 19. M, A., F. R, and A. R, Elevated Interleukin-6 and Severe COVID-19: A Meta-Analysis. Journal of medical virology, 2020.

20. F, W., et al., The Laboratory Tests and Host Immunity of COVID-19 Patients With Different Severity of Illness. JCI insight, 2020.

21. T, H. and M. M, COVID-19: A New Virus, but a Familiar Receptor and Cytokine Release Syndrome. Immunity, 2020.

22. Marrero, F, et al., Complex Network of NKT Cell Subsets Controls Immune Homeostasis in Liver and Gut. Front Immunol, 2018. 9: p. 2082.

23. Borger, J.G., M. Lau, and M.L. Hibbs, The Influence of Innate Lymphoid Cells and Unconventional T Cells in Chronic Inflammatory Lung Disease. Front Immunol, 2019.

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24. Z, Z., et al., Risk Factors of Critical & Mortal COVID-19 Cases: A Systematic Literature Review and Meta-Analysis. The Journal of infection, 2020.

25. GH, P. and O. P, Potential Implications of COVID-19 in Non-Alcoholic Fatty Liver Disease. Liver international : official journal of the International Association for the Study of the Liver, 2020.

26. Q, Z., et al., The Impact of COPD and Smoking History on the Severity of COVID-19: A Systemic Review and Meta-Analysis. Journal of medical virology, 2020.

27. Wolf, M. J., et al., Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell, 2014. 26(4): p. 549-64.

28. Ren, Y., et al., A Novel Mouse Model of iNKT Cell-deficiency Generated by CRLSPR/Cas9 Reveals a Pathogenic Role of iNKT Cells in Metabolic Disease. Sci Rep, 2017. 7(1): p. 12765.

29. de Lalla, C., et al., Production ofprofibrotic cytokines by invariant NKT cells characterizes cirrhosis progression in chronic viral hepatitis. J Immunol, 2004. 173(2): p. 1417-25. 30. Syn, W.K., et al., Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology, 2010. 51(6): p. 1998-2007.

31. Wei, X., et al., Hyperactivated peripheral invariant natural killer T cells correlate with the progression of HBV-relative liver cirrhosis. Scand J Immunol, 2019: p. el2775. 32. Jahng, A., et al., Prevention of autoimmunity by targeting a distinct, noninvariant CDld- reactive T cell population reactive to sulfatide. J Exp Med, 2004. 199(7): p. 947-57.

33. O, A., et al., CD4+ Invariant T-cell-receptor+ Natural Killer T Cells in Bronchial Asthma. The New England journal of medicine, 2006. 354(11).

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35. Pan, H., et al., Sulfatide-activated type II NKT cells suppress immunogenic maturation of lung dendritic cells in murine models of asthma. Am J Physiol Lung Cell Mol Physiol, 2019. 317(5): p. L578-L590.

36. Tsao, C.C., et al., Repeated Activation of Lung Invariant NKT Cells Results in Chronic Obstructive Pulmonary Disease-Like Symptoms. PLoS One, 2016. 11(1): p. e0147710.

37. H, S., et al., Radiological Findings From 81 Patients With COVID-19 Pneumonia in Wuhan, China: A Descriptive Study. The Lancet. Infectious diseases, 2020. 20(4).

Claims

WHAT IS CLAIMED IS:

1. A method for the treatment and prevention of an inflammatory condition associated with Novel Coronavirus SARS-CoV-2 comprising administering to a subject one or more of the compounds substantially described and illustrated herein.

2. A method of treating a patient with a SARS-CoV-2 infection comprising administering to a subject one or more of the compounds substantially described and illustrated herein.