Prevention and treatment of inflammatory conditions
Inventors
Assignees
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Publication Number
US-9949996-B2
Publication Date
2018-04-24
Expiration Date
Abstract
The present embodiments relate to methods for the prevention and treatment of inflammatory conditions such as alcoholic liver disease (ALD). More specifically the present embodiments relate to the prevention and treatment of ALD through the administration of an Retinoic Acid Receptor (RAR) agonist. Some embodiments relate to use of tazarotene in the prevention and treatment of alcohol-induced liver injury, alcohol-related liver disease, fatty liver disease, hepatic steatosis, alcoholic hepatitis or alcoholic cirrhosis.
Core Innovation
The invention relates to preventing and treating inflammatory liver conditions by modulating innate immunity through retinoic acid receptor (RAR) agonists. In particular, the disclosed methods administer a RARγ-selective agonist effective to inhibit activation and activity of type I NKT cells in a patient, with the inhibition of type I NKT cell activity described as a mechanism for treating inflammatory conditions, including fatty liver disease and alcohol induced hepatitis.
The disclosure further includes inhibiting pathogenic type I NKT cells and optionally administering sulfatide and synthetic sulfatide analogs to activate regulatory type II NKT cells that suppress type I NKT activity. The downstream immune effects are described in terms of reduced IFN-γ and reduced recruitment of myeloid and NK cells, leading to reduced hepatic tissue injury.
The material also supports this RARγ-selective strategy by listing numerous RAR agonists and retinoid agents, including ATRA, tazarotene, tazarotenic acid, tretinoin, 9-cis retinoic acid, 13-cis retinoic acid, retinol, isoretinoin, acitretin, etretinate, and isotretinoin, as well as RAR subtype-selective agents. The compounds may be provided as pharmaceutically acceptable salts.
Claims Coverage
The independent claim set includes 2 independent claims. Both claims center on administering an amount of a RARγ-selective agonist to inhibit type I NKT cell activity, with one claim specifically directed to non-alcoholic steatosis hepatitis.
Rarγ-selective agonist inhibiting type I nkt cell activation
A method for treating at least one inflammatory condition in a patient by administering an amount of a RARγ-selective agonist effective to inhibit activation of type I NKT cells, thereby inhibiting type I NKT cell activity in the patient, wherein the inflammatory condition is selected from fatty liver disease, alcohol induced hepatitis, non-alcoholic steatosis hepatitis, cirrhosis, fulminating cirrhosis, idiopathic hepatitis, viral-induced hepatitis, inflammatory hepatitis associated with hepato-biliary carcinoma, multiple sclerosis, type 1 diabetes, ischemic reperfusion injury, solid organ transplantation, systemic lupus erythematosus, rheumatoid arthritis, amyotrophic lateral sclerosis, inflammatory bowel disease, insulin dependent diabetes mellitus, autoimmune hepatitis, asthma, and celiac disease.
Rarγ-selective agonist reducing type I nkt cell activity for non-alcoholic steatosis hepatitis
A method for treating non-alcoholic steatosis hepatitis in a patient comprising administering to the patient an amount of a RARγ-selective agonist effective to reduce an activity of type I NKT cells, thereby reducing an activity of type I NKT cells in the patient.
Across both independent claims, the core inventive coverage is therapeutic modulation of innate immunity via a RARγ-selective agonist that reduces or inhibits type I NKT cell activation/activity, with the second claim narrowing the indication to non-alcoholic steatosis hepatitis.
Stated Advantages
Inhibits activation of type I NKT cells and thus inhibits type I NKT cell activity in the patient.
Reduces activity of type I NKT cells in the patient for treatment of non-alcoholic steatosis hepatitis.
Documented Applications
Treatment of inflammatory conditions selected from fatty liver disease, alcohol induced hepatitis, non-alcoholic steatosis hepatitis, cirrhosis, fulminating cirrhosis, idiopathic hepatitis, viral-induced hepatitis, inflammatory hepatitis associated with hepato-biliary carcinoma, multiple sclerosis, type 1 diabetes, ischemic reperfusion injury, solid organ transplantation, systemic lupus erythematosus, rheumatoid arthritis, amyotrophic lateral sclerosis, inflammatory bowel disease, insulin dependent diabetes mellitus, autoimmune hepatitis, asthma, and celiac disease.
Treatment of non-alcoholic steatosis hepatitis by reducing activity of type I NKT cells.
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