Prevention and treatment of inflammatory conditions
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Publication Number
US-10925886-B2
Publication Date
2021-02-23
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 a method of treating an inflammatory condition of the liver in a subject in need thereof by administering an amount of an RARγ-selective agonist sufficient to inhibit activation of pro-inflammatory type I NKT cells. The administered RARγ-selective agonist inhibits activation of pro-inflammatory type I NKT cells in the subject, thereby treating the inflammatory condition of the liver.
The description identifies RARγ-selective agonists and related retinoid compounds used in the context of suppressing pro-inflammatory type I NKT cell activity. Named agents include tazarotene and tazarotenic acid, and retinoids and retinol isomers, along with other RAR agonists such as ATRA/retinoids and RAR subtype-selective agonists including CD1530, AC55649, and AM580.
The rationale links selectivity for RARβ/RARγ to suppression of inflammatory type I NKT cell proliferation and cytokine production. The document discusses inhibition of type I NKT cell proliferation and inhibition of IFN-γ and IL-2 in the context of sulfatide and RAR agonists, with emphasis on agents such as ATRA and tazarotene and RAR-subtype agonists.
In the disclosed use context, the method is applied to inflammatory liver conditions including alcohol-induced liver injury, alcoholic liver disease, fatty liver disease, hepatic steatosis, alcoholic hepatitis, alcoholic cirrhosis, ConA-induced hepatitis, ethanol/chronic-plus-binge ALD in mice, and hepatic reperfusion injury. The inflammatory outcomes discussed include type I NKT cell activation readouts and liver injury readouts, and the document further describes administration schedules and formulation/kit concepts in connection with these retinoid/RAR agonist agents.
Claims Coverage
The document includes one independent claim covering a liver-inflammation treatment method using an RARγ-selective agonist to inhibit activation of pro-inflammatory type I NKT cells. Dependent claims refine the inflammatory liver condition scope and add an explicit dosing range.
Treating inflammatory liver conditions by administering an RARγ-selective agonist to inhibit pro-inflammatory type I NKT cell activation
Administering an amount of an RARγ-selective agonist sufficient to inhibit activation of pro-inflammatory type I NKT cells to the subject, wherein the administered RARγ-selective agonist inhibits activation of pro-inflammatory type I NKT cells in the subject, thereby treating the inflammatory condition of the liver.
Treating specified inflammatory liver conditions
The method of treating an inflammatory condition of the liver is defined by a selection including 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, ischemic reperfusion injury, and solid organ transplantation.
Treating alcohol-induced liver injury
The liver inflammatory condition is alcohol-induced liver injury selected from alcohol-related liver disease, fatty liver disease, hepatic steatosis, alcoholic hepatitis, and alcoholic cirrhosis.
Using hepatic reperfusion injury as the inflammatory liver condition
The liver inflammatory condition is hepatic reperfusion injury.
Using a dosing range of an RARγ-selective agonist
Carrying out the method using an amount of the RARγ-selective agonist ranging from about 1 mg/day to about 50 mg/day.
Across the independent and dependent claims, the central inventive concept is treatment of inflammatory liver disease by administering an RARγ-selective agonist to inhibit activation of pro-inflammatory type I NKT cells. Dependent claims further specify which inflammatory liver conditions are covered, including alcohol-induced liver injury subsets and hepatic reperfusion injury, and provide a quantitative dosing range.
Stated Advantages
Inhibits activation of pro-inflammatory type I NKT cells in the subject.
Treats an inflammatory condition of the liver.
Documented Applications
Prevention and treatment of inflammatory liver conditions, including alcohol-induced liver injury and alcoholic liver disease, based on inhibition of pro-inflammatory type I NKT cell activation.
Treating inflammatory liver conditions by suppressing pro-inflammatory type I NKT cell activity, including ConA-induced hepatitis and ethanol/chronic-plus-binge ALD in mice.
Assessing inhibition of type I NKT cell proliferation and reduction of IFN-γ and IL-2 using in vitro assays with sulfatide and RAR agonists.
Inflammatory liver conditions include fatty liver disease, non-alcoholic steatosis hepatitis, cirrhosis, fulminating cirrhosis, idiopathic hepatitis, viral-induced hepatitis, inflammatory hepatitis associated with hepato-biliary carcinoma, ischemic reperfusion injury, and solid organ transplantation.
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