Uses of oxygenated cholesterol sulfates (OCS)
Inventors
Ren, Shunlin • Theeuwes, Felix • Brown, James E. • Lin, WeiQi
Assignees
Virginia Commonwealth University • Durect Corp • US Department of Veterans Affairs
Publication Number
US-11612609-B2
Publication Date
2023-03-28
Expiration Date
2034-12-23
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Abstract
Methods of preventing and/or treating ischemia, organ dysfunction and/or organ failure, including multiple organ dysfunction syndrome (MODS), and necrosis and apoptosis associated with organ dysfunction/failure, are provided. For instance, the methods involve contacting organ(s) with an oxygenated cholesterol sulfate (OCS), e.g. 5-cholesten-3,25-diol, 3-sulfate (25H-C3S). The organ(s) may be in vivo (e.g. in a patient that is treated with the OCS) or ex vivo (e.g. an organ that has been harvested from a donor and is to be transplanted).
Core Innovation
The invention provides methods and compositions for preventing and/or treating ischemia, organ dysfunction and/or organ failure, including multiple organ dysfunction syndrome (MODS), and necrosis and apoptosis associated with organ dysfunction or failure. The methods involve contacting an organ with one or more oxygenated cholesterol sulfates (OCS), such as 5-cholesten-3,25-diol, 3-sulfate (25HC3S). This contact may occur in vivo, by administering the OCS to a patient, or ex vivo, by applying the OCS to an organ harvested for transplantation.
A major problem addressed by the invention is the lack of effective agents that can prevent or reverse organ dysfunction and failure, which have significant clinical and economic impacts and for which current therapies are limited to treating root causes and supportive care. Organs harvested for transplantation face viability issues due to ischemia and inflammatory cytokines during storage and transport. Existing preservation methods are inadequate, necessitating biocompatible agents like OCS to maintain organ viability and to prevent cell death mechanisms such as necrosis and apoptosis.
Claims Coverage
The patent includes one independent claim specifically describing a method of treating acute liver dysfunction or failure in humans using a sodium salt of 5-cholesten-3,25-diol, 3-sulfate (25HC3S).
Method of treating acute liver dysfunction or failure using 25HC3S
Administering to a human subject an amount of a sodium salt of 5-cholesten-3,25-diol, 3-sulfate (25HC3S) sufficient to treat acute liver dysfunction or acute liver failure, particularly alcoholic hepatitis, with administration routes including oral, subcutaneous, intramuscular, intravenous, and injection, optionally with a pharmaceutically acceptable carrier, and dose ranges from about 0.001 mg/kg to about 100 mg/kg, administered from once to three times per day.
The independent claim centers on the medical use of 25HC3S in treating acute liver dysfunction or failure, highlighting various administration routes and dosage regimens to effectively treat conditions such as alcoholic hepatitis.
Stated Advantages
25HC3S is highly bioavailable even when administered orally.
Administration of 25HC3S significantly reduces mortality in animal models of acetaminophen-induced acute liver failure.
25HC3S treatment can restore markers of liver and kidney function towards normal levels.
Administration of 25HC3S reduces post-ischemic mortality in heart ischemia-reperfusion injury models.
25HC3S shows beneficial effects in animal models of brain ischemia, reducing brain lesion volumes and edema.
25HC3S prolongs survival in animal models of sepsis induced by lipopolysaccharide.
In human Phase I trials, 25HC3S was well tolerated at doses up to 600 mg with no observed adverse effects and demonstrated high bioavailability.
Documented Applications
Preventing and/or treating ischemia, including cardiac, brain, bowel, limb, and cutaneous ischemia, especially related to surgery.
Preventing and/or treating organ dysfunction and failure, including treatment of acute liver failure, kidney failure, multiple organ dysfunction syndrome (MODS), and dysfunction caused by acetaminophen toxicity.
Preserving ex vivo cells, organs, or tissues during transplant procedures, including contacting harvested material with 25HC3S to maintain viability.
Treating necrosis and apoptosis associated with organ dysfunction/failure.
Prophylactically treating sepsis and systemic inflammatory response syndrome (SIRS).
Using 25HC3S as a protective agent against organ damage caused by drugs such as acetaminophen, aspirin, and ibuprofen.
Treatment of various organ dysfunctions such as heart failure, pancreas failure, brain dysfunction, and kidney injury.
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