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-10272097-B2
Publication Date
2019-04-30
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 (25HC3S). 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 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 or failure. The methods involve contacting one or more organs with an oxygenated cholesterol sulfate (OCS), particularly 5-cholesten-3,25-diol, 3-sulfate (25HC3S). The organs can be either in vivo, such as organs within a living patient, or ex vivo, such as organs harvested from a donor and prepared for transplantation.
The problem being addressed is the lack of available agents that can reverse established organ failure and the limited effectiveness of current therapies, which focus primarily on treating causative factors and supportive care. Organ dysfunction and failure, often caused by ischemia followed by inflammation and necrosis, have major clinical and economic impacts with high mortality rates. Additionally, organs harvested for transplantation suffer from functional decline due to ischemia and other factors during transport and storage, and better biologically compatible agents to maintain organ viability are needed.
Claims Coverage
The patent includes one independent claim related to a method of treating acute kidney dysfunction or acute kidney failure. The inventive features focus on administration of 25HC3S to treat acute kidney conditions in subjects without hyperlipidemia.
Method of treating acute kidney dysfunction or failure using 25HC3S
Administering to a subject an amount of 5-cholesten-3,25-diol, 3-sulfate (25HC3S) or its pharmaceutically acceptable salt sufficient to treat acute kidney dysfunction or failure, wherein the subject does not have hyperlipidemia. The administration may be performed orally or by various injection routes. Dosage ranges from about 0.001 mg/kg to about 100 mg/kg, with administration optionally occurring for not more than 14 days.
The claims cover the therapeutic administration of 25HC3S to treat acute kidney dysfunction or failure, including dose ranges and routes of administration, specifically in subjects without hyperlipidemia.
Stated Advantages
The at least one oxygenated cholesterol sulfate (OCS) has high bioavailability, even when administered orally.
Administration of 25HC3S significantly decreases mortality in animal models of acute liver failure induced by acetaminophen.
Treatment with 25HC3S reduces markers of liver and kidney damage and improves survival in various organ ischemia and reperfusion models.
25HC3S administration prolongs life and reduces mortality in mice exposed to endotoxin-induced sepsis.
No adverse effects were observed in a human Phase I study, indicating good tolerability and safety of 25HC3S in escalating doses.
Documented Applications
Prevention and treatment of ischemia induced by surgery, including cardiac, brain, bowel, limb, and cutaneous ischemia.
Prevention and treatment of organ dysfunction and failure in organs such as liver, kidney, heart, brain, and pancreas, including conditions caused by acetaminophen toxicity and multiple organ dysfunction syndrome (MODS).
Preservation of ex vivo cells, organs, or tissues for transplantation by contacting them with 25HC3S to maintain viability during storage and transport.
Treatment and prevention of acute liver failure and acute kidney failure caused by acetaminophen overdose.
Treatment of necrosis and apoptosis associated with organ dysfunction or failure.
Prophylactic and therapeutic treatment of sepsis, endotoxemia, and septic shock in subjects.
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