Extracellular histones as biomarkers for prognosis and molecular targets for therapy
Inventors
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Assignees
Member
Oklahoma Medical Research FoundationFounded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Founded in 1946, this independent nonprofit biomedical research institute conducts basic, translational, and clinical research in critical areas such as heart disease, cancer, autoimmune, and neurodegenerative diseases. Its mission focuses on understanding biological mechanisms and advancing diagnostics and therapeutics. Activities include conducting clinical trials, managing a patent portfolio, commercializing biotechnologies, and supporting the biotech community. Research efforts are funded by grants and philanthropy, and the institute hosts advanced facilities, interdisciplinary research teams, and collaborations with academia and industry.
Publication Number
US-10238711-B2
Publication Date
2019-03-26
Expiration Date
Abstract
Hyper-inflammatory responses can lead to a variety of diseases including sepsis. It is now shown that extracellular histones released in response to inflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death during sepsis. As such, they can be targeted pharmacologically by inhibitors, as well as used as biomarkers for prognosis of sepsis and other diseases.
Core Innovation
The invention identifies extracellular histones H3 and H4 as circulating cytotoxic mediators in hyper-inflammatory states that cause endothelial dysfunction, organ failure and death, and proposes their use as prognostic biomarkers and molecular therapeutic targets. The disclosure describes diagnostic assessment of extracellular histone levels [procedural detail omitted for safety] and therapeutic approaches comprising anti-H3 or anti-H4 antibodies, an H4 peptide comprising residues 50-67 (SEQ ID NO:19), and enzymes that cleave histones.
The background describes a need to detect and neutralize extracellular histone-mediated cytotoxicity in hyper-inflammatory conditions including sepsis, severe acute pancreatitis, acute respiratory distress syndrome and ischemia–reperfusion injury, where histones cause endothelial dysfunction, impair protein C activation, signal via TLR2 and TLR4, and contribute to organ failure and death. The invention aims to provide prognostic and therapeutic measures to reduce histone-mediated tissue injury.
Claims Coverage
One independent claim is present and recites three main inventive features related to sampling, measurement, and treatment.
Obtaining a serum or plasma sample
Obtaining a serum or plasma sample from said subject.
Determining extracellular H3 and/or H4 histone content
Determining the extracellular H3 and/or H4 histone content of said sample.
Treatment with inhibitors of H3 or H4 histone cytotoxicity
Treating the subject with a first inhibitor of H3 or H4 histone cytotoxicity wherein the first inhibitor is an anti-H3 antibody, an anti-H4 antibody, or an H4 histone peptide comprising residues 50-67 of H4 (SEQ ID NO:19).
The independent claim covers obtaining a serum or plasma sample, determining extracellular H3/H4 histone content, and treating the subject with specified inhibitors of H3 or H4 histone cytotoxicity (anti-H3, anti-H4, or H4 residues 50-67 peptide).
Stated Advantages
Extracellular histone levels serve as prognostic biomarkers.
Anti-H4 monoclonal antibody or activated protein C rescues survival in animal models challenged with extracellular histones.
Activated protein C cleavage of H4 generates peptides that retain bactericidal activity while having reduced endothelial cytotoxicity.
Documented Applications
Sepsis
Severe acute pancreatitis
Acute respiratory distress syndrome (ARDS)
Ischemia-reperfusion injury
Trauma and surgery
Cardiovascular disease
Autoimmune disease (excluding systemic lupus erythematosus in some claims)
Chemotherapy and radiotherapy toxicity
Burns
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