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-11458187-B2
Publication Date
2022-10-04
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 disclosure identifies extracellular histones H3 and H4 as mediators of endothelial cytotoxicity, organ failure and death in hyper-inflammatory states such as sepsis and as biomarkers for prognosis. Therapeutic approaches described include inhibitors of histone cytotoxicity exemplified by anti-H3 antibodies, anti-H4 antibodies, an H4 peptide comprising residues 50-67 (SEQ ID NO:19), cocktails of peptides or antibodies, proteolytic enzymes such as activated protein C and granzymes, and heparin.
Activated protein C is shown to cleave histone H4, reduce histone-mediated endothelial toxicity, inhibit histone-induced IL-6 and IL-8 via TLR2 and TLR4 signaling, and rescue animals in LPS and E. coli sepsis models. An H4-derived cleavage peptide (H4P39/40-78) is described to retain bactericidal activity while exhibiting reduced endothelial cytotoxicity and to rescue LPS-treated mice.
Claims Coverage
Overview: the independent claim discloses 2 inventive features.
Method of treating sepsis, severe acute pancreatitis, acute respiratory distress syndrome or ischemia-reperfusion injury by administering an inhibitor of H3 or H4 histone cytotoxicity
A method comprising treating a subject having sepsis, severe acute pancreatitis, acute respiratory distress syndrome or ischemia-reperfusion injury by administering a first inhibitor of H3 or H4 histone cytotoxicity.
First inhibitor comprising anti-H3 antibody, anti-H4 antibody or H4 histone peptide comprising residues 50-67 (SEQ ID NO:19)
The first inhibitor of H3 or H4 histone cytotoxicity is specified as an anti-H3 antibody, an anti-H4 antibody, or an H4 histone peptide comprising residues 50-67 (SEQ ID NO:19).
The independent claim covers a method of treating sepsis, severe acute pancreatitis, acute respiratory distress syndrome or ischemia-reperfusion injury by administering an inhibitor of H3 or H4 histone cytotoxicity, where the inhibitor is an anti-H3 antibody, an anti-H4 antibody, or an H4 peptide comprising residues 50-67 (SEQ ID NO:19).
Stated Advantages
Reduction of endothelial cytotoxicity.
Reduction of organ failure and death in hyper-inflammatory states.
Rescue of animals in LPS and E. coli sepsis models.
H4-derived cleavage peptide retains bactericidal activity with reduced endothelial cytotoxicity.
Inhibition of histone-induced IL-6 and IL-8 via TLR2 and TLR4 signaling.
Use of extracellular histone measurement in serum or plasma as a prognostic biomarker.
Documented Applications
Sepsis.
Severe acute pancreatitis.
Acute respiratory distress syndrome.
Ischemia-reperfusion injury.
Cardiovascular and various inflammatory and trauma contexts.
Diagnostic prognosis by measuring extracellular histone in serum or plasma [procedural detail omitted for safety].
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