Compounds for treating and preventing extracellular histone mediated pathologies
Inventors
Parish, Christopher • O'MEARA, CONNOR • COUPLAND, LUCY • QUAH, BENJAMIN JU CHYE • KORDBACHEH, FARZANEH • Orlov, Anna • BROWNE, ANNA • Stephens, Ross • Tredwell, Gregory David • Philip, Lee Andrew • KNOX, KAREN • Von Itzstein, Laurence Mark • Chang, Chih-Wei • BRÜSTLE, ANNE • DAVIS, DAVID ANAK SIMON
Assignees
Australian National University • Griffith University
Publication Number
US-11628179-B2
Publication Date
2023-04-18
Expiration Date
2038-12-14
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Abstract
The present invention relates to compounds with high chemical stability and methods for inhibiting the pathological activity of extracellular histones in a subject. In particular, the invention relates to compounds with high chemical stability, uses thereof and methods for inhibiting or ameliorating extracellular histone mediated ailments (such as, for example, sepsis, systemic immune response syndrome (SIRS) and ischemia reperfusion injury (IRI)). More particularly, the invention relates to methods and uses of a polyanionic sulfated cellobioside modified with a small uncharged glycosidically linked substituent at its reducing terminus, wherein the presence of the substituent results in a molecule with high chemical stability without affecting the ability of the molecule to be effective in the therapy of extracellular histone mediated ailments. For example, the present invention relates to methods and uses of β-O-methyl cellobioside sulfate (mCBS) or a pharmaceutically acceptable salt thereof (e.g., mCBS.Na), in the therapy of a range of extracellular histone mediated ailments in subjects.
Core Innovation
The invention relates to compounds with high chemical stability and methods for inhibiting the pathological activity of extracellular histones in a subject. More particularly, it relates to compounds, uses, and methods for inhibiting or ameliorating extracellular histone mediated ailments such as sepsis, systemic immune response syndrome (SIRS), and ischemia reperfusion injury (IRI). The invention specifically concerns polyanionic sulfated cellobiosides modified with a small uncharged glycosidically linked substituent at their reducing terminus, which imparts high chemical stability without compromising therapeutic efficacy.
The background addresses the problem that extracellular histones, released during inflammatory processes, mediate endothelial dysfunction, organ failure, and death in severe diseases including sepsis. Existing therapies such as monoclonal antibodies, activated protein C, thrombomodulin, and heparin have limited clinical efficacy or unacceptable side effects. Moreover, purified human coagulation factors like recombinant activated protein C have shown little clinical impact due to anticoagulant-related bleeding risks and slow action. Hence, diseases mediated by extracellular histones remain largely untreated, representing a significant clinical concern.
The invention is predicated on the finding that certain highly stable polyanionic sulfated disaccharides, particularly β-O-methyl cellobioside sulfate (mCBS) and its pharmaceutically acceptable salts, can interact electrostatically with extracellular histones to neutralize their cytotoxic, red blood cell damaging, platelet activating, and pro-coagulant properties. This neutralization protects endothelial cells from histone-induced cytotoxicity and reduces or reverses histone-induced damage including red blood cell aggregation and lysis, thereby protecting against cell injury and organ dysfunction in affected subjects.
Claims Coverage
The patent contains two independent claims directed to methods of treating extracellular histone mediated ailments by administering therapeutically effective amounts of polyanionic sulfated cellobioside compounds, particularly β-O-methyl cellobioside sulfate or its sodium salt.
Method of treating extracellular histone mediated ailments
Administering therapeutically effective amounts of polyanionic sulfated cellobioside compounds having a defined general structure composed of a polyanionic sulfated cellobioside modified with a small uncharged glycosidically linked substituent at the reducing terminus or a pharmaceutically acceptable salt thereof to treat extracellular histone mediated ailments.
Treatment of specific diseases using the sulfated cellobioside compound
Using the polyanionic sulfated cellobioside compound or pharmaceutically acceptable salts for treating sepsis, systemic immune response syndrome (SIRS), ischemia reperfusion injury (IRI), acute respiratory distress syndrome (ARDS), and multiple sclerosis in subjects in need thereof.
Administration regimens
Administering the therapeutically effective amount in a single dose or in multiple doses.
Adjunct therapy co-administration
Administering concomitantly a second active agent such as an anti-inflammatory, antibiotic, antiviral, or antifungal agent as an adjunct treatment for the disease or medical condition.
Use of specific compound forms
Using sulfated β-O-methyl cellobioside disaccharide or sodium β-O-methyl cellobioside sulfate as the active compound in the treatment methods.
The independent claims cover methods of treating extracellular histone mediated ailments by administering therapeutically effective amounts of chemically stable polyanionic sulfated cellobioside compounds specifically including β-O-methyl cellobioside sulfate, with possibilities of single or multiple dosing and optional adjunct therapies.
Stated Advantages
The compounds provide high chemical stability compared to polyanions sulfated at the reducing terminus.
They effectively neutralize the pathological activity of extracellular histones, protecting endothelial cells and preventing red blood cell aggregation and lysis.
The compounds exhibit minimal anticoagulant activity, significantly lower than heparins, thus reducing bleeding risk.
Treatment with these compounds can ameliorate or prevent ailments mediated by extracellular histones such as sepsis, SIRS, IRI, and autoimmune diseases.
Documented Applications
Treatment and prevention of sepsis and systemic immune response syndrome (SIRS).
Treatment and prevention of ischemia reperfusion injury (IRI), including cardiac and transplantation associated IRI.
Treatment of acute respiratory distress syndrome (ARDS).
Treatment of coagulation disorders and thrombosis, including deep vein thrombosis (DVT).
Treatment of autoimmune and inflammatory diseases such as multiple sclerosis and rheumatoid arthritis.
Use in cancer therapy to ameliorate side effects of chemotherapy, radiation, and cytokine therapy.
Promotion of wound healing by ameliorating histone-induced cytotoxicity in wound tissues.
Treatment of retinal detachment and fibrosis associated with extracellular histone toxicity.
Treatment of diabetes and reduction of related inflammation associated with extracellular histones.
Use in trauma, surgery, burns, and traumatic hemorrhage to inhibit extracellular histone mediated damage.
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