Hyper inflammation induced by bacteria or bacterial products through toll like receptor 4 (TLR4) leads to sepsis and hence current approaches are directed towards blockade of such receptors. While many such candidate antagonists have shown promise they also result in induction of inappropriate innate immune responses thus increasing risk of development of shock leading to death. We have described a novel approach to treat endotoxemia associated with sepsis, fundamentally different from other reports. AyuV-1, a small molecular weight polysaccharide by virtue of its ability to bind to active sites of TLR4 inhibited LPS induced production of inflammatory mediators by human monocytes. AyuV-1 reversed inflammation and protected mice even 24/48 h after onset of LPS induced endotoxemia. Apart from competitively inhibiting LPS induced inflammation AyuV-1 also activated alternate pathway of macrophages (Arginase-1, and IL-10). Such macrophages are known to display increased phagocytic activity, are resistant to LPS induced activation and associated with resolution of inflammation and tissue repair. The companys overarching goal is to develop and commercialize a small molecular weight, water soluble, non-toxic natural oligosaccharide useful in adjunctive and/or in combination therapy for sepsis, severe sepsis via intravenous (IV) dosing. In the preliminary data, we have designed, synthesized a novel oligosaccharide analog AyuV-25 as potent TLR4 antagonist. Compound AyuV-25 has demonstrated high in vivo efficacy (high survival rate, organ protection) in a cecal ligation and puncture (CLP) sepsis mouse model and downregulated the inflammatory cytokines. During Phase-I of this proposal, aim-1: We will monitor the hemodynamic changes in inflammatory biomarkers of sepsis pathogenesis such as iNOS, MIP-1(Macrophage inflammatory protein), MIF (Macrophage migration inhibitory factor) as well as the markers of alternate activation pathways i.e. IL-10, arginase, and MCP-1 in mice CLP model after dosing AyuV-25. We will also do the microbiology studies to monitor the septicemia (CFU) and effect of AyuV-25 at different time points. Aim-2: Our second goal is to evaluate AyuV- 25 in CLP model in aged mice via IV dosing and study the survival and organ protection. A mortality score of >40% will be indicative of an efficacious end point as protective effect of AyuV- 25 to aged mice. This result will be a very important finding to progress to our future phase-II project where preclinical formulation, PK, ADME/TOX will be done in collaboration with UNTHSC pre-clinical service.
Public Health Relevance Statement: Project narrative: Hyper inflammation induced by bacteria or bacterial products through toll like receptor 4 (TLR4) leads to sepsis and hence current approaches are directed towards blockade of such receptors. However, designing a small molecule which can competitively inhibit LPS induced inflammation as well as activate alternate pathway of macrophages with ability to resolve inflammation leading to organ protection and tissue repair is not explored. The company objective is to develop a small molecular weight, water soluble, non-toxic natural oligosaccharide molecule useful in adjunctive therapy for sepsis, severe sepsis and septicemia via intravenous (IV) dosing.
Project Terms: Active Sites; ADME Study; Age; aged; analog; animal facility; Animal Model; Anti-inflammatory; Anti-Inflammatory Agents; Antibiotics; Antibodies; arginase; Bacteria; Bacterial Infections; Biological Markers; Blood; CCL2 gene; Cells; Cessation of life; Chemistry; Clinical; Clinical Services; Clinical Trials; Collaborations; Combined Modality Therapy; commercialization; Complex; cytokine; Data; design; Development; dosage; Dose; Drug Kinetics; efficacy study; efficacy testing; Endotoxemia; Endotoxins; experience; Formulation; Functional disorder; Funding; Future; Goals; Gram-Negative Bacteria; hemodynamics; Histopathology; Human; Immune; Immune system; in vivo; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injection of therapeutic agent; Innate Immune Response; innovation; Interleukin-10; Intravenous; Investigational Drugs; Investments; Letters; Ligation; Lipopolysaccharides; Logistics; macrophage; Macrophage Activation; Macrophage Inflammatory Protein-1; Measures; Microbiology; Migration Inhibitory Factor; Modeling; Molecular Weight; Monitor; monocyte; mortality; mouse model; Mus; nanoscope; novel; novel strategies; Oligosaccharides; Organ; Organ Survival; Pathogenesis; Pathologic; Pathologist; Pathology; Pathway interactions; Patient Selection; Patients; Phagocytes; Phagocytosis; Phase; phenylpyruvate tautomerase; Polysaccharides; potential biomarker; pre-clinical; prevent; Process; Production; protective effect; Puncture procedure; receptor; Regulation; Reporting; Research Personnel; Resistance; Resolution; Risk; Seeds; Sepsis; Septic Shock; Septicemia; Shock; small molecule; Survival Rate; Techniques; Testing; Therapeutic; Time; tissue repair; Tissues; TLR4 gene; Toll-like receptors; Toxic effect; Water; Work
