Novel multifunctional oligosaccharide for treating sepsis and severe sepsis

Project Summary Hyper inflammation induced by bacteria or bacterial products through toll like receptor TLR 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 a small molecular weight polysaccharide by virtue of its ability to bind to active sites of TLR inhibited LPS induced production of inflammatory mediators by human monocytes AyuV reversed inflammation and protected mice even h after onset of LPS induced endotoxemia Apart from competitively inhibiting LPS induced inflammation AyuV also activated alternate pathway of macrophages Arginase and IL 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 company s 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 as potent TLR antagonist Compound AyuV 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 We will monitor the hemodynamic changes in inflammatory biomarkers of sepsis pathogenesis such as iNOS MIP Macrophage inflammatory protein MIF Macrophage migration inhibitory factor as well as the markers of alternate activation pathways i e IL arginase and MCP in mice CLP model after dosing AyuV We will also do the microbiology studies to monitor the septicemia CFU and effect of AyuV at different time points Aim Our second goal is to evaluate AyuV in CLP model in aged mice via IV dosing and study the survival and organ protection A mortality score of andgt will be indicative of an efficacious end point as protective effect of AyuV 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 Project Narrative Hyper inflammation induced by bacteria or bacterial products through toll like receptor TLR 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