Development of heparan sulfate-based therapeutics to treat inflammatory diseases

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Abstract The goal of this SBIR phase I project is aimed at completing a larger synthesis scale and pharmacokinetic studies for 18-mer, a lead candidate anti-inflammatory heparan sulfate oligosaccharide. 18-mer decreased neutrophil infiltration in murine diseases model of peritonitis, liver ischemia/reperfusion injury, and acetaminophen-induced acute liver failure (APAP-induced ALF). 18-mer targets to high mobility group box 1 (HMGB1) protein and attenuates HMGB1- mediated inflammation characterized by neutrophil infiltration to the injury site. In addition to these disease models, HMGB1 is involved a numerous local and systemic inflammation disorders including sepsis and trauma injury. Currently, there are no approved therapeutics targeting HMGB1-mediated inflammation. This work is focused on developing 18-mer as a therapeutic for APAP-induced ALF. Confidence to pursue 18-mer stems from screening experiments using other oligosaccharides in the APAP model that were ineffective compared to 18-mer and demonstrating 18-mer’s anti-inflammatory effect is multiple inflammatory mouse models. This SBIR phase I application contains two specific aims. In Aim 1, we plan to increase the synthetic scale to 10 g, about 30-fold increase from the current production scale. The improved synthesis will use a 12-mer intermediate as the starting material, shortening the synthetic steps to 16 from 36. Aim 2 is to develop a LC- MS/MS based method to quantify the 18-mer in blood and urine. This method will allow us to obtain pharmacokinetic parameters in the subsequent preclinical development. In the phase II studies, we will focus on increasing the scale-up synthesis to 100g, IND-enabling studies and tissue distribution of the oligosaccharides. The success of this project will provide a new approach to treat drug induced liver toxicity by targeting to HMGB1-mediated inflammation.