Development of heparan sulfate-based therapeutics to treat inflammatory diseases

开发基于硫酸乙酰肝素的炎症性疾病疗法

基本信息

批准号：
10324781
负责人：
Katelyn Arnold
金额：
$ 23.11万
依托单位：
GLYCAN THERAPEUTICS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-14 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10324781
关键词：
Acetaminophen Acute Acute Liver Failure Address Animal Sources Anti-Inflammatory Agents Anticoagulants Antiinflammatory Effect Attenuated Biological Process Blood Blood Coagulation Disorders Brain Clinical Trials Complex Mixtures Development Disease Disease model Drug Kinetics Drug or chemical Tissue Distribution Funding Goals HMGB1 Protein Heparin Heparitin Sulfate Hepatotoxicity Hospitals Human Immune response Inflammation Inflammatory Inflammatory Response Injury Investigation Ischemia Kilogram Label Liver Failure Mediating Metabolic Clearance Rate Methods Modeling Monosaccharides Mus Neutrophil Infiltration Oligosaccharides Pattern Peritonitis Pharmaceutical Preparations Phase Plasma Polysaccharides Preparation Principal Investigator Production Publications Publishing Reperfusion Injury Reperfusion Therapy Reporting Route Scheme Sepsis Series Site Small Business Innovation Research Grant Source Structure Sulfate Therapeutic Therapeutic Agents Toxic effect Translational Research Trauma Universities Urine Work acetaminophen overdose base chemical synthesis cost design drug candidate experimental study improved innovation lead candidate liver injury liver ischemia mouse model novel strategies novel therapeutics phase 1 study phase 2 study preclinical development programs receptor for advanced glycation endproducts scale up screening stem subcutaneous success sugar systemic inflammatory response therapeutic target translational medicine

项目摘要

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.

抽象的该SBIR I期项目的目标旨在完成更大的合成量表和 18-MER的药代动力学研究，一种铅候选抗炎乙酰肝素硫酸盐 18-mer在腹膜炎的鼠疾病模型中降低中性粒细胞浸润，肝脏缺血/再灌注损伤和对乙酰氨基酚诱导的急性肝衰竭（APAP诱导 Alf）。 18-MER的目标靶标组1（HMGB1）蛋白质，并减弱HMGB1- 介导的炎症为特征，以中性粒细胞浸润到损伤部位。此外这些疾病模型，HMGB1涉及众多局部和全身性炎症包括败血症和创伤损伤在内的疾病。目前，没有批准的疗法靶向HMGB1介导的炎症。这项工作的重点是开发18-mer作为APAP诱导的ALF的疗法。信心使用APAP中的其他寡糖从筛选实验中购买18-MER的步骤与18-mer相比无效的模型并证明了18-Mer的抗炎效果是多种炎症小鼠模型。此SBIR I阶段应用程序包含两个具体目标。在AIM 1中，我们计划将合成量表提高到10 g，大约增加30倍来自当前的生产规模。改进的合成将使用12-mer中间体作为起始材料将合成步骤从36缩短为16。目标2是开发LC- 基于MS/MS的方法来量化血液和尿液中的18-MER。这种方法将使我们能够在随后的临床前开发中获得药代动力学参数。在第二阶段研究，我们将专注于将规模化的合成提高到100克，辅助研究和寡糖的组织分布。该项目的成功将为新的通过针对HMGB1介导的炎症来治疗药物诱导的肝毒性的方法。