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Development ofsynthetic heparin to protect liver graft from ischemia reperfusion injury duringtransplantation

开发合成肝素以保护移植肝免受移植过程中的缺血再灌注损伤

基本信息

批准号：
10759102
负责人：
Katelyn Arnold
金额：
$ 40万
依托单位：
GLYCAN THERAPEUTICS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10759102
关键词：
Anions Anti-Inflammatory Agents Anticoagulants Bile fluid Biliary Biological Markers Biological Response Modifiers Blood Circulation Blood flow Chromatography Clinical Coagulation Process Collaborations Communication Complication Cryopreservation Data Development Diagnosis Disease Dose Effectiveness Flushing Future Glycocalyx Goals Heart Arrest Heparin Histology Hypoxia Infiltration Inflammation Ischemia Legal patent Letters Liver Liver neoplasms Malignant Neoplasms Malignant neoplasm of liver Mediating Methods Modeling Morbidity - disease rate Neoplasm Circulating Cells Nitrogen Dioxide North Carolina Oligosaccharides Organ Organ Preservation Organ Procurements Organ Transplantation Orphan Orphan Drugs Outcome Patients Perfusion Phase Polysaccharides Portal Pressure Predisposition Primary carcinoma of the liver cells Procedures Process Production Publishing Pump Rattus Recommendation Recurrent Malignant Neoplasm Recurrent tumor Recycling Regional Perfusion Regulatory Pathway Reperfusion Injury Reperfusion Therapy Retrospective Studies Risk Reduction Small Business Technology Transfer Research Structure Surgical Models Surgical complication Technology Testing Therapeutic Thrombophilia Time Tissues Transplantation Universities Warm Ischemia adverse outcome animal data cancer recurrence cohort curative treatments effective therapy experience experimental study graft function improved in vivo in vivo Model inflammatory marker ischemic injury liver cancer patient liver function liver injury liver ischemia liver preservation liver transplantation mortality mouse model natural hypothermia neutrophil novel pharmacokinetics and pharmacodynamics post-transplant pre-clinical preservation product development success transplant model

项目摘要

Project Summary/Abstract According to the most recent data published by the Global Cancer Observatory, over 900,000 patients worldwide were diagnosed with liver cancer in 2020. For patients with hepatocellular carcinoma, the most common type of liver cancer, liver transplantation is the only potentially curative treatment option. Liver transplantation inevitably involves periods of time where the liver is removed from blood circulation during procurement. When the liver is connected to the recipient and blood flow is restored, the ischemia phase damage causes inflammation and coagulation complications. This ischemia reperfusion (IRinj)ury is a key factor in morbidity and mortality after transplantation. Furthermore, there is preclinical and clinical evidence that IR injury leads to cancer recurrence in over 20% of patients within 3 years. Despite these poor outcomes, there are no approved therapeutics available targeting IR injury during liver transplantation. Potential therapeutics could improve post-transplant organ function and reduce the risk of cancer recurrence. This phase I STTR is focused on developing a therapeutic strategy to decrease IR injury during liver transplantation. We have identified a novel synthetic oligosaccharide structure called dekaparin, produced exclusively by Glycan Therapeutics, with a dual mechanism of action. IR injury leads to a hypercoagulable state with a flux of immune mediators, primarily neutrophils, infiltrating reperfused tissue resulting in tissue damage. Dekaparin has anticoagulant and anti-inflammatory activity and is effective in reducing warm IR- mediated liver injury in a mouse model that mimics surgical complication. The necessity of dual activity was demonstrated using other oligosaccharides that have only anticoagulant or anti- inflammatory activity. Single activity oligosaccharides decreased liver injury when combined but not when used separately. In this current application, we propose to evaluate dekaparin’s therapeutic potential against ischemia injury happening during graft procurement and preservation using an ex vivo model of rat liver perfusion after cold storage. Five tasks are planned to support this single aim: 1) Complete 10 g synthesis of dekaparin for ex vivo studies; 2) Establish ex vivo model of isolated perfused rat liver; 3) Evaluate effect of dekaparin on IR injury in ex vivo model; 4) Use extended criteria liver grafts in ex vivo model with dekaparin; 5) Purify dekaparin from spent perfusate to recycle material for future use. In Phase II, we will use the ex vivo model to explore different doses of dekaparin. We will conduct the in vivo orthotopic liver transplantation model in rats. Lastly, we will evaluate the metastatic ability of circulating tumor cells in the transplant model with dekaparin treatment to determine tumor recurrence potential.

项目总结/文摘