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

• 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
• 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

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/摘要 根据全球癌症观察站发布的最新数据， 2020年，全世界的患者被诊断出患有肝癌。对于肝细胞癌患者 肝癌是最常见的肝癌类型，肝移植是唯一潜在的 治愈性治疗选择。肝移植不可避免地涉及肝脏 在采集过程中从血液循环中清除当肝脏与受体相连时 并且血流恢复时，缺血期损伤引起炎症和凝血 并发症这种缺血再灌注（IR）损伤是发病率和死亡率的关键因素 移植后。此外，有临床前和临床证据表明，IR损伤 导致超过20%的患者在3年内癌症复发。尽管结果不佳， 在肝移植过程中，还没有批准的靶向IR损伤的治疗剂可用。 潜在的治疗方法可以改善移植后器官功能，降低 癌症复发该I期STTR的重点是开发治疗策略， 减少肝移植中的IR损伤。我们发现了一种新的合成物 一种名为dekaparin的寡糖结构，由Glycan Therapeutics独家生产， 双重作用机制。IR损伤导致高凝状态，伴随免疫反应的流动。 介质，主要是中性粒细胞，浸润再灌注组织，导致组织损伤。 地卡肝素具有抗凝和抗炎活性，可有效降低温热IR- 介导的肝损伤的小鼠模型，模拟手术并发症。双重的必要性 使用仅具有抗凝血剂或抗- 炎症活动。单一活性低聚糖联合使用可减轻肝损伤 但当单独使用时则不是。在本申请中，我们建议评价地卡肝素的 对移植物获取过程中发生的缺血损伤的治疗潜力， 在冷藏后使用大鼠肝脏灌注的离体模型进行保存。五项任务是 计划支持这一单一目标：1）完成10 g地卡肝素的合成，用于离体研究; 2） 建立离体大鼠肝脏灌流模型; 3）评价地卡肝素对肝脏缺血再灌注损伤的影响。 离体模型; 4）在具有地卡肝素的离体模型中使用扩展标准肝移植物; 5）纯化 从用过的灌注液中回收地卡肝素以供将来使用。在第二阶段，我们将使用前 体内模型，以探索不同剂量的地卡肝素。我们将进行活体原位肝移植 大鼠移植模型。最后，我们将评估循环肿瘤的转移能力 用地卡肝素处理移植模型中的细胞以确定肿瘤复发潜力。