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.

项目摘要/摘要 根据全球癌症观察站公布的最新数据，超过90万人 2020年，世界各地的患者被诊断出患有肝癌。适用于肝细胞癌患者 癌症是最常见的肝癌类型，肝移植是唯一有潜力的 治愈性治疗选择。肝移植不可避免地涉及到一段时间，肝脏 在采购过程中从血液循环中移除。当肝脏与受体相连时 血流恢复，缺血期损伤导致炎症和凝血 并发症。这种缺血再灌流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年内复发。尽管结果不佳， 目前尚无公认的针对肝移植中IR损伤的治疗方法。 潜在的治疗方法可以改善移植后的器官功能，降低 癌症复发。这一第一阶段STTR的重点是开发一种治疗策略，以 减少肝移植中的IR损伤。我们已经确定了一种新型的合成材料 寡糖结构，称为去肝素，由葡聚糖治疗公司独家生产，具有 双重作用机制。IR损伤导致高凝状态，免疫流出 介质，主要是中性粒细胞，渗入再灌流的组织，导致组织损伤。 地卡肝素具有抗凝和抗炎活性，能有效降低热IR-IR。 在模拟手术并发症的小鼠模型中介导性肝损伤。对偶的必然性 使用其他只含有抗凝血剂或抗凝血剂的寡糖显示了活性。 炎症活动。单活性低聚糖联合应用可减轻肝损伤 但单独使用时就不会了。在目前的应用中，我们建议评估地卡肝素的 对移植物获取和移植过程中发生的缺血损伤的治疗潜力 采用冷藏后大鼠肝脏灌流的体外模型进行保存。五项任务是 计划支持这一单一目标：1)完成10克地卡肝素的合成，用于体外研究；2) 建立离体大鼠肝脏灌流模型；3)评价地高肝素对大鼠肝脏缺血再灌注损伤的影响。 体外模型；4)使用扩展标准的肝移植在体外模型中使用地卡肝素；5)纯化 从用过的灌流液中提取肝素，以回收材料供将来使用。在第二阶段，我们将使用EX 体内模型探讨不同剂量地卡肝素的作用。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。 在移植模型中用地卡肝素治疗细胞，以确定肿瘤复发的可能性。