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.

项目概要/摘要 根据全球癌症观察站最新发布的数据，超过 900,000 2020 年，全球有患者被诊断出患有肝癌。对于肝细胞癌患者 癌，最常见的肝癌类型，肝移植是唯一可能的治疗方法 治愈性治疗选择。肝移植不可避免地涉及肝脏的一段时间 在采购过程中从血液循环中去除。当肝脏与受体相连时 血流恢复后，缺血期损伤引起炎症和凝血 并发症。这种缺血再灌注 (IRinj)ury 是发病率和死亡率的关键因素 移植后。此外，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， 目前还没有针对肝移植过程中 IR 损伤的批准治疗方法。 潜在的治疗方法可以改善移植后器官功能并降低移植后的风险 癌症复发。第一阶段 STTR 的重点是制定治疗策略 减少肝移植过程中的IR损伤。我们已经鉴定出一种新型合成物 称为十卡肝素 (dekaparin) 的寡糖结构，由 Glycan Therapeutics 独家生产，具有 双重作用机制。 IR 损伤导致高凝状态和免疫通量 介质，主要是中性粒细胞，浸润再灌注组织，导致组织损伤。 Dekaparin 具有抗凝和抗炎活性，可有效减少热 IR- 在模拟手术并发症的小鼠模型中介导肝损伤。双轨制的必要性 使用其他仅具有抗凝血或抗凝血作用的寡糖证明了其活性 炎症活动。单一活性寡糖联合使用可减少肝损伤 但单独使用时则不然。在当前的应用中，我们建议评估地卡肝素的 针对移植物获取过程中发生的缺血性损伤的治疗潜力 使用冷藏后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 地卡肝素合成，用于离体研究； 2） 建立大鼠离体肝脏灌注模型； 3) 评估地卡肝素对 IR 损伤的影响 离体模型； 4) 在含有地卡肝素的离体模型中使用扩展标准肝移植； 5) 净化 从用过的灌注液中提取去卡肝素，以回收材料以供将来使用。在第二阶段，我们将使用 ex 体内模型探索不同剂量的地卡肝素。我们将进行体内原位肝脏 大鼠移植模型。最后，我们将评估循环肿瘤的转移能力 用地卡肝素治疗移植模型中的细胞以确定肿瘤复发的可能性。