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 根据全球癌症天文台发布的最新数据，超过900,000 全球患者在2020年被诊断出患有肝癌。 癌是肝癌的最常见类型，肝移植是唯一的潜在 治疗方法。肝移植不可避免地涉及肝脏的时间 在采购过程中将从血液循环中取出。当肝脏连接到接受者时 血流恢复，缺血相损害会导致感染和凝结 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，有临床前和临床证据表明红外损伤 3年内，超过20％的患者导致癌症复发。尽管结果不佳， 在肝移植期间，没有可用的靶向IR损伤的批准治疗。 潜在的疗法可以改善移植后器官功能，并降低 癌症复发。这一阶段I STTR专注于制定一种治疗策略 减少肝移植期间的IR损伤。我们已经确定了一种新颖的合成 寡糖结构称为脱卡帕林，由聚糖治疗剂独家生产， 双重作用机理。 IR损伤导致具有免疫通量的高凝状态 介体，原发性中性粒细胞，浸润的重新融化组织，导致组织损伤。 脱卡帕林具有抗凝剂和抗炎活性，可有效降低温暖的IR- 在模仿手术并发症的小鼠模型中介导的肝损伤。必要的双重 使用仅具有抗凝剂或抗抗凝剂的其他寡糖证明了活性 炎症活动。合并时，单活性寡糖降低了肝损伤 但是当单独使用时不会。在当前的应用程序中，我们建议评估Dekaparin的 在接枝采购期间发生的缺血损伤的治疗潜力和 冷藏后使用大鼠肝灌注的离体模型保存。五个任务是 计划支持这个单一目标：1）完成脱卡帕林的10 g合成用于离体研究； 2） 建立孤立的灌注大鼠肝脏的离体模型； 3）评估脱卡帕林对IR损伤的影响 离体模型； 4）在脱卡帕林的离体模型中使用延长的标准； 5）净化 从花费灌注液到回收材料以供将来使用的脱卡帕林。在第二阶段，我们将使用EX 体内模型以探索不同剂量的去卡帕林。我们将进行体内原位肝 大鼠的移植模型。最后，我们将评估循环肿瘤的转移能力 脱卡帕林处理的移植模型中的细胞确定肿瘤复发潜力。