A Novel Therapeutic Approach for Liver Injury

肝损伤的新治疗方法

• 批准号: 7743161
• 负责人: Xiaoling Qiang
• 金额: $ 20万
• 依托单位: THERASOURCE, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743161
• 关键词: Animals; Apoptosis; Attenuated; Bilirubin; Binding Proteins; Body Weight; Cessation of life; Cleaved cell; Clinical; Clinical Trials; Coagulation Process; Complication; Continuous Infusion; Creatinine; Cytochrome P450; Development; Dose; Enzymes; Excision; Future; Glutathione S-Transferase; Goals; HMGB1 Protein; Heart; Hepatic; Hepatocyte; Human; Human Development; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Intervention; Ischemia; Kidney; Ligation; Liver; Liver Disease Shock Liver; Liver Failure; Liver diseases; Lung; Marketing; Measures; Medical; Modality; Modeling; Monitor; Multiple Organ Failure; Necrosis; Neutrophil Infiltration; Operative Surgical Procedures; Organ; Outcome; Patients; Peptides; Peroxidases; Phase; Rattus; Reperfusion Injury; Reperfusion Therapy; Research; Septic Shock; Serum; Shock; Small Business Innovation Research Grant; Small Intestines; Staining method; Stains; TdT-Mediated dUTP Nick End Labeling Assay; Techniques; Testing; Therapeutic Agents; Time; Tissues; Trauma; Water; adrenomedullin; bile duct; caspase-3; clinically relevant; commercialization; cost; cytokine; dosage; effective therapy; heat injury; human adrenomedullin-binding protein 1; improved; liver transplantation; mortality; novel; novel therapeutic intervention; novel therapeutics; preclinical study; prevent; public health relevance; research study; response

DESCRIPTION (provided by applicant): Liver injury induced by hepatic ischemia and reperfusion (I/R) is a major cause of liver failure after severe trauma, thermal injury, hemorrhagic and septic shock, liver resection, or liver transplantation. Hepatic I/R contributes significantly to multiple organ failure and mortality. Although various modalities and substances have been studied to reduce hepatic I/R-induced mortality, none have been entirely successful. Thus, the development of novel treatments to prevent or at least minimize hepatic I/R injury is of tremendous benefit to the patient. The market potential for hepatic I/R treatment is estimated at >$10 billion per year in the US alone. We have recently demonstrated that administration of human adrenomedullin (AM, a recently-discovered potent vasoactive peptide) in combination with human AM binding protein-1 (AMBP-1, a novel specific binding protein for AM) immediately at the onset of reperfusion, downregulated pro-inflammatory cytokines, decreased hepatic neutrophil infiltration, inhibited liver cell apoptosis and necrosis, and reduced liver injury and mortality in a rat model of hepatic I/R. However, it remains unknown whether delayed administration of human AM/AMBP-1 (which is more clinically relevant) is also equally protective after hepatic I/R injury with or without pre-existing liver diseases such as hepatic injury induced by bile duct ligation (BDL). Another obstacle hampering the development of human AM/AMBP-1 as a novel therapeutic agent for hepatic I/R is the extremely high cost of commercial human AMBP-1. To overcome this, we have successfully isolated and purified AMBP-1 from normal human serum at a much lower cost. We therefore hypothesize that delayed administration of human AM/AMBP-1 attenuates hepatic injury and inflammation, and reduces hepatic I/R-induced mortality even under pre- existing liver diseases. The primary aim of this project is targeted toward demonstrating the feasibility of further development and commercialization of human AM/AMBP-1 as a novel therapeutic approach to reduce mortality after hepatic I/R. The optimal dosage(s) of human AM/AMBP-1 (delayed treatment) will be determined by assessing 1) the dose-response effect of human AM/AMBP-1 on tissue injury and inflammatory responses after hepatic I/R; 2) the time-course of human AM/AMBP-1's beneficial effects; and 3) the effect of human AM/AMBP-1 on mortality induced by hepatic I/R with or without BDL. Our ultimate goal (SBIR Phase II and beyond) is to obtain commercial utilization of human AM/AMBP-1 as a safe and effective treatment for patients with hepatic I/R injury associated with pre-existing liver conditions. PUBLIC HEALTH RELEVANCE: Recent advances in surgical techniques and pharmacological interventions have moderately improved the outcome of trauma surgery, liver resection, liver transplantation, and shock. However, liver failure due to ischemia-reperfusion (I/R) injury continues to be a major complication in the clinical arena. Hepatic I/R with or without pre-existing liver diseases contributes significantly to multiple organ failure and death of such patients. It is obvious that there is an urgent medical need for the development of novel treatments to prevent or at least minimize hepatic I/R injury.

描述（由申请人提供）：肝缺血和再灌注引起的肝损伤（I/R）是严重创伤，热损伤，出血和败血性休克，肝切除或肝移植后肝衰竭的主要原因。肝I/R对多器官衰竭和死亡率产生了重大贡献。尽管已经研究了各种方式和物质以降低肝I/R诱导的死亡率，但没有一个完全成功。因此，开发新的治疗方法以预防或至少最大程度地减少肝I/R损伤对患者带来了巨大的好处。仅在美国，肝I/R治疗的市场潜力估计为每年100亿美元。 We have recently demonstrated that administration of human adrenomedullin (AM, a recently-discovered potent vasoactive peptide) in combination with human AM binding protein-1 (AMBP-1, a novel specific binding protein for AM) immediately at the onset of reperfusion, downregulated pro-inflammatory cytokines, decreased hepatic neutrophil infiltration, inhibited liver cell apoptosis and necrosis, and reduced肝I/R大鼠模型中的肝损伤和死亡率。但是，在肝I/R损伤之后，有或没有预先存在的肝疾病（例如由胆管连接引起的肝损伤）（BDL），肝脏I/R损伤（BDL）是否同样具有保护性，尚不清楚人/AM/AMBP-1（更临床相关）是否同样具有保护作用。另一个阻碍了人类/AMBP-1作为肝I/R的新型治疗剂的发展的障碍是商业人类AMBP-1的极高成本。为了克服这一点，我们以低得多的成本从正常的人血清中成功地隔离和纯化了AMBP-1。因此，我们假设人类AM/AMBP-1延迟给药会减轻肝损伤和炎症，即使在现有的肝脏疾病之前，也会降低肝I/R诱导的死亡率。该项目的主要目的旨在证明人类/AMBP-1作为一种新型治疗方法的进一步发展和商业化的可行性，以降低肝I/R后死亡率。人类AM/AMBP-1的最佳剂量（延迟治疗）将通过评估1）1）人类AM/AMBP-1对肝I/R后组织损伤和炎症反应的剂量反应效应； 2）人类AM/AMBP-1的有益效果的时间顺序； 3）人类/AM/AMBP-1对肝I/R诱导的死亡率的影响或不带有BDL。我们的最终目标（SBIR II阶段及以后）是获得对人类/AMBP-1的商业利用，作为对肝I/R损伤患者的安全有效治疗，与现有的肝脏疾病有关。公共卫生相关性：手术技术和药理干预措施的最新进展已适度改善了创伤手术，肝切除，肝移植和震动的结果。但是，由于缺血 - 灌注（I/R）损伤引起的肝衰竭仍然是临床领域的主要并发症。有或没有预先存在的肝病的肝I/R对此类患者的多个器官衰竭和死亡产生了重大贡献。显然，紧急医疗需要开发新的治疗方法，以预防或最小化肝I/R损伤。