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（I/R）诱导的肝损伤是严重创伤、热损伤、出血性和脓毒性休克、肝切除术或肝移植后肝衰竭的主要原因。肝脏I/R是多器官功能衰竭和死亡率的重要原因。虽然已经研究了各种方式和物质来降低肝脏I/R诱导的死亡率，但没有一种是完全成功的。因此，开发新的治疗方法以预防或至少最小化肝I/R损伤对患者具有巨大的益处。仅在美国，肝脏I/R治疗的市场潜力估计为每年> 100亿美元。我们最近证明，给予人肾上腺髓质素（AM，最近发现的有效的血管活性肽）与人AM结合蛋白-1的组合（AMBP-1，一种新的AM特异性结合蛋白）在再灌注开始时立即下调促炎细胞因子，减少肝脏中性粒细胞浸润，抑制肝细胞凋亡和坏死，并降低肝I/R大鼠模型的肝损伤和死亡率。然而，仍然不清楚延迟施用人AM/AMBP-1（其更临床相关）是否在具有或不具有预先存在的肝脏疾病（例如由胆管结扎（BDL）诱导的肝损伤）的肝I/R损伤后也具有同样的保护作用。阻碍人AM/AMBP-1作为肝I/R的新型治疗剂的开发的另一个障碍是商业化人AMBP-1的极高成本。为了克服这一点，我们已经成功地从正常人血清中分离和纯化AMBP-1，成本低得多。因此，我们假设人AM/AMBP-1的延迟施用减弱了肝损伤和炎症，并且即使在预先存在的肝病下也降低了肝I/R诱导的死亡率。该项目的主要目的是证明进一步开发和商业化人AM/AMBP-1作为降低肝I/R后死亡率的新型治疗方法的可行性。人AM/AMBP-1的最佳剂量（延迟治疗）将通过评估1）人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AM/AMBP-1的有益效应的时间过程;和3）人AM/AMBP-1对有或无BDL的肝I/R诱导的死亡率的效应来确定。我们的最终目标（SBIR II期及以后）是获得人AM/AMBP-1的商业利用，作为与预先存在的肝脏疾病相关的肝I/R损伤患者的安全有效的治疗。公共卫生关系：外科技术和药物干预的最新进展适度改善了创伤手术、肝切除术、肝移植和休克的结局。然而，由于缺血再灌注（I/R）损伤导致的肝功能衰竭仍然是临床竞技场的主要并发症。肝脏I/R伴或不伴既存肝脏疾病是导致此类患者多器官功能衰竭和死亡的重要原因。显然，迫切需要开发新的治疗方法来预防或至少最小化肝I/R损伤。