A New Therapy for Bowel Ischemia-Reperfusion Injury

肠道缺血再灌注损伤的新疗法

• 批准号: 7993922
• 负责人: RONGQIAN WU
• 金额: $ 39.74万
• 依托单位: THERASOURCE, LLC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993922
• 关键词: Adult; Animal Model; Animals; Apoptosis; Area Under Curve; Attenuated; Bacterial Translocation; Binding Proteins; Blood; Blood Vessels; Body Weight; Cardiac Output; Cleaved cell; Clinical; Clinical Trials; Complex; Continuous Infusion; Creatinine; Development; Development Plans; Dose; Drug Kinetics; Edema; Enzymes; Evaluation; Family suidae; Future; Goals; HMGB1 Protein; Half-Life; Heart; Hemorrhagic Shock; Human; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Intestines; Investigation; Ischemia; Ischemic Bowel Disease; Kidney; Label; Life; Liver; Lung; Marketing; Measures; Medical; Mesentery; Modality; Modeling; Monitor; Morphology; Neutrophil Infiltration; Operative Surgical Procedures; Organ; Patients; Peptides; Performance; Perfusion; Peripheral Resistance; Peroxidases; Pharmaceutical Preparations; Phase; Production; Property; Radioactive; Rat Protein; Rattus; Reperfusion Injury; Reperfusion Therapy; Research; Resuscitation; Sepsis; Serum; Small Business Innovation Research Grant; Small Intestines; Staining method; Stains; Superior mesenteric artery structure; Survival Rate; TdT-Mediated dUTP Nick End Labeling Assay; Technology; Time; Tissue Sample; Tissues; Transplantation; Water; adrenomedullin; artery occlusion; caspase-3; cost; cytokine; dosage; drug clearance; effective therapy; human adrenomedullin-binding protein 1; immunogenicity; improved; lymph nodes; male; mortality; novel; phase 1 study; pre-clinical; preclinical study; prevent; protective effect; public health relevance; research and development; research study; response; scale up

DESCRIPTION (provided by applicant): The purpose of this SBIR Phase II proposal is to further develop a novel treatment that will be used to save the lives of patients with intestinal ischemia/reperfusion (I/R) injury. Although various modalities and substances have been studied to reduce intestinal I/R-induced mortality, none have been entirely successful. As such, the development of novel treatments to prevent or at least minimize intestinal I/R injury is of tremendous benefit to the patient. The market potential for intestinal I/R treatment as a whole is estimated at $2-5 billion per year in the US alone. We have recently demonstrated that administration of rat adrenomedullin (AM), a recently-discovered potent vasoactive peptide, in combination with human adrenomedullin binding protein-1 (AMBP-1), a novel specific binding protein of AM, immediately at the beginning of reperfusion attenuated tissue injury and inflammatory responses in a rat model of intestinal I/R induced by superior mesenteric artery occlusion (SMAO). To avoid the potential immunogenicity of rat proteins in humans, human AM was proposed in the Phase I project. The above protective effects have been confirmed using commercial human AMBP-1 in combination with human AM in the same animal model of SMAO. The dose-response study showed that the highest dosage of human AM/AMBP-1 proposed in the Phase I project achieved a better protection after intestinal I/R. However, the extremely high cost of commercial human AMBP-1 limits the further development of AM/AMBP-1. To overcome this obstacle, we have successfully isolated and purified AMBP-1 from human serum at a much lower cost. We therefore continue to hypothesize that administration of human AM/AMBP-1 attenuates organ injury and inflammation, and reduces mortality following after intestinal I/R injury. In this Phase II proposal, we will first scale up the production of human AMBP-1 and, then, perform additional efficacy studies in order to determine the optimal protective dosage of human AM/AMBP-1 in intestinal I/R in the rat. Moreover, the pharmacokinetic characterization of human AM/AMBP-1 after intestinal I/R will be assessed. To advance our technology to the clinical trials, the efficacy of human AM/AMBP-1 will be investigated in a swine model of intestinal I/R. Our ultimate goal is to develop the commercial utilization of human AM/AMBP-1 as a safe and effective treatment for patients with intestinal I/R injury. PUBLIC HEALTH RELEVANCE: Intestinal ischemia-reperfusion (I/R) is a common clinical problem in the settings of sepsis, hemorrhagic shock, vascular surgery and small bowel transplantation. Although various modalities and substances have been studied to reduce intestinal I/R-induced mortality, none have been entirely successful. As such, the development of novel treatments to prevent or at least minimize intestinal I/R injury is of tremendous benefit to the patient. The market potential for intestinal I/R treatment is estimated at $2-5 billion per year in the US alone. It is obvious that there is an urgent medical need for the development of an effective and novel resuscitation approach for the treatment of patients with intestinal I/R injury.

描述（由申请人提供）：SBIR II期提案的目的是进一步开发一种新的治疗方法，用于挽救肠缺血/再灌注（I/R）损伤患者的生命。虽然已经研究了各种方式和物质来降低肠I/R诱导的死亡率，但没有一种是完全成功的。因此，预防或至少最小化肠I/R损伤的新治疗的开发对患者具有巨大的益处。据估计，仅在美国，肠道I/R治疗作为一个整体的市场潜力就为每年20 - 50亿美元。我们最近发现，在上级肠系膜动脉闭塞（SMAO）诱导的大鼠肠I/R模型中，在再灌注开始时立即给予大鼠肾上腺髓质素（AM）（一种最近发现的有效的血管活性肽）和人肾上腺髓质素结合蛋白-1（AMBP-1）（一种新的AM特异性结合蛋白）可减轻组织损伤和炎症反应。为了避免大鼠蛋白在人体中的潜在免疫原性，在I期项目中提出了人AM。上述保护作用已经在相同的SMAO动物模型中使用商业人AMBP-1与人AM的组合得到证实。剂量反应研究表明，I期项目中提出的人AM/AMBP-1的最高剂量在肠I/R后达到了更好的保护作用。然而，商业化人AMBP-1的极高成本限制了AM/AMBP-1的进一步开发。为了克服这一障碍，我们成功地从人血清中以低得多的成本分离和纯化了AMBP-1。因此，我们继续假设施用人AM/AMBP-1减轻了器官损伤和炎症，并降低了肠I/R损伤后的死亡率。在这个II期计划中，我们将首先扩大人AMBP-1的生产，然后进行额外的功效研究，以确定人AM/AMBP-1在大鼠肠道I/R中的最佳保护剂量。此外，将评估肠I/R后人AM/AMBP-1的药代动力学特征。为了将我们的技术推进到临床试验，将在猪肠道I/R模型中研究人AM/AMBP-1的功效。我们的最终目标是开发人AM/AMBP-1的商业利用，作为肠I/R损伤患者的安全有效的治疗方法。 公共卫生相关性：肠缺血-再灌注（I/R）是脓毒症、失血性休克、血管外科和小肠移植等临床常见问题。虽然已经研究了各种方式和物质来降低肠I/R诱导的死亡率，但没有一种是完全成功的。因此，预防或至少最小化肠I/R损伤的新治疗的开发对患者具有巨大的益处。仅在美国，肠I/R治疗的市场潜力估计为每年20 - 50亿美元。很明显，有一个迫切的医疗需求，为发展一种有效的和新的复苏方法治疗肠I/R损伤的患者。