A New Therapy for Bowel Ischemia-Reperfusion Injury

描述（由申请方提供）：急性肠系膜缺血是一种腹部急症，死亡率高达60- 80%。尽管已经研究了许多方式和物质来降低肠缺血/再灌注（I/R）诱导的死亡率，但没有一种是完全成功的。因此，开发有效的策略来预防和治疗肠道I/R后的循环衰竭和器官损伤对于改善此类条件下的患者结局至关重要。仅在美国，肠道I/R治疗的市场潜力估计为每年20 - 50亿美元。我们最近已经证明，大鼠肾上腺髓质素（AM），一种最近发现的有效的血管舒张肽，与其新的特异性结合蛋白（即，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，AMBP-1减轻了组织损伤和炎症反应。阻碍AM/AMBP-1作为肠I/R治疗剂的一个障碍是大鼠蛋白在人体中的潜在免疫原性。尽管我们已经表明，在再灌注开始时给予大鼠AM加人AMBP-1是保护性的，但仍然不知道人AM和人AMBP-1的组合是否也是有益的，如果是这样，延迟给予AM/AMBP-1（其更临床相关）是否降低肠I/R诱导的死亡率。因此，我们假设，即使在再灌注后，施用人AM/AMBP-1也能改善心血管功能，减弱器官损伤和炎症反应，并降低肠道I/R损伤后的死亡率。该项目的主要目的是证明进一步开发和商业化人AM/AMBP-1作为降低肠道I/R后死亡率的新型复苏方法的可行性。人AM/AMBP-1的最佳剂量将通过评估1）AM/AMBP-1的剂量-反应对肠I/R后心血管功能、组织损伤和炎症反应的影响; 2）AM/AMBP-1的剂量-反应对肠I/R诱导的死亡率的影响;和3）AM和AMBP-1在正常动物中和在肠I/R后的药代动力学来确定。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，作为肠I/R损伤患者的安全有效的治疗方法。

DESCRIPTION (provided by applicant): Acute mesenteric ischemia is an abdominal emergency with a mortality rate of up to 60-80%. Even though numerous modalities and substances have been studied to reduce gut ischemia/reperfusion (I/R)-induced mortality, none have been entirely successful. As such, the development of effective strategies for preventing and treating circulatory collapse and organ injury after gut I/R is critical for the improvement of patient outcome under such conditions. The market potential for gut I/R treatment is estimated at $2-5 billion per year in the U.S. alone. We have recently demonstrated that administration of rat adrenomedullin (AM), a recently-discovered potent vasodilatory peptide, in combination with its novel specific binding protein (i.e., AMBP-1), at the beginning of reperfusion attenuated tissue injury and inflammatory responses in a rat model of gut I/R induced by superior mesenteric artery occlusion (SMAO). One obstacle hampering development of AM/AMBP-1 as a therapeutic agent for gut I/R is the potential immunogenicity of rat proteins in humans. Although we have shown that administration of rat AM plus human AMBP-1 at the beginning of reperfusion is protective, it remains unknown whether a combination of human AM and human AMBP-1 is also beneficial and, if so, whether delayed administration of AM/AMBP-1 (which is more clinically relevant) reduces gut I/R-induced mortality. We therefore hypothesize that administration of human AM/AMBP-1, even after reperfusion, improves cardiovascular function, attenuates organ injury and inflammation responses, and reduces mortality following gut I/R injury. 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 resuscitation approach in reducing mortality after gut I/R. The optimal dosage(s) of human AM/AMBP-1 will be determined by assessing 1) the effect of a dose-response of AM/AMBP-1 on cardiovascular function, tissue injury and inflammatory responses after gut I/R; 2) the effect of a dose-response of AM/AMBP-1 on gut I/R-induced mortality; and 3) the pharmacokinetics of AM and AMBP-1 in normal animals and after gut I/R. 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 gut I/R injury.