A New Therapy for Bowel Ischemia-Reperfusion Injury

描述（由申请人提供）：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法和物质来降低肠道缺血/再灌注（I/R）引起的死亡率，但没有一种是完全成功的。因此，制定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患者在这种情况下的预后至关重要。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。我们最近证明，在肠系膜上动脉闭塞（SMAO）引起的大鼠肠I/R模型中，在再灌注开始时给予大鼠肾上腺髓质素（AM），一种最近发现的强效血管舒张肽，与它的新型特异性结合蛋白（即AMBP-1）联合，可以减轻组织损伤和炎症反应。阻碍AM/AMBP-1作为肠道I/R治疗剂发展的一个障碍是大鼠蛋白在人类中的潜在免疫原性。虽然我们已经证明在再灌注开始时给药大鼠AM加人AMBP-1具有保护作用，但尚不清楚人AM和人AMBP-1联合是否也有益，如果有益，是否延迟给药AM/AMBP-1（更具有临床相关性）可以降低肠道I/ r诱导的死亡率。因此，我们假设，即使在再灌注后，给药人AM/AMBP-1也能改善心血管功能，减轻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为了证明进一步开发和商业化人类AM/AMBP-1作为一种降低肠道I/R后死亡率的新型复苏方法的可行性。人类AM/AMBP-1的最佳剂量将通过评估1)AM/AMBP-1对肠道I/R后心血管功能、组织损伤和炎症反应的剂量反应影响来确定；2) AM/AMBP-1的剂量反应对肠道I/ r致死亡率的影响；3) AM和AMBP-1在正常动物体内及肠I/R后的药代动力学。我们的最终目标（SBIR II期及以后）是获得人类AM/AMBP-1作为一种安全有效的治疗肠道I/R损伤患者的商业利用。

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.