A New Therapy for Bowel Ischemia-Reperfusion Injury

描述(由申请人提供)：这项SBIR第二阶段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法和物质来降低肠道I/R诱导的死亡率，但没有一种方法和物质完全成功。因此，开发新的治疗方法来预防或至少减少肠道I/R损伤对患者来说是巨大的好处。仅在美国，肠道I/R治疗作为一个整体的市场潜力估计为每年20-50亿美元。我们最近证实，大鼠肾上腺髓质素(AM)是最近发现的一种有效的血管活性多肽，与人肾上腺髓质素结合蛋白-1(AMBP-1)相结合，可减轻肠系膜上动脉阻塞(SMAO)所致的大鼠肠I/R模型的组织损伤和炎症反应。为了避免大鼠蛋白在人体内潜在的免疫原性，在第一阶段项目中提出了人AM。商业化的人AMBP-1与人AM联合应用，在相同的SMAO动物模型上证实了上述保护作用。剂量-反应研究表明，一期工程提出的人AM/AMBP-1的最大剂量对肠I/R后有较好的保护作用，但商品化的人AMBP-1的极高成本限制了AM/AMBP-1的进一步发展。为了克服这一障碍，我们以低得多的成本成功地从人血清中分离和纯化了AMBP-1。因此，我们继续假设，给予人AM/AMBP-1可以减轻肠I/R损伤后的器官损伤和炎症，并降低死亡率。在这个第二阶段的方案中，我们将首先扩大人AMBP-1的生产，然后进行额外的疗效研究，以确定人AM/AMBP-1在大鼠肠道I/R中的最佳保护剂量。此外，还将评估人AM/AMBP-1在肠道I/R后的药代动力学特征。为了将我们的技术推向临床试验，我们将在猪的肠道I/R模型中研究人AM/AMBP-1的疗效。我们的最终目标是开发人AM/AMBP-1的商业应用，作为一种安全有效的治疗肠道I/R损伤的方法。 公共卫生相关性：肠缺血再灌注(I/R)是败血症、失血性休克、血管外科和小肠移植中常见的临床问题。虽然已经研究了各种方法和物质来降低肠道I/R诱导的死亡率，但没有一种方法和物质完全成功。因此，开发新的治疗方法来预防或至少减少肠道I/R损伤对患者来说是巨大的好处。仅在美国，肠道I/R治疗的市场潜力估计就达到每年20-50亿美元。显然，迫切需要开发一种有效的、新颖的复苏方法来治疗肠I/R损伤患者。

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.