A New Therapy for Bowel Ischemia-Reperfusion Injury

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.