Disease definition: Adhesions, fibrous scars abnormally conjoining adjacent tissues, are primarily caused by surgical procedures. They can arise in many areas of the body as common sequelae of abdominal, gynecological, thoracic, and cardiac procedures [1-5]. Adhesions can cause not only pain and discomfort, but also loss of organ function and even death. While the technology described herein will effect prevention of all adhesion types, the high-need, high-burden abdominal (specifically small bowel) adhesion prevention application will be the focus of this grant submission. Burden of disease: Abdominal adhesions occur at high frequency and have tremendous associated burden of disease. Adhesions form in conjunction with virtually every abdominal surgery. Multiple studies cite that, of those patients who have abdominal surgery, up to 93% will develop adhesions [6, 7]. Transforming Growth Factor-21 and other cytokines are known to initiate adhesion formation through activation of mitogen activated protein kinase activated kinase (MK2). MK2 is implicated in the connective tissue growth factor (CTGF) and collagen type I up regulation that promotes adhesions. The proposed MK2 inhibitor peptide therapeutic (MK2i) inhibits these scar inducing activities, thus offering the potential of becoming an effective targeted therapy to prevent adhesions [8]. The primary objective of this proposal is to commercially develop MK2i for the treatment of adhesive disorders;the following study plan, outlined below, has been constructed to meet regulatory requirements mandated by the FDA for IND submission. The following aims will be completed as part of this work: 1. Conduct preliminary safety testing of MK2i in vivo. a. Develop an immunoassay for MK2i. b. Conduct pharmacodynamic studies to determine the effect of MK2i on major physiological systems. c. Monitor pharmacokinetics (metabolism and distribution) after intravenous injection of MK2i. 2. Conduct final safety testing of MK2i for IND (Investigational New Drug) submission to FDA. a. Produce MK2i under GMP (Good Manufacturing Practice) conditions. b. Conduct acute, subacute, and genetic toxicity testing of GMP grade MK2i. 3. Prepare IND submission for advancement into Phase I clinical trials. Through these rigorous product development activities in preparation to begin clinical trials, a therapeutic that can be sprayed or otherwise directly applied into the abdomen during invasive or minimally invasive surgery will be on the path to becoming a reality.
Burden of disease: Abdominal adhesions occur at high frequency and have tremendous associated burden of disease. Multiple studies cite that, of those patients who have abdominal surgery, up to 93% will develop adhesions [1, 2]. Adhesions can cause not only pain and discomfort, but also loss of organ function and even death. The proposed therapy will inhibit adhesion formation.
