SBIR-STTR Award

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 [4, 5, 8-10]. 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 [1, 2]. 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 connective tissue growth factor (CTGF) and collagen type I up regulation. The proposed MK2 inhibitor peptide therapeutic will inhibit the scar inducing activities thus offering the potential of being a rapid, targeted therapy to prevent adhesions [7]. Through this phase I SBIR plan final optimization and selection of the therapeutic peptide, in addition to initial purity, solubility and stability testing will be achieved. The following aims will be competed: 1) Optimization and specificity testing of MK2 inhibitors will be completed. Based upon knowledge gained in preliminary experiments, peptide variants will be synthesized to improve activity while maintaining specificity. Activity will be evaluated using an in vitro kinase assay. Specificity of the four top drug candidates will be tested in a kinase profiler assay to determine if enhancing MK2 inhibition activity affects specificity. Finally, evaluation of MK2i inhibition of CTGF expression in a human fibroblast cell line will be performed. 2) Preliminary biophysical evaluation: purity, solubility, stability. Purity will be determined by elemental analysis and quantitative amino acid analysis. Maximum solubility testing will be performed in PBS and confirmed using quantitative amino acid analysis. To predict drug product stability, we will perform preliminary aqueous-based stability testing. Candidates will be solubilized in buffer, stored at 4, 25 or 40 C for four weeks and degree of degradation will be evaluated using an HPLC assay.

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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.

Public Health Relevance:
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.

Thesaurus Terms:
Abdomen; Abdominal; Acute; Adhesions; Adhesives; Animal Growth Regulators, Transforming Growth Factors; Area; Authorization; Authorization Documentation; Body Tissues; Ctgf; Cardiac; Cells; Cessation Of Life; Chest; Cicatrix; Clinical Data; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Collagen Type I; Conduct Clinical Trials; Death; Disease; Disorder; Drug Kinetics; Drugs; Drugs, Investigational; Ec 2.7; Ec 2.7.2-; Early-Stage Clinical Trials; Extracellular Signal-Regulated Kinases; Frequencies (Time Pattern); Frequency; Gastrointestinal Tract, Small Intestine; Genetic Toxicity Tests; Genotoxicity Tests; Goals; Grant; Igf-Binding Protein-Related Protein-2; Igfbp-8; Igfbp-Rp2; Immunoassay; Intermediary Metabolism; Intestines, Small; Investigational Drugs; Investigational New Drug Application; Investigational New Drugs; Kinases; Map Kinase; Mapk; Metbl; Marketing; Medication; Metabolic Processes; Metabolism; Mitogen-Activated Protein Kinases; Monitor; Mutagen Screening; Mutagenicity Tests; Operation; Operative Procedures; Operative Surgical Procedures; Organ; Pain; Painful; Patients; Peptides; Permission; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Pharmacokinetics; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phosphotransferases; Physiologic; Physiological; Preparation; Prevention; Procedures; Proteins; Proteomics; Sales; Scars; Shipping; Ships; Small Intestines; Surgical; Surgical Interventions; Surgical Procedure; System; System, Loinc Axis 4; Technology; Therapeutic; Thorace; Thoracic; Thorax; Tissues; Transforming Growth Factors; Transphosphorylases; Tumor Growth Factors; Type 1 Collagen; United States; Up-Regulation; Up-Regulation (Physiology); Upregulation; Work; Base; Burden Of Disease; Burden Of Illness; Clinical Investigation; Clinical Research Site; Clinical Site; Connective Tissue Growth Factor; Cytokine; Disease Burden; Disease/Disorder; Drug/Agent; Fisp12 Protein; Gene Product; In Vivo; Inhibitor; Inhibitor/Antagonist; Insulin-Like Growth Factor Binding Protein 8; Intravenous Injection; Meetings; Minimally Invasive; Mutagen Testing; Phase 1 Study; Phase 1 Trial; Phase I Trial; Pre-Clinical; Preclinical; Prevent; Preventing; Product Development; Protein Function; Protocol, Phase I; Public Health Relevance; Response; Safety Testing; Small Bowel; Stressor; Surgery; Tool; Uptake; Years Of Life Lost To Disability; Years Of Life Lost To Disease