Development of a New Treatment for Diabetic Wounds

Abstract: Non-healing wounds affect ~25% of people with diabetes and represent a primary cause of amputation of lower limbs, which is an enormous clinical problem and a substantial economic burden. Given the lack of approved agents that effectively aid in the healing of diabetic wounds, a major need exists for developing novel pharmacological agents for treating diabetic wounds. Chronic diabetic wounds are characterized by a highly proteolytic microenvironment. The elevated proteolytic activity leads to a continuous breakdown of the extracellular matrix proteins such as collagen, sustaining a prolonged destructive state that delays wound-healing. Cathepsin K is the most potent mammalian collagenolytic enzyme known. Preliminary studies show that skin tissues from diabetic human subjects have lower levels of collagen and elevated levels of the cathepsin K compared to the skin from non-diabetic humans. Furthermore, cathepsin K is upregulated in the skin tissue from diabetic mouse, and pharmacological inhibition of cathepsin K accelerated wound-healing in the diabetic pig model, providing a strong rationale for this project. The overall goal of this Phase I STTR project is to develop/validate/commercialize a new approach to treat diabetic wounds by using a potent, and selective inhibitor of cathepsin K that has previously undergone clinical trials for other application. The Specific Aims of this Phase I feasibility project are to 1) Determine the efficacy of intradermal injection of the cathepsin K inhibitor in healing diabetic wounds in a translationally relevant porcine model of diabetic wound-healing, and 2) Evaluate molecular changes in the diabetic wound in response to treatment with the cathepsin K inhibitor. We will determine the percent wound closure with five predetermined doses of the inhibitor and compare it with Regranex® gel (an FDA approved growth-factor for treating diabetic wounds) and vehicle at days 3, 7, 15, and full closure (~day 21) in both diabetic and non-diabetic pigs. Treatment with the inhibitor (0.3-30ng/mm2 wound area) is expected to induce complete reepithelization (100% wound closure) by post-wounding day 15. Furthermore, at the molecular level, we will assess the degree to which treatment with the inhibitor will reduce epithelial gap, lower cathepsin K levels, increase collagen content, and augment angiogenesis in the wound on day seven following wounding, as compared to Regranex® and vehicle treatment. A andgt;50% change from vehicle-treated wounds in the aforementioned parameters will be considered as molecular validation for accelerated healing by the inhibitor, whereas a andgt;25% change in these parameters compared to Regranex® would be deemed as ‘superior’ outcome. We anticipate this Phase I STTR project will significantly build upon the strong preliminary data to establish concept feasibility and to set the stage for a Phase II STTR project designed to validate the potential for clinical efficacy and, ultimately, product commercialization. We expect success with this multi-phase project to lead to broad-based commercial deployment that greatly benefits human health while substantially reducing medical costs.PROJECT NARRATIVE Non-healing diabetic wounds are a serious clinical problem and the leading cause of amputations among diabetics. Our inability to effectively heal diabetic ulcers has a severe impact on quality of life and even survival for patients, while costing our healthcare system billions in the U.S. alone. Through this Phase I STTR project, Nutriwyo LLC proposes to establish the feasibility of a novel therapeutic approach to facilitate healing of diabetic wounds as a next-generation treatment.