2020 |
Nair, Sreejayan |
R41Activity Code Description: To support cooperative R&D projects between small business concerns and research institutions, limited in time and amount, to establish the technical merit and feasibility of ideas that have potential for commercialization. Awards are made to small business concerns only. |
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 >50% change from vehicle-treated wounds in the aforementioned parameters will be considered as molecular validation for accelerated healing by the inhibitor, whereas a >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.
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