Development of a New Treatment for Diabetic Wounds

开发糖尿病伤口新疗法

基本信息

批准号：
10081437
负责人：
SREEJAYAN NAIR
金额：
$ 24.11万
依托单位：
NUTRIWYO, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-04 至 2022-09-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10081437
关键词：
Affect Amputation Area Arts Becaplermin Businesses Cell Proliferation Chronic Clinical Clinical Trials Collagen Complications of Diabetes Mellitus Data Debridement Development Diabetes Mellitus Diabetic Foot Ulcer Diabetic mouse Dose Economic Burden Economics Enzymes Epithelial Epithelium Equilibrium Event Extracellular Matrix Extracellular Matrix Proteins FDA approved Family suidae Foot Ulcer Fracture Funding Gel Goals Growth Factor Health Healthcare Systems Human Immunohistochemistry Impaired wound healing Individual Infection Control Inflammatory Lead Legal patent Letters Lower Extremity Medical Medical Care Costs Methods Modeling Molecular Operative Surgical Procedures Outcome Outcome Study Patients Peptide Hydrolases Persons Pharmaceutical Preparations Pharmacology Phase Platelet-Derived Growth Factor Postmenopausal Osteoporosis Postmenopause Private Sector Privatization Process Quality of life Research Personnel Skin Skin Tissue Small Business Technology Transfer Research Technology Telephone United States United States National Institutes of Health Validation Woman Wyoming angiogenesis base cancer risk cardiovascular risk factor cathepsin K cell motility chronic wound clinical efficacy clinically relevant commercialization cost design diabetic diabetic ulcer diabetic wound healing foot healing human subject improved industry partner inhibitor/antagonist intradermal injection lifetime risk limb amputation mortality next generation non-diabetic non-healing wounds novel novel strategies novel therapeutic intervention phase III trial pressure response social success treatment response wound wound closure wound environment wound healing wound treatment

项目摘要

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.

摘要：非治疗伤口影响约25％的糖尿病患者，代表了下肢的截肢是一个巨大的临床问题，也是一个实质性的经济负担。给出缺乏有效帮助糖尿病伤口治愈的批准代理，存在着主要需求开发用于治疗糖尿病伤口的新型药理剂。慢性糖尿病伤口是以高度蛋白水解的微环境为特征。升高的蛋白水解活性导致连续细胞外基质蛋白（如胶原蛋白）的分解，维持长期破坏性状态延迟伤口治疗。组织蛋白酶K是最有效的哺乳动物胶原式酶。初步的研究表明，来自糖尿病人类受试者的皮肤组织的胶原蛋白水平较低和水平升高与非糖尿病人类的皮肤相比，组织蛋白酶K此外，组织蛋白酶K已更新来自糖尿病小鼠的皮肤组织以及组织蛋白酶K加速伤口愈合的药物抑制在糖尿病猪模型中，为该项目提供了强大的理由。我sttr的总体目标项目是通过使用潜力来开发/验证/商业化一种治疗糖尿病伤口的新方法，施依然K的选择性抑制剂先前已进行了其他应用临床试验。具体该阶段I可行性项目的目的是1）确定组织蛋白酶内皮内注射的效率在糖尿病伤口愈合的翻译相关猪模型中愈合糖尿病伤口中的K抑制剂， 2）评估糖尿病伤口的分子变化，以响应组织蛋白酶K抑制剂的治疗。我们将用五个预定剂量的抑制剂确定伤口闭合百分比，并将其与 Regranex®凝胶（FDA批准的用于治疗糖尿病伤口的生长因子）和第3、7、15天的媒介物糖尿病和非糖尿病猪的完全闭合（〜21天）。用抑制剂治疗（0.3-30ng/mm2伤口预计区域将在第15天后诱发完全重新上述（100％伤口闭合）。此外，在分子水平上，我们将评估用抑制剂治疗的程度上皮间隙，较低的组织蛋白酶水平，增加胶原蛋白含量和伤口的血管生成与Regranex®和车辆处理相比，在接下来的第七天翼。 a> 50％从在大概参数中，经媒介物处理的逻辑将被视为分子验证抑制剂加速愈合，而与Regranex®相比，这些参数的变化> 25％将被视为“优越”的结果。我们预计这一阶段I STTR项目将大大建立强大的初步数据，以建立概念可行性并为II期STTR项目奠定基础旨在验证临床效率的潜力，并最终是产品商业化。我们期望通过这个多相项目的成功，可以导致广泛的商业部署，从而极大地好处人类健康，同时大大降低了医疗费用。