Novel peptide for enhancing diabetic wound healing

项目摘要/摘要 糖尿病(DM)，一种以胰岛素信号转导缺陷和血液升高为特征的代谢紊乱 葡萄糖，已成为一种公共卫生流行病，有一半的美国人被诊断为糖尿病或糖尿病前期 糖尿病。失控的糖尿病最常见和最具破坏性的后遗症之一是慢性糖尿病的发展 无法愈合的伤口。据估计，25%的糖尿病患者一生中都会患上慢性无法愈合的溃疡。 考虑到糖尿病相关的糟糕的血管和免疫缺陷，这是非常容易发生的 感染，经常导致截肢。糖尿病目前是美国第七大死因。 目前的管理主要集中在控制伤口生物接触以促进伤口愈合，这是 包括压力卸载、抗菌药物和敷料、明智的伤口护理和优化 生活方式因素。然而，伤口完全闭合的复杂因素是细胞迁移和损伤。 在糖尿病创面中的作用。因此，迫切需要开发新的糖尿病治疗方法。 直接恢复促进适当皮肤修复所需的分子和细胞过程的伤口。 糖尿病患者的损伤经常持续并进展。慢性糖尿病导致以下几个方面的显著变化 生理性伤口愈合机制，损害及时的细胞渗透/迁移，肉芽组织形成， 和伤口收缩。基于20多年来对伤口愈合管理的研究，我们有 开发了一种技术创新的基于纤维调素(FMOD)的氨基酸序列SLI-F06，该序列 显著刺激成纤维细胞和内皮细胞迁移以及肌成纤维细胞分化/收缩 促进伤口及时闭合。以前，我们证明SLI-F06显著促进急性伤口 在临床前动物研究中，在最大可行剂量下治愈而不会引起任何不良影响 正在进行的以急性伤口愈合为目标的1/2a期临床试验。令人兴奋的是，我们已经证明了重复的SLI- F06显著加速糖尿病小鼠(NONcNZO10/LTJ)创面闭合 与人类2型糖尿病非常相似。当前Fast-Track SBIR应用的目标是获得密钥 SLI-F06局部反复给药的临床前疗效和作用机制 糖尿病创面应用治疗扩大SLI-F06的临床适应证。总体而言，这 提案将实现加快商业化的关键功效和行动机制(MOA)目标 以SLI-F06为基础的糖尿病创面治疗。本产品能显著提高糖尿病患者的生活质量。 患有慢性伤口的患者，可能会导致截肢和死亡。

PROJECT SUMMARY/ABSTRACT Diabetes Mellitus (DM), a metabolic disorder characterized by defective insulin signaling and elevated blood glucose, has become a public health epidemic with half of the US population diagnosed with either DM or pre- diabetes. One of the most common and devastating sequelae of uncontrolled DM is the development of chronic non-healing wounds. An estimated 25% of diabetic patients develop chronic non-healing ulcers in their lifetime that, given the poor vascularity and immunodeficiency associated with diabetes, are highly susceptible to infection and frequently result in limb amputation. DM is currently the seventh leading cause of death in the U.S. Current management primarily focuses on controlling wound bioburden to promote wound healing, which includes pressure off-loading, antimicrobial medications and dressings, judicious wound care, and optimization of lifestyle factors. However, complete wound closure is complicated by impairment of cellular migration and function in DM wounds. Therefore, there is a pressing need to develop novel therapeutic methods for diabetic wounds that directly restore the molecular and cellular processes required to promote proper cutaneous repair. Injuries in diabetic patients often persist and progress. Chronic DM causes significant alterations to several physiologic wound healing mechanisms that impair timely cell infiltration/migration, granulation tissue formation, and wound contraction. Based on more than 20 years of research on wound healing management, we have developed a technologically innovative fibromodulin (FMOD)-based amino acid peptide sequence, SLI-F06, that markedly stimulates fibroblast and endothelial cell migration and myofibroblast differentiation/contraction to promote timely wound closure. Previously, we demonstrated that SLI-F06 significantly promotes acute wound healing without eliciting any adverse effects in preclinical animal studies at maximal feasible dosing as well as in ongoing Phase 1/2a clinical trial targeting acute wound healing. Excitingly, we have shown that repeated SLI- F06 administration significantly accelerates diabetic wound closure in a mouse model (NONcNZO10/LtJ) that closely simulates human type 2 DM. The goal of the current Fast-track SBIR application is to obtain the key preclinical efficacy and mechanism of action data for SLI-F06 as a repeatedly administered, locally applied therapeutic for diabetic wounds for expanding the clinical indication of SLI-F06. Overall, this proposal will accomplish key efficacy and mechanism of action (MOA) objectives to expedite commercialization of SLI-F06-based therapy for diabetic wounds. This product can significantly improve the quality of life of diabetic patients suffering from chronic wounds that can lead to amputations and death.