Novel peptide for enhancing diabetic wound healing

项目总结/摘要 糖尿病（DM）是一种代谢性疾病，其特征是胰岛素信号传导缺陷和血胰岛素水平升高。 葡萄糖，已经成为一种公共卫生流行病，一半的美国人口被诊断患有糖尿病或糖尿病前期， 糖尿病不受控制的DM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%的糖尿病患者在其一生中发展为慢性不愈合溃疡 由于与糖尿病相关的血管分布和免疫缺陷不良， 感染并经常导致截肢。糖尿病目前是美国第七大死亡原因。 目前的管理主要集中在控制伤口生物负载以促进伤口愈合， 包括减压、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，完全伤口闭合由于细胞迁移受损而复杂化， 在DM伤口中发挥作用。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。 糖尿病患者的损伤通常持续存在并进展。慢性糖尿病导致几个显著的改变， 生理伤口愈合机制损害适时的细胞浸润/迁移，肉芽组织形成， 和伤口收缩。基于20多年的伤口愈合管理研究，我们 开发了一种技术创新的基于纤维调节蛋白（FMOD）的氨基酸肽序列SLI-F06， 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。之前，我们证明了SLI-F06显著促进急性创伤， 在临床前动物研究中，在最大可行剂量下愈合而不引起任何不良反应，以及 正在进行的针对急性伤口愈合的1/2a期临床试验。令人兴奋的是，我们已经证明，重复的SLI- F06给药显著加速了小鼠模型（NONcNZO 10/LtJ）中的糖尿病伤口闭合， 与人类2型糖尿病非常相似。当前快速通道SBIR应用程序的目标是获得密钥 SLI-F06作为局部重复给药的临床前疗效和作用机制数据 用于糖尿病伤口的治疗，以扩大SLI-F06的临床适应症。总的来说，这 该提案将实现关键的功效和作用机制（MOA）目标，以加快商业化 糖尿病伤口的SLI-F06治疗。本品能显著提高糖尿病患者的生活质量 患有慢性创伤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.