A novel anti-scar peptide for cutaneous wound repair

描述(由申请人提供)：皮肤纤维化(疤痕形成)每年影响多达1亿名患者，这是5500万次择期手术和2500万次创伤后手术的结果。除了美容方面的问题外，疤痕形成还可能产生重大的功能后遗症。总体而言，皮肤的疤痕预防策略效果甚微。目前可用的技术侧重于减少已经形成的疤痕(例如，硅胶薄膜、外用药膏和激光)的外观。其他针对疤痕形成过程的减疤策略，如类固醇和放射治疗，可能会产生不良的副作用。有了这些实质性的局限性，仍然迫切需要开发预防皮肤疤痕的替代疗法。通过对胎儿伤口愈合模型的持续11年的研究，我们已经确定纤维调素(FMOD)是胎儿无疤痕皮肤修复所需的一种新分子。FMOD蛋白可减少成人创面的瘢痕形成并改善细胞外基质(ECM)的组织。这些发现已经在多个哺乳动物物种中得到证实。在一项技术创新中，我们鉴定了一个40个氨基酸的多肽序列F06-C40，其抗纤维化作用与完整的FMOD蛋白相似。这使我们可以绕过昂贵的基于细胞的蛋白质生产技术，转而使用能够快速、廉价和高纯度生产的合成FMOD多肽。最近，我们在初步研究中使用了一种猪模型，证明FMOD蛋白及其多肽衍生物F06-C40都能显著减少瘢痕的形成。在这个提议中，我们将检验假设F06-C40将 与安慰剂相比，在减少皮肤疤痕形成方面，在不改变安全性的情况下，有更好的疗效。目标1(1-12个月)：优化F06-C40预防皮肤疤痕。目的1优化F06-C40治疗皮肤瘢痕的剂量和持续时间。将使用猪的主要意图伤口闭合模型。猪皮是最接近人类皮肤的动物，也是FDA首选的伤口愈合产品测试模型系统。主要结果指标将包括在不降低伤口抗张强度的情况下改善肉眼外观。目标2(13-24个月)：进行F06-C40系统和局部毒理学研究。AIM 2将启动FDA要求的F06-C40安全性研究，以提交研究用新药(IND)。将在大鼠身上进行递增剂量的静脉研究，在猪身上进行递增剂量的皮内研究。皮肤疤痕会导致严重的功能和美容损伤。到目前为止，还没有FDA批准的预防瘢痕复发的药物。这项第一阶段的SBIR方案重点是优化F06-C40的治疗方案，并证明其安全性和有效性。

DESCRIPTION (provided by applicant): Cutaneous fibrosis (scarring) affects up to 100 million patients per year as a result of 55 million elective operations and 25 million operations after trauma. Besides concerns of cosmesis, scarring can have significant functional sequel. Overall, scar prevention strategies for skin are minimally effective. Currently available techniques focus on reducing the appearance of already formed scars (e.g., silicone sheeting, topical ointments, and lasers). Other scar reduction strategies that target the scar formation process such as steroids and radiation can have undesirable side effects. With these substantial limitations, there remains a pressing need for the development of alternative therapies for the prevention of cutaneous scarring. Through a sustained, 11-year research effort examining models of fetal wound healing; we have identified fibromodulin (FMOD) as a novel molecule required for fetal scarless skin repair. FMOD protein decreases scarring and improves extracellular matrix (ECM) organization in adult wounds. These finding have been confirmed across multiple mammalian species. In a technological innovation, we have identified a 40 amino acid peptide sequence, F06-C40, with similar anti-fibrotic effects to the full FMOD protein. This allows us to bypass costly cell-based techniques for protein production in favor of a synthetic FMOD peptide that can be produced rapidly, inexpensively, and with high purity. Most recently, using a pig model we demonstrated in pilot studies that both FMOD protein and its peptide derivative, F06-C40, significantly reduce scar formation. In this proposal we will test the hypothesis that F06-C40 will have improved efficacy without a change in safety in comparison to placebo for the reduction of cutaneous scar formation. AIM 1 (Months 1-12): Optimize F06-C40 for cutaneous scar prevention. AIM 1 will optimize the dose and duration of F06-C40 for cutaneous scar reduction. A porcine primary intention wound closure model will be used. Porcine skin is the closest animal equivalent to human skin, and is the FDA-preferred model system for testing of wound healing products. Primary outcome measures will include improved gross visual appearance without reduction in wound tensile strength. AIM 2 (Months 13-24): Perform F06-C40 systemic and local toxicology studies. AIM 2 will initiate F06- C40 safety studies required by the FDA for an Investigational New Drug (IND) submission. An escalating dose intravenous study will be performed in rats, and an escalating dose intradermal study will be conducted in pigs. Cutaneous scars cause significant functional and cosmetic impairment. To this day, there exist no FDA approved drugs for prevention of scar recurrence. This Phase I SBIR proposal focuses on optimizing the treatment regimen for F06-C40 and proving its safety and efficacy.