A novel anti-scar peptide for cutaneous wound repair

描述（由申请人提供）：皮肤纤维化（瘢痕）每年影响多达1亿患者，这是5500万例选择性手术和2500万例创伤后手术的结果。除了美容方面的问题，疤痕还会有重要的功能后遗症。总的来说，预防皮肤疤痕的策略是最低限度的有效。目前可用的技术侧重于减少已经形成的疤痕的外观（例如，硅胶片，局部软膏和激光）。其他针对疤痕形成过程的疤痕减少策略，如类固醇和放疗，可能会产生不良副作用。由于这些实质性的限制，仍然迫切需要开发替代疗法来预防皮肤瘢痕形成。通过持续的，11年的研究努力检查胎儿伤口愈合模型；我们已经确定纤维调节素（FMOD）是胎儿无疤痕皮肤修复所需的新分子。FMOD蛋白减少瘢痕形成，改善成人伤口的细胞外基质（ECM）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，我们已经鉴定出一个40个氨基酸的肽序列F06-C40，与完整的FMOD蛋白具有相似的抗纤维化作用。这使我们能够绕过昂贵的基于细胞的蛋白质生产技术，转而使用合成的FMOD肽，可以快速、廉价、高纯度地生产。最近，我们利用猪模型进行了初步研究，证明FMOD蛋白及其肽衍生物F06-C40都能显著减少疤痕的形成。在本提案中，我们将测试F06-C40将

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.