A novel anti-scar peptide for cutaneous wound repair

描述（由申请人提供）：由于5500万例择期手术和2500万例创伤后手术，皮肤纤维化（瘢痕形成）每年影响多达1亿例患者。除了美观的问题，疤痕可以有显着的功能后遗症。总的来说，皮肤疤痕预防策略的效果最小。目前可用的技术集中于减少已经形成的疤痕的外观（例如，硅酮薄片、局部软膏和激光）。其他针对疤痕形成过程的疤痕减少策略，如类固醇和放射治疗，可能会产生不良副作用。由于这些实质性的限制，仍然迫切需要开发用于预防皮肤瘢痕形成的替代疗法。通过持续的，11年的研究工作，检查胎儿伤口愈合模型，我们已经确定了纤维调节蛋白（FMOD）作为一种新的分子所需的胎儿无瘢痕皮肤修复。FMOD蛋白减少瘢痕形成并改善成人伤口中的细胞外基质（ECM）组织。这些发现已在多个哺乳动物物种中得到证实。在一项技术创新中，我们已经鉴定了40个氨基酸的肽序列F06-C40，其具有与完整FMOD蛋白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，而有利于快速，廉价和高纯度的合成FMOD肽。最近，使用猪模型，我们在初步研究中证明FMOD蛋白及其肽衍生物F06-C40均显著减少瘢痕形成。在本提案中，我们将检验F06-C40将 与安慰剂相比，在减少皮肤瘢痕形成方面具有改善的功效，而安全性没有变化。目的1（1 - 12个月）：优化F06-C40预防皮肤瘢痕。AIM 1将优化F06-C40的剂量和持续时间，以减少皮肤瘢痕。将使用猪主要意图伤口闭合模型。猪皮是最接近人类皮肤的动物等效物，并且是FDA用于测试伤口愈合产品的首选模型系统。主要结局指标将包括改善大体视觉外观，而不降低伤口抗张强度。目的2（第13 - 24个月）：进行F06-C40全身和局部毒理学研究。AIM 2将启动FDA要求的F06-C40安全性研究，以提交研究性新药（IND）。将在大鼠中进行递增剂量静脉内研究，并将在猪中进行递增剂量皮内研究。皮肤瘢痕会导致显著的功能和外观损害。迄今为止，还没有FDA批准的用于预防疤痕复发的药物。该I期SBIR提案的重点是优化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.