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、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，14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。这些发现已经在多个哺乳动物物种中得到证实。作为技术创新，我们开发了40个氨基酸的FMOD肽序列F06-C40，可以快速廉价地生产，并且在抗纤维化作用方面与376个氨基酸的全FMOD蛋白相似。由于猪皮是与人类皮肤最接近的动物皮肤，并且是食品和药物管理局（FDA）用于测试伤口愈合产品的首选模型，因此我们建立了F06- C40的最佳剂量和方案（F06-C40 OPT），其有效地改善总体视觉外观，减小疤痕尺寸，并在模拟人类瘢痕修复手术的约克郡猪原发性伤口闭合模型中保持伤口张力。此外，我们已经证实F06-C40 OPT在模拟人类增生性瘢痕的红色杜洛克猪模型中具有相同的作用，我们准备将其应用于试验性新药（IND）使能研究。此外，我们已经证明，F06-C40在小鼠、大鼠和猪中没有体内不良局部作用-值得注意的是，在猪模型中1.5 cm（10 mg/cm）的伤口上应用了高达50 mg/ml的0.3 ml。此外，我们还证明，在大鼠中使用高达100 mg/kg的F06-C40 [可转换为16 mg/kg的人体等效剂量（HED）;对于60 kg的雄性动物，该剂量可转换为约960 mg的总剂量，足以治疗960 cm的线性瘢痕]时，未观察到显著的全身毒性。这远远超过了典型疤痕的大小和治疗所需的F06-C40的预期量（例如每线性cm疤痕1 mg）]。因此，我们已经实现了我们之前的SHIFT-SBIR第一阶段合同（1 R43 AR 064126 - 01）中提出的所有目标。目前SBIR II期申请的目标是为首次人体F06-C40临床试验进行关键的IND使能研究，并允许基于FMOD肽的治疗从实验室到床边的转化，以减少皮肤瘢痕形成。

 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 sequelae. 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, 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, 14-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 findings have been confirmed across multiple mammalian species. As a technological innovation, we have developed a 40 amino acid FMOD peptide sequence, F06-C40, which can undergo rapid and inexpensive production and is similar to the 376 amino acid full FMOD protein in its anti-fibrotic effects. Because porcine skin is the closest animal skin equivalent to that of humans and is the Food and Drug Administration (FDA)- preferred model for testing wound healing products, we have established the optimal dose and regimen of F06- C40 (F06-C40OPT) that effectively improves gross visual appearance, reduces scar size, and maintains wound tensile in a Yorkshire pig primary wound closure model simulating human scar revision surgery. In addition, we have confirmed that F06-C40OPT has the same effects in a red Duroc pig model simulating human hypertrophic scarring, and we are ready to apply it to Investigational New Drug (IND)-enabling studies. Moreover, we have demonstrated that F06-C40 does not have in vivo adverse local effects in mice, rats, and pigs - notably, up to 50 mg/ml with 0.3 ml was applied for 1.5 cm (10 mg/cm) of wound in the porcine models. Furthermore, we have also proved that no significant systemic toxicity is observed in rats with up to 100 mg/kg F06-C40 [which can be converted to a 16 mg/kg human equivalent dose (HED); for a 60 kg male, this dose can be translated to approximately a 960 mg total dose, enough to treat a 960 cm linear scar. This far exceeds the size of typical scars and the anticipated amount of F06-C40 required for treatment (e.g. 1 mg per every linear cm of scar)]. Thus, we have accomplished all aims proposed in our previous SHIFT-SBIR Phase I award (1 R43 AR064126- 01). The goal of the current SBIR Phase II application is to perform critical IND-enabling studies for first-in-man F06-C40 clinical trials an to allow bench to bedside translation of FMOD peptide-based therapy to prophylactically reduce cutaneous scar formation.