A novel anti-scar peptide for cutaneous wound repair

一种用于皮肤伤口修复的新型抗疤痕肽

• 批准号: 8455289
• 负责人: Shen Pang
• 金额: $ 19.97万
• 依托单位: SCARLESS LABORATORIES, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8455289
• 关键词: Adult; Adverse effects; Affect; Algorithms; Alternative Therapies; Amino Acids; Animals; Appearance; Area; Atrophic condition of skin; Biological Models; Biomechanics; Burn injury; Bypass; Cells; Cicatrix; Clinical; Cornea; Cosmetics; Cutaneous; Data; Dental Hygiene; Development; Disease; Dose; Drug Formulations; Extracellular Matrix; FDA approved; Face; Family suidae; Fibrosis; Goals; Granuloma; Growth; Histology; Human; Impairment; Intention; Intravenous; Investigational Drugs; Keloid; Keratopathy; Kidney; Knockout Mice; Laboratories; Lasers; Liver; Liver Cirrhosis; Lung; Microstomia; Modeling; Mus; Ointments; Operative Surgical Procedures; Oral; Outcome Measure; Pathologic; Patients; Peptides; Pharmaceutical Preparations; Phase; Pilot Projects; Placebos; Prevention; Prevention strategy; Process; Production; Proteins; Pulmonary Fibrosis; Radiation; Rattus; Recurrence; Refractory; Research; Safety; Scleroderma; Side; Silicones; Skin; Small Business Innovation Research Grant; Steroids; Techniques; Tensile Strength; Testing; Time; Toxicology; Trauma; Treatment Protocols; Visual; Wound Healing; analog; base; body system; cleft lip and palate; commercialization; cost; design; fetal; fibromodulin; improved; innovation; novel; operation; palate repair; primary outcome; protein aminoacid sequence; public health relevance; repaired; safety study; standard of care; success; technological innovation; wound

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.

描述（由申请人提供）：由于 5500 万次选择性手术和 2500 万次创伤后手术，皮肤纤维化（疤痕）每年影响多达 1 亿患者。除了美观之外，疤痕还可能产生重要的功能后果。总体而言，皮肤疤痕预防策略的效果甚微。目前可用的技术侧重于减少已形成疤痕的出现（例如硅胶片、外用药膏和激光）。其他针对疤痕形成过程的疤痕减少策略（例如类固醇和辐射）可能会产生不良副作用。由于这些巨大的限制，仍然迫切需要开发替代疗法来预防皮肤疤痕。通过持续 11 年的研究工作，检查胎儿伤口愈合模型；我们已经确定纤维调节蛋白（FMOD）是胎儿无疤痕皮肤修复所需的新型分子。 FMOD 蛋白可减少成人伤口的疤痕形成并改善细胞外基质 (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，我们鉴定了 40 个氨基酸的肽序列 F06-C40，其具有与完整 FMOD 蛋白类似的抗纤维化作用。这使我们能够绕过昂贵的基于细胞的蛋白质生产技术，转而采用可以快速、廉价且高纯度生产的合成 FMOD 肽。最近，我们使用猪模型在初步研究中证明，FMOD 蛋白及其肽衍生物 F06-C40 都能显着减少疤痕形成。在本提案中，我们将测试 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，疗效有所提高。目标 1（第 1-12 个月）：优化 F06-C40 以预防皮肤疤痕。 AIM 1 将优化 F06-C40 的剂量和持续时间，以减少皮肤疤痕。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。主要结果指标包括在不降低伤口拉伸强度的情况下改善总体视觉外观。目标 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 提交研究性新药 (IND) 所需的 F06-C40 安全性研究。将在大鼠中进行剂量递增的静脉研究，并将在猪中进行剂量递增的皮内研究。皮肤疤痕会导致严重的功能和美观损害。迄今为止，尚无 FDA 批准的药物用于预防疤痕复发。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。