Anti-scar peptide for cleft lip repair

描述(申请人提供)：唇腭裂(CLP)是美国最常见的头面部先天性畸形。由于CLP如果得不到纠正，可能会导致严重的发育、功能、美学和心理障碍，因此它是最常见的需要手术治疗的出生缺陷。不幸的是，增生性瘢痕(HS)的形成是唇裂修复手术的常见并发症(根据各种研究，8%-47%)，经常需要多次手术翻修。在修复CLP时，HS处理明显比其他疤痕更具挑战性，原因是：1)缺乏组织(裂隙)；2)由于组织缺失、口周肌肉活动和头部生长导致修复裂隙过度紧张；以及3)对美学的更高期望。目前的治疗方法，如皮质类固醇，有不良的副作用，如伤口强度降低和皮肤萎缩，而放射治疗则有未来恶性的风险。因此，迫切需要替代疗法来减少HS的形成，特别是在中电维修中。我们先前发现纤维调素(FMOD)在胎儿无疤痕皮肤修复中起关键作用。值得注意的是，将FMOD蛋白应用于成人伤口可以减少瘢痕形成，而不会降低包括小鼠、大鼠和猪在内的多种哺乳动物的伤口抗张强度。在一项技术创新中，我们开发了一种合成的40个氨基酸的FMOD多肽序列F06-C40，其显示出与376个氨基酸的FMOD全蛋白相似的功效。与FMOD蛋白相比，F06-C40的生产速度更快、成本更低、纯度更高。与FMOD类似，F06-C40在两个不同的猪模型(模拟正常人类疤痕的约克夏猪和更接近人类HS的红色杜洛克猪)中显著减少了疤痕，而不影响伤口强度。重要的是，在我们最近的预研新药(IND)会议上，食品和药物管理局(FDA)明确列出了F06-C40首例临床试验之前所需的安全性研究。这项快速跟踪SBIR建议的目标是执行这些关键的IND研究，以加速FMOD多肽治疗的床边转换，以最大限度地减少CLP患者HS的形成。第一阶段的里程碑将是建立一个优化的F06-C40剂量(“可测试产品配方”)，显示出(与对照相比)在改善肉眼外观、缩小疤痕大小和保持伤口抗张强度方面的显著效果。有了“可测试产品配方”，第二阶段的里程碑将是完成F06-C40的作用模式和FDA要求的安全性研究，建立F06-C40的质量控制分析，并提交FDA接受的得到良好支持的IND申请，以启动临床第一阶段研究。总体而言，这项建议将实现关键的监管、化学、制造、控制(CMC)和业务目标，以加快F06-C40产品的商业化进程。如果成功，基于F06-C40的治疗可以显著改善患有HS的CLP患者和因烧伤、手术或其他创伤而患有HS的患者的生活质量。

DESCRIPTION (provided by applicant): Cleft lip and palate (CLP) is the most common craniofacial congenital anomaly in the US. Since CLP can cause severe developmental, functional, aesthetic, and psychological difficulties if not corrected, it is the most frequently reported birth defect requiring surgery. Unfortunately, hypertrophic scar (HS) formation is a common complication of cleft lip repair surgery (8%-47% according to various studies) and often requires multiple surgical revisions. HS management in CLP repair is significantly more challenging than other scars due to: 1) lack of tissue (cleft); 2) excessive tension in the repaire cleft due to missing tissue, action of the perioral muscles, and head growth; and 3) higher expectations for aesthetics. Current treatments such as corticosteroids have undesirable side effects such as reduced wound strength and skin atrophy while radiation carries a risk of future malignancy. Therefore, there is a pressing need for alternative therapies to reduce HS formation especially in CLP repair. We previously identified fibromodulin (FMOD) as being critical for fetal scarless skin repair. Remarkably, FMOD protein application to adult wounds can decrease scarring without reducing wound tensile strength in multiple mammalian species including mouse, rat, and pig. In a technological innovation, we have developed a synthetic 40 amino acid FMOD peptide sequence, F06-C40, that exhibits similar efficacy as the 376 amino acid FMOD whole protein. F06-C40 can be produced much more rapidly, inexpensively, and with higher purity than FMOD protein. Like FMOD, F06-C40 significantly reduced scar without compromising wound strength in two separate pig models (Yorkshire pigs simulating normal human scar and red Duroc Pigs more closely simulating human HS). Importantly, at our recent pre- Investigational New Drug (IND) meeting, the Food and Drug Administration (FDA) clearly outlined the required safety studies before first-in-man F06-C40 clinical trials. The goal of this Fast-Track SBIR proposal is to perform these critical IND-enabling studies to accelerate bench to bedside translation of FMOD peptide-based therapy to minimize HS formation in CLP patients. The Phase I Milestone will be to establish an optimized F06-C40 dose ("testable product formulation") demonstrating significant efficacy (compared with control) in improved gross visual appearance, scar size reduction, and wound tensile strength maintenance. With the "testable product formulation" in hand, the Phase II Milestones will be to complete F06- C40 mode of action and FDA-required safety studies, establish quality control assays for F06-C40, and submit a well-supported IND application that is accepted by the FDA to initiate Clinical Phase I studies. Overall, this proposal will accomplish key regulatory, Chemistry, Manufacturing, Controls (CMC), and business objectives to expedite F06-C40 product commercialization. If successful, F06-C40-based therapy can significantly improve the quality of life of CLP patients suffering from HS and patients with HS from burns, surgery, or other trauma.