Anti-scar peptide for cleft lip repair

描述（由申请人提供）：唇腭裂（CLP）是美国最常见的颅面先天性异常。由于CLP如果不纠正会导致严重的发育、功能、美学和心理困难，因此它是最常报告的需要手术的出生缺陷。不幸的是，增生性瘢痕（HS）形成是唇裂修复手术的常见并发症（根据各种研究，发生率为8%-47%），通常需要多次手术翻修。CLP修复中的HS管理明显比其他瘢痕更具挑战性，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，修复裂隙中的张力过大; 3）对美观的期望更高。目前的治疗，如皮质类固醇具有不良的副作用，如伤口强度降低和皮肤萎缩，而放射线具有未来恶性肿瘤的风险。因此，迫切需要替代疗法来减少HS形成，特别是在CLP修复中。我们以前确定纤维调节蛋白（FMOD）是胎儿无瘢痕皮肤修复的关键。值得注意的是，在包括小鼠、大鼠和猪在内的多种哺乳动物物种中，FMOD蛋白应用于成人伤口可以减少瘢痕形成而不降低伤口拉伸强度。在技术创新中，我们开发了合成的40个氨基酸的FMOD肽序列F06-C40，其表现出与376个氨基酸的FMOD全蛋白相似的功效。F06-C40可以比FMOD蛋白质更快速、更便宜和更高纯度地生产。与FMOD一样，F06-C40在两个单独的猪模型（约克郡猪模拟正常人瘢痕和红色杜洛克猪更接近地模拟人HS）中显著减少瘢痕而不损害伤口强度。重要的是，在我们最近的新药临床试验（IND）前会议上，美国食品药品监督管理局（FDA）明确概述了首次人体F06-C40临床试验之前所需的安全性研究。这项快速通道SBIR提案的目标是进行这些关键的IND使能研究，以加速基于FMOD肽的治疗从实验室到床边的转化，从而最大限度地减少CLP患者的HS形成。第I阶段的里程碑将是建立一种优化的F06-C40剂量（“可测试的产品制剂”），该剂量在改善大体视觉外观、减少瘢痕大小和维持伤口拉伸强度方面显示出显著疗效（与对照相比）。在“可测试的产品配方”在手的情况下，II期Milestone将完成F06- C40的作用模式和FDA要求的安全性研究，建立F06-C40的质量控制测定，并提交FDA接受的支持良好的IND申请，以启动临床I期研究。总体而言，本提案将实现关键的监管、化学、生产、控制（CMC）和业务目标，以加快F06-C40产品的商业化。如果成功，基于F06-C40的治疗可以显著改善患有HS的CLP患者和患有烧伤、手术或其他创伤的HS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.