A Novel Therapeutic that Harnesses MIcrotubules to Enhance Corneal Wound Healing Following an Alkaline Burn

一种利用微管促进碱性烧伤后角膜伤口愈合的新型疗法

• 批准号: 9894005
• 负责人: Roy S Chuck
• 金额: $ 1.12万
• 依托单位: MICROCURES, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2019-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894005
• 关键词: Address; Alkalies; Animal Model; Animals; Architecture; Area; Biological Assay; Burn injury; Caring; Cells; Cicatrix; Clinical; Clinical Chemistry; Complex; Cornea; Corneal Injury; Corneal Ulcer; Cytoskeleton; Data; Development; Dose; Down-Regulation; Encapsulated; Epithelial; Epithelial Cells; Evaluation; Eye; Goals; Grant; Hematology; Histologic; Histopathology; Hospitals; Human; In Situ Nick-End Labeling; In Vitro; Inflammation; Injury; Lead; Left; Marketing; Mediating; Medical center; Medicine; Microtubule Depolymerization; Microtubules; Modeling; Molecular Biology; Mus; Nerve; Ophthalmologist; Outcome; Pain; Pathologic; Patient-Focused Outcomes; Pharmacologic Substance; Phase; Phase III Clinical Trials; Preparation; Property; RNA Interference; Rattus; Reagent; Recovery; Risk; Running; Safety; Severities; Site; Small Interfering RNA; Steroids; Technology; Time; Tissues; Topical application; Toxic effect; Vision; Visit; Visual Acuity; Work; Wound Healing; Wounds and Injuries; alkalinity; cell motility; college; comparative efficacy; corneal burn; corneal epithelium; design; effective therapy; genetic regulatory protein; healing; improved; improved outcome; infection risk; innovation; knock-down; lead concentration; migration; nanoparticle; negative affect; nerve supply; novel; novel therapeutics; patient population; phase 2 study; pre-clinical; repaired; research and development; research clinical testing; response; restoration; seal; tissue repair; wound; wound closure

The cornea is one of the most important tissues in the eye and its transparency is critical for good visual function in humans. Corneal tissue injuries are the most common everyday issue for practicing ophthalmologists and can run the gamut in severity. In severe models, such as corneal alkaline burns, extensive healing is needed and often the burn victim is left with reduced visual acuity. Healing of large corneal wounds, such as alkali burns, involves extended migration of epithelial cells. However, complications from injury induced inflammation slows epithelial migration and worsens outcomes. The inability to seal the corneal epithelium results in persisting inflammation and increases the risk for corneal ulceration. As strategies for wound care have evolved, most innovation has continued to focus on minimizing inflammation. These approaches are important for coaxing cells to migrate and heal the corneal epithelium, but do little for remodeling and repair of the tissue, resulting in weakly attached tissue and slow healing. Thus, to improve patient outcomes there is a need for a safe and effective therapy that both expedites migration soon after injury and results in a more efficiently closed and effectively matured wound. Ideally, mechanisms that deliver factors to enhance corneal wound healing would be safe, applied topically, remain localized at the site of application, and provide a rapid but sustained release of the active reagent. Fidgetin-like 2 (FL2) is a recently discovered regulator of the microtubule cytoskeleton that severs and depolymerizes microtubules. Down-regulation of FL2 expression enhanced microtubule function to promote cell motility in vitro and improved healing both clinically and histologically in murine animal models. MicroCures aims to optimize the efficacy of a novel treatment, nanoparticle encapsulated FL2-siRNA (FL2-NP-si), through a dose response assay to directly enhance the wound-closure and healing function of corneal epithelial cells thereby addressing, for the first time, the challenge of accelerated healing and tissue repair in corneal wounds. Thus, wound healing would reduce scarring and pain, improve vision, and lower the risk of infection due to faster wound closure, as well as improve restoration of corneal architecture. The goal for this proposed project is to optimize the FL2-siRNA concentration encapsulated in the nanoparticle via a dose response study in terms of efficacy (Specific Aim 1), and the best concentration used in a preliminary safety evaluation (Specific Aim 2) in a rat animal model of corneal alkaline burns, in preparation for a larger and more comprehensive Phase II IND-enabling studies. Time to wound healing and histopathology at the wound site, as well as local toxicity will be evaluated. At the end of the project period, we will show that FL2-NP-si is both safe and efficacious for the treatment of corneal alkaline burn wounds.

角膜是眼睛最重要的组织之一，其透明度对于良好的视觉功能至关重要 在人类中。角膜组织损伤是执业眼科医生最常见的日常问题，可以 严格程度涵盖所有范围。在严重的模型中，例如角膜碱烧伤，需要广泛的愈合，并且 烧伤患者的视力常常会下降。 大角膜伤口（例如碱烧伤）的愈合涉及上皮细胞的延长迁移。然而， 损伤引起的炎症并发症会减慢上皮迁移并使结果恶化。无能 封闭角膜上皮会导致持续炎症并增加角膜溃疡的风险。作为 伤口护理策略已经发展，大多数创新仍然集中在最大限度地减少炎症上。 这些方法对于诱导细胞迁移和愈合角膜上皮很重要，但对于 组织的重塑和修复，导致组织附着力薄弱和愈合缓慢。因此，为了改善患者 结果需要一种安全有效的治疗方法，既可以加速受伤后的迁移，又可以 导致伤口更有效地闭合和成熟。理想情况下，传递因子的机制 促进角膜伤口愈合是安全的，局部应用，保持局部在伤口部位 应用，并提供活性试剂的快速但持续的释放。 Fidgetin-like 2 (FL2) 是最近发现的微管细胞骨架调节因子，可切断和 解聚微管。下调FL2表达增强微管功能促进细胞 体外运动并改善小鼠动物模型的临床和组织学愈合。微疗 旨在优化纳米颗粒封装的 FL2-siRNA (FL2-NP-si) 新型治疗的功效， 通过剂量反应测定直接增强角膜的伤口闭合和愈合功能 上皮细胞从而首次解决加速愈合和组织的挑战 修复角膜伤口。因此，伤口愈合将减少疤痕和疼痛，改善视力，并降低 伤口闭合更快，从而降低感染风险，并改善角膜结构的恢复。 该项目的目标是优化封装在纳米颗粒中的 FL2-siRNA 浓度 通过功效方面的剂量反应研究（具体目标 1），以及初步使用的最佳浓度 在大鼠角膜碱烧伤动物模型中进行安全性评估（具体目标 2），为更大范围的研究做准备 更全面的 II 期 IND 支持研究。伤口愈合时间和伤口的组织病理学 将评估部位以及局部毒性。在项目期结束时，我们将证明 FL2-NP-si 是 对于治疗角膜碱烧伤创面既安全又有效。