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.

角膜是眼睛中最重要的组织之一，其透明度对于良好的视觉功能至关重要 在人类中。角膜组织损伤是实践眼科医生的最常见日常问题，可以 严重运行范围。在严重的模型（例如角膜碱性烧伤）中，需要广泛的愈合，并且 通常，烧伤受害者的视力降低。 大角膜伤口的愈合，例如碱性烧伤，涉及上皮细胞的扩展迁移。然而， 受伤引起的炎症并发症会减慢上皮迁移并恶化。无法 密封角膜上皮会导致持续炎症并增加角膜溃疡的风险。作为 伤口护理的策略已经发展，大多数创新一直集中在最小化炎症上。 这些方法对于哄骗细胞迁移和治愈角膜上皮很重要，但对 组织的重塑和修复，导致弱附着的组织和缓慢的愈合。因此，改善患者 结果需要进行安全有效的疗法，这两者都在受伤后不久加快迁移和 导致更有效的闭合和有效成熟的伤口。理想情况下，提供因素的机制 为了增强角膜伤口的愈合将是安全的，局部应用，保持位于 应用，并提供活跃试剂的快速但持续释放。 fidgetin样2（FL2）是最近发现的微管细胞骨架的调节剂 取代微管。 FL2表达增强的微管功能的下调以促进细胞 在鼠类动物模型中，体外运动并改善了临床和组织学上的愈合。微邻 旨在优化一种新型处理的纳米颗粒封装的FL2-SIRNA（FL2-NP-SI）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 上皮细胞因此首次解决了加速愈合和组织的挑战 修复角膜伤口。因此，伤口愈合会减轻疤痕和疼痛，改善视力并降低 由于伤口闭合的速度更快，并改善了角膜结构的恢复。 该提议的项目的目标是优化纳米颗粒中封装的FL2-SIRNA浓度 通过剂量反应研究（特定目标1），以及初步使用的最佳浓度 在角膜碱性燃烧的大鼠动物模型中，安全评估（特定目标2），为更大的和 更全面的II期索引研究。是在伤口上伤口愈合和组织病理学的时间 将评估部位以及局部毒性。在项目结束时，我们将证明FL2-NP-SI是 安全有效地治疗角膜碱性烧伤。