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

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 在人类身上。角膜组织损伤是执业眼科医生最常见的日常问题， 在严厉程度上达到了所有的程度。在严重的模型中，例如角膜碱烧伤，需要广泛的愈合， 通常烧伤患者留下降低的视觉灵敏度。 大的角膜伤口的愈合，如碱烧伤，涉及上皮细胞的延长迁移。然而，在这方面， 损伤引起的炎症的并发症减缓了上皮迁移和炎症的结果。无法 封闭角膜上皮导致持续的炎症并增加角膜溃疡的风险。作为 虽然伤口护理的策略已经发展，但大多数创新仍然集中在使炎症最小化。 这些方法对于诱导细胞迁移和愈合角膜上皮很重要，但对于诱导细胞迁移和愈合角膜上皮几乎没有作用。 组织的重塑和修复，导致弱附着的组织和缓慢愈合。为了改善患者 结果需要一种安全有效的治疗方法，既能在损伤后迅速促进迁移， 导致伤口更有效地闭合和有效地成熟。理想情况下，传递因素的机制 以促进角膜伤口愈合将是安全的，局部应用， 应用，并提供活性试剂的快速但持续的释放。 Fidgetin-like 2（FL 2）是最近发现的微管细胞骨架的调节剂，其切断并 使微管解聚。下调FL 2表达增强微管功能，促进细胞增殖 在体外的运动性和改善愈合的临床和组织学在小鼠动物模型。微固化 旨在优化一种新的治疗方法，纳米颗粒封装的FL 2-siRNA（FL 2-NP-si）， 通过剂量反应试验，直接增强角膜的伤口闭合和愈合功能， 上皮细胞，从而解决，第一次，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 由于更快的伤口闭合以及改善角膜结构的恢复而导致的感染风险。 该项目的目标是优化封装在纳米颗粒中的FL 2-siRNA浓度 通过剂量反应研究（具体目标1），初步研究中使用的最佳浓度 在角膜碱烧伤的大鼠动物模型中进行安全性评价（具体目标2），为更大的 更全面的第二阶段IND赋能研究。伤口愈合时间和伤口组织病理学 将对部位以及局部毒性进行评价。在项目结束时，我们将证明FL 2-NP-si是 对角膜碱烧伤创面的治疗安全有效。

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.