A Novel Therapeutic to Promote Corneal Repair

促进角膜修复的新疗法

• 批准号: 10758863
• 负责人: Roy S Chuck
• 金额: $ 38万
• 依托单位: MICROCURES, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10758863
• 关键词: Acceleration; Agreement; Alkalies; Anatomy; Animal Model; Apoptosis; Architecture; Biological Assay; Burn injury; Cattle; Cells; Chemical Burns; Cicatrix; Clinic; Clinical; Clinical Protocols; Clinical Research; Complex; Contracts; Cornea; Corneal Injury; Corneal Opacity; Corneal Ulcer; Cytoskeleton; Data; Development; Down-Regulation; Emergency Situation; Encapsulated; Ensure; Epithelial Cells; Epithelium; Eye; Formulation; Future; Goals; Histologic; Hospitals; Human; In Vitro; Inflammation; Injury; Investigational New Drug Application; Irritants; Lead; Lipids; Marketing; Mediating; Microtubule Depolymerization; Microtubules; Modeling; Mus; Neurons; Ophthalmologist; Oryctolagus cuniculus; Outcome; Pain; Particle Size; Patient-Focused Outcomes; Permeability; Phase; Positioning Attribute; Process; Publishing; RNA Interference; Rattus; Reagent; Research Design; Risk; Running; Severities; Site; Small Interfering RNA; Standard Model; Structure; Time; Tissues; Topical application; Toxic effect; Toxicology; Vision; Visit; Visual Acuity; Work; burn wound; cell motility; corneal burn; corneal epithelial wound healing; corneal epithelium; corneal regeneration; corneal repair; effective therapy; genetic regulatory protein; healing; improved; improved outcome; in vivo; infection risk; innovation; irritation; manufacturing organization; meetings; meter; migration; nanoparticle; nanoparticle delivery; nerve damage; novel therapeutics; ocular surface; reinnervation; repaired; restoration; retinal toxicity; seal; therapeutic RNA; tissue injury; tissue repair; wound; wound care; wound closure; wound healing; wound injury

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. Healing of large corneal wounds, such as alkali burns, involves extended migration of epithelial cells as well as reinnervation of the cornea. However, complications from injury induced inflammation slows these processes and worsens outcomes. The inability to seal and reinnervate 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 and reinnervation 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 (MT). Down-regulation of FL2 expression enhanced MT function to promote cell motility in vitro and improved healing both clinically and histologically in murine animal models. MicroCures aims to develop nanoparticle encapsulated FL2-siRNA (SiFi2) to directly enhance the wound-closure and healing function of corneal epithelial cells as well as reinnervation thereby offering the potential for 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. In proof of principle work, the optimal concentration of SiFi2 was determined in a rat model resulting in a shorter time to re-epithelialization, reduced corneal opacity, and restoration of anatomical corneal structure, with no evidence of nerve damage or apoptosis. This Fast Track Phase II proposal will initiate steps towards an IND filing, including defining the formulation to be used. This will be accomplished over four specific aims: (1) develop a SiFi2 formulation using an ex vivo based assay; (2) evaluate toxicity in a rabbit ocular tolerability model; and (3) verify efficacy in a rabbit model of corneal burn; and (4) hold a pre-IND meeting with the FDA.

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。角膜组织损伤是眼科医生最常见的日常问题， 可以达到各种严重程度大的角膜伤口的愈合，如碱烧伤，涉及延长迁移 以及角膜的神经再生。然而，损伤引起的并发症 减缓了这些过程并使结果变糟。无法封闭和重新支配角膜上皮 导致持续性炎症并增加角膜溃疡的风险。作为伤口护理的策略 虽然已经发展，但大多数创新仍然专注于最大限度地减少炎症。这些方法 对于诱导细胞迁移和愈合角膜上皮很重要，但对于角膜上皮的重塑和修复作用不大。 组织，导致弱附着的组织和缓慢愈合。因此，为了改善患者的预后， 需要一种安全有效的治疗方法，既能加速损伤后的迁移，又能促进神经再生， 在更有效闭合和有效成熟的伤口中。理想情况下，将因素传递给 增强角膜伤口愈合将是安全的，局部应用，保持局部在 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（MT）解聚。下调FL 2表达增强MT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 旨在开发纳米颗粒封装的FL 2-siRNA（SiFi 2）以直接增强伤口闭合， 角膜上皮细胞的愈合功能以及神经再支配，从而提供了 加速角膜伤口的愈合和组织修复。因此，伤口愈合将减少瘢痕形成， 疼痛，改善视力，并降低感染的风险，由于更快的伤口闭合，以及改善恢复 角膜结构。 在原理工作的证明中，在大鼠模型中确定SiF 12的最佳浓度，从而导致较短的时间。 上皮再形成时间、角膜混浊减少和角膜解剖结构恢复， 神经损伤或细胞凋亡的证据。该快速通道第二阶段提案将启动IND的步骤 提交，包括确定使用的配方。这将通过四个具体目标来实现：（1）发展 （2）在兔眼耐受性模型中评估毒性;和 (3)在兔角膜烧伤模型中验证疗效;（4）与FDA举行IND前会议。