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， 可以在严重程度上运行色域。大面积角膜伤口的愈合，如碱烧伤，需要更长时间的迁移。 角膜上皮细胞的再生以及角膜的神经再生。然而，损伤引起的并发症会引发炎症。 会减缓这些过程，并使结果恶化。无法封闭和重新支配角膜上皮 会导致持续的炎症并增加角膜溃疡的风险。作为伤口护理的策略 随着时间的推移，大多数创新都继续专注于将炎症降至最低。这些方法是 对于诱导细胞迁移和修复角膜上皮很重要，但对角膜重建和修复几乎没有作用 组织，导致组织附着较弱，愈合缓慢。因此，为了改善患者的预后，有一种 需要一种安全有效的治疗方法，在损伤和结果发生后立即加速迁移和神经再支配 在一个更有效的闭合和有效成熟的伤口中。理想情况下，将因素传递给 促进角膜创面愈合是安全的，局部应用，仍局限于 应用，并提供快速但持续的活性试剂释放。 Fidgetin-like 2(Fl2)是一种新近发现的微管细胞骨架调节剂，它能服务于和 解聚微管(MT)。下调Fl2表达增强MT促进细胞功能 体外活动能力和改善临床和组织学小鼠动物模型的愈合。微创治疗 目的开发包裹Fl2-siRNA的纳米颗粒(SiF2)，以直接促进创面闭合，并 角膜上皮细胞的愈合功能以及再神经支配，从而提供了 加速角膜伤口的愈合和组织修复。因此，伤口愈合将减少疤痕和 疼痛，改善视力，由于伤口更快闭合而降低感染风险，以及改善恢复 角膜结构的特征。 在原理工作的证明中，在大鼠模型中确定了SiFi2的最佳浓度，导致较短的 重新上皮化的时间，减少角膜混浊，恢复解剖的角膜结构，没有 神经损伤或细胞凋亡的证据。这一快速通道第二阶段提案将启动IND的步骤 备案，包括定义要使用的配方。这将通过四个具体目标来实现：(1)发展 使用基于体外试验的SiFi2制剂；(2)在兔眼耐受性模型中评估毒性；以及 (3)在兔角膜烧伤模型上验证疗效；(4)与FDA举行IND前会议。