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.

角膜是人眼最重要的组织之一，其透明度对良好的视觉功能至关重要