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.
Public Health Relevance Statement: Corneal injury is one of the most common causes for ocular related hospital visits, giving rise to tissue scarring and corneal haze, as well as reducing visual acuity. At present there is no clinically proven treatment to improve corneal wound healing due to alkaline burns. Our goal is to develop and bring to the market a novel therapeutic that stimulates wound healing in the cornea via RNAi- mediated silencing of the microtubule regulatory protein, Fidgetin-Like 2 (FL2).
Project Terms: Address; Alkalies; alkalinity; Animal Model; Animals; Architecture; Area; Biological Assay; Burn injury; Caring; cell motility; Cells; Cicatrix; Clinical; Clinical Chemistry; college; comparative efficacy; Complex; Cornea; corneal burn; corneal epithelium; Corneal Injury; Corneal Ulcer; Cytoskeleton; Data; design; Development; Dose; Down-Regulation; effective therapy; Encapsulated; Epithelial; Epithelial Cells; Evaluation; Eye; genetic regulatory protein; Goals; Grant; healing; Hematology; Histologic; Histopathology; Hospitals; Human; improved; improved outcome; In Situ Nick-End Labeling; In Vitro; Infection; Inflammation; Injury; innovation; knock-down; Lead; lead concentration; Left; Marketing; Mediating; Medical center; Medicine; Microtubule Depolymerization; Microtubules; migration; Modeling; Molecular Biology; Mus; nanoparticle; negative affect; Nerve; nerve supply; novel; novel therapeutics; Ophthalmologist; Outcome; Pain; Pathologic; patient population; Patient-Focused Outcomes; Pharmacologic Substance; Phase; phase 2 study; Phase III Clinical Trials; pre-clinical; Preparation; Property; Rattus; Reagent; Recovery; repaired; research and development; research clinical testing; response; restoration; Risk; RNA Interference; Running; Safety; seal; Severities; Site; Small Interfering RNA; Steroids; Technology; Time; tissue repair; Tissues; Topical application; Toxic effect; Vision; Visit; Visual Acuity; Work; wound; wound closure; Wound Healing; Wounds and Injuries
