The cornea is one of the most important tissues in the eye and its transparency is critical for good visual functionin humans. Corneal tissue injuries are the most common, everyday issue for practicing ophthalmologists andcan run the gamut in severity. Healing of large corneal wounds, such as alkali burns, involves extended migrationof epithelial cells as well as reinnervation of the cornea. However, complications from injury induced inflammationslows these processes and worsens outcomes. The inability to seal and reinnervate the corneal epitheliumresults in persisting inflammation and increases the risk for corneal ulceration. As strategies for wound carehave evolved, most innovation has continued to focus on minimizing inflammation. These approaches areimportant for coaxing cells to migrate and heal the corneal epithelium, but do little for remodeling and repair ofthe tissue, resulting in weakly attached tissue and slow healing. Thus, to improve patient outcomes there is aneed for a safe and effective therapy that both expedites migration and reinnervation soon after injury and resultsin a more efficiently closed and effectively matured wound. Ideally, mechanisms that deliver factors toenhance corneal wound healing would be safe, applied topically, remain localized at the site ofapplication, 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 anddepolymerizes microtubules (MT). Down-regulation of FL2 expression enhanced MT function to promote cellmotility in vitro and improved healing both clinically and histologically in murine animal models. MicroCuresaims to develop nanoparticle encapsulated FL2-siRNA (SiFi2) to directly enhance the wound-closure andhealing function of corneal epithelial cells as well as reinnervation thereby offering the potential foraccelerated healing and tissue repair in corneal wounds. Thus, wound healing would reduce scarring andpain, improve vision, and lower the risk of infection due to faster wound closure, as well as improve restorationof corneal architecture.In proof of principle work, the optimal concentration of SiFi2 was determined in a rat model resulting in a shortertime to re-epithelialization, reduced corneal opacity, and restoration of anatomical corneal structure, with noevidence of nerve damage or apoptosis. This Fast Track Phase II proposal will initiate steps towards an INDfiling, including defining the formulation to be used. This will be accomplished over four specific aims: (1) developa 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.
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 and reinnervation. Our goal is to
develop and bring to the market a novel therapeutic that stimulates wound healing and
reinnervation in the cornea to treat corneal burns via RNAi-mediated silencing of the microtubule
regulatory protein, Fidgetin-Like 2 (FL2).
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