A Novel Therapeutic that Harnesses MIcrotubules to Enhance Corneal Wound Healing Following an Alkaline Burn - 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.
