Project Grant R42EY034791

A NOVEL THERAPEUTIC TO PROMOTE CORNEAL REPAIR - 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.