Glaucoma is the leading cause of irreversible blindness in the world. Because elevated intraocular pressure (IOP) and IOP fluctuations are the primary risk factors for loss of visual field, the current standard of care for adult-onset glaucoma includes treatment with IOP-lowering medications, which are typically delivered topically as eye drops. Unfortunately, the need for self-administration negatively affects patient compliance. Moreover, there are a limited number of drug families that are in use. In a major step toward addressing the limitations of currently marketed IOP-lowering drops, we engineered a novel non-irritative microemulsion (ME) formulation that provides extended release of pregabalin (PRG)¾a repurposed FDA-approved drug with a new mechanism of action for IOP-lowering. While our ME has many features that position it to fill major gap in IOP management, it requires daily self-dosing. To directly address this unmet clinical need, we will optimize and evaluate the IOP-lowering properties and safety of a subconjunctival biodegradable electrospun depot containing PRG. OculoTherapy’s long-term research goal is to develop therapies that preserve vision in glaucoma patients. In this current SBIR Phase I application, we test the hypothesis that a subconjunctival depot comprised of slowly biodegradable and biocompatible nanospun polymers can be engineered to provide zero order release of PRG, which will maintain IOP in the physiological range until the depot is spent. Our objective is to ultimately achieve 6 months of release from a single depot. Our hypothesis is supported our preliminary data demonstrating that PRG-loaded nanofibers comprised of a polymeric blend provide release of PRG with only 54.4% of loaded drug being released after 21 weeks, demonstrating that 6 months of release from a single depot is well within range. Overall strengths of this project include: 1) a strong and experienced interdisciplinary OculoTherapy team; 2) engineering of an innovative delivery strategy using a polymeric biocompatible depot that is expected to provide extended drug release; 3) the use of a highly promising FDA-approved drug that is being repurposed as a glaucoma therapeutic; and 4) the potential for a highly significant increase in patient adherence because the need for daily input from the patient is eliminated. In this Phase I SBIR proposal, we provide proof-of-concept data and address key feasibility questions by establishing the safety and efficacy of a bioengineered subconjunctivally placed polymer depot. Aim 1: We test the hypothesis that a subconjunctival electrospun depot comprised of biodegradable and biocompatible polymers can provide up to 6 months of zero order release of PRG. Several polymers and polymer blends will be evaluated either alone or in combination. Aim 2: We test the hypothesis that our subconjunctival PRG depot is biocompatible and efficacious. IOP and safety will be evaluated. Ocular biodistribution studies will also...