Glaucoma is a major cause of blindness, affecting over 70 million people worldwide. The development of glaucoma is most often associated with elevated intraocular pressure (IOP) which is induced by the dysfunction of the trabecular meshwork (TM) leading to inhibition of aqueous humor outflow. In most patients, constant elevated IOP results in the loss of retinal ganglion cells (RGC), and can lead to blindness. Current therapies involve the administration of eye drops containing IOP lowering agents, a notoriously inefficient means for ocular drug delivery, with less than 1% of the therapeutic agent reaching the aqueous humor. Therefore, repeated daily dosing is required for efficient IOP management. Compliance, especially among older patients, is an issue, with estimates of noncompliance up to 95%. Topical administration may also lead to extensive systemic drug absorption which can have serious adverse side effects. To improve the visual outcome of patients with glaucoma, new treatment strategies to maintain IOP lowering are warranted. Ethacrynic acid (ECA), FDA-approved for systemic use as a diuretic, exerts its effect directly on the TM. When delivered intracamerally to human glaucoma patients ECA was demonstrated to reduce elevated IOP with no adverse effects. In contrast, topical delivery of ECA is inefficient and produces ocular side effects thought to be caused, at least in part, by its binding to free thil groups. The use of ECA-cysteine conjugates was demonstrated to reduce thiol binding and topical toxicity while maintaining IOP lowering effects. Therefore, the development of sustained-release ECA-cysteine formulations that display long-term IOP lowering would represent a significant treatment advance. GrayBug, LLC has developed a proprietary ocular drug delivery system composed of a biodegradable polymer-drug conjugate that mediates sustained drug release with no ocular toxicity. Using this established technology, GrayBug has successfully produced particles composed of ECA-cysteine covalently conjugated to the biodegradable polymer. Preliminary analyses demonstrated that the ECA-cysteine particles (PolyiRx-ECA) mediated IOP lowering in normal mice without ocular toxicity. Here, the PolyiRx-ECA particles will be rigorously evaluated, using alternative ocular delivery routes, for IOP lowering and safetyin normal rodents. Efficacy of the chosen delivery route will be verified in a rodent model of elevated IOP. The proposal has three Specific Aims. In Aim 1, PolyiRx-ECA particles will be produced using the proprietary GrayBug technology exclusively licensed from Johns Hopkins. The production will be optimized to achieve high drug loading. The particles will be characterized fully and the duration of drug release in vitro will be evaluated. In Aim 2, the PolyiRx-ECA particles will be evaluated in normal mice for IOP lowering compared to free ECA-cysteine. Alternative particle delivery methods will be tested, including subconjunctival, intracameral, and episcleral administration and preliminary safety analyses will be performed. In Aim 3, the efficacy of the PolyiRx-ECA particles in lowering IOP will be verified in the rat model of laser-induced glaucoma. The demonstration of sustained IOP lowering in normal mice with verification of the efficacy of PolyiRx-ECA in the rat glaucoma model, with no overt toxicity to th eye, would provide compelling evidence of the therapeutic potential of the PolyiRx-ECA particle drug delivery strategy for the treatment of glaucoma. Successful completion of these specific aims will lead us to a Phase II proposal where the toxicity and efficacy of the PolyiRx-ECA particles will be rigorously evaluated in a large animal glaucoma model, which will lead ultimately to human clinical evaluation.
Thesaurus Terms: Absorption;Adverse Effects;Affect;Angiogenesis Inhibitors;Animal Disease Models;Animal Model;Animals;Anterior Chamber;Aqueous Humor;Binding (Molecular Function);Biodegradable Polymer;Biodistribution;Blindness;Chemicals;Clinical Research;Compliance Behavior;Copolymer;Cysteine;Development;Disease;Diuretics;Dose;Drug Delivery Systems;Drug Formulations;Ethacrynic Acid;Evaluation;Eye;Eyedrops;Fda Approved;Functional Disorder;Glaucoma;Goals;Human;Improved;In Vitro;In Vivo;Inflammation;Investigational New Drug Application;Kinetics;Lasers;Latanoprost;Lead;Licensing;Marketing;Mediating;Methods;Modeling;Morphology;Mus;Neovascular;Neovascularization;Non-Compliance;Nonhuman Primate;Novel;Ocular Neovascularization;Older Patient;Ophthalmologist;Oryctolagus Cuniculus;Outcome;Particle;Particle Size;Patients;Pharmaceutical Preparations;Phase;Phase 2 Study;Physiologic Intraocular Pressure;Polyethylene Glycols;Preparation;Production;Public Health Relevance;Rattus;Receptor;Research Clinical Testing;Retinal Ganglion Cells;Rodent;Rodent Model;Route;Safety;Sebacic Acid;Sulfhydryl Compounds;Synthetic Prostaglandins;Technology;Testing;Therapeutic;Therapeutic Agents;Therapeutic Evaluation;Timolol;Tissues;Topical Application;Toxic Effect;Trabecular Meshwork Structure;Treatment Strategy;Vision;Visit;Visual;
