Strategies to achieve sustained medication delivery in glaucoma treatment



 DESCRIPTION (provided by applicant): Vision loss and blindness from glaucoma can be prevented. Medications that lower intraocular pressure (IOP) prevent the onset of glaucoma and glaucoma's progression to a debilitating, vision threatening disease. The effectiveness of IOP lowering drops, however, is hindered by topical side effects and toxicity, poor patient adherence, poor bioavailability, and systemic side effects. Only 40% of patients fill the first prescription tey are given. Monitored adherence with eyedrops is less than 75% even under ideal conditions [1]. Given these limitations, it is not surprising that continued worsening of vision status among glaucoma patients continues to an unacceptable degree. Glaucoma treatment could be greatly improved by better drug delivery, specifically an approach that removes the patient from the equation by placing the agent on the eye at the time of doctor visits. I plan a multi-year period of clinical-scientist training focused on improved drug delivery systems for glaucoma therapy. This training will be carried out with a mentor group of experienced scientists, each bringing expertise in vital areas of my training. The group of senior investigators who have agreed to mentor me already works productively together on multiple NEI---NIH sponsored research grants. Dr. Harry Quigley is principal investigator for the Wilmer K12 program and has 40 years of experience in glaucoma models in animals. My second principal mentor will be Dr. Justin Hanes, who heads the Center for Nanomedicine at Wilmer/Hopkins and has already produced ocular drug delivery systems using biodegradable polymer microparticles for treatment of glaucoma [2]. Using these sustained release formulations, a single dosage of an IOP lowering medication or neuroprotective agent could have an effect that lasts for several months, while overcoming side---effects, toxicity, adherence failure, and inadequate bioavailability. During my present clinical fellowship year at Wilmer in Glaucoma, I have begun pilot research training with Drs. Harry Quigley with Dr. Justin Hanes. In addition, I will benefit from inclusion of 3 other investigators who have agreed to provide specific mentored training in important aspects of my program. Henry Edelhauser, PhD., (Emory University) is a world---expert in drug delivery to the eye. He has agreed to provide expert guidance on drug penetration methodologies. Jie Fu, PhD., is a member of the Center for Nanomedicine at Wilmer/Hopkins, who is expert in controlled drug formulation. She will provide both her formulation skills and training for me to develop these formulations. Dana Ferraris, PhD is a medicinal chemist, who has agreed to advise me in this program. Although we intend to formulate multiple IOP lowering medications for sustained release, we have chosen the sustained release of dorzolamide as an initial research area for my training, as it illustrates several important aspects of the research problem and has a high probability of practical application. Dorzolamide lowers IOP through action as a topical carbonic anhydrase inhibitor but, in drop form, its efficacy is limited by toxicity and poo patient adherence due to the need for dosing two or three times daily. We hypothesize that these limitations can be overcome by formulating dorzolamide for injection under the conjunctiva or into the eye, in a sustained release delivery system. In Aim 1, we will generate and characterize biodegradable, polymer microparticles for sustained release of dorzolamide to the eye. Once conditions are optimized for sustained release of dorzolamide, additional IOP lowering medications will be formulated for controlled release. Prior to in vivo experiments ex vivo assays using rabbit and human sclera will be performed to evaluate trans---scleral delivery of medication by these formulations. In Aim 2, we will evaluate pharmacokinetics, IOP lowering, and retinal ganglion cell (RGC) protection by dorzolamide microparticle formulations in rabbit and rodent eyes. We will also test efficacy in RGC protection upon injection of a combination of our new controlled release formulation with an existing controlled release neuroprotection formulation recently developed by Hanes in collaboration with Quigley and Zack (2). I plan a career as a university-based clinician scientist, providing patient care with a major effort in clinical and laboratory research in novel therapeutic approaches to treating glaucoma. To develop the necessary skills and knowledge to conduct competitive research. I propose this multi-year research program with faculty who has expertise in creating controlled release formulations, targeted drug delivery, and animal models of glaucoma.