Glaucoma is a major cause of blindness, affecting over 70 million people worldwide. Glaucoma is a neurodegenerative optic neuropathy caused by the loss of retinal ganglion cells (RGC), leading to loss of vision. Current therapies are all directed at lowering intraocular pressure (IOP), and yet RGC loss still continues in many patients despite IOP lowering. The identification of an agent that complements IOP lowering by promoting RGC survival would be a significant advance toward improving the visual outcomes of patients with glaucoma. Using cultures of primary RGC, we screened more than 10,000 compounds and identified candidates with potent neuroprotective properties, including a drug that is FDA-approved for an unrelated indication. We further characterized the novel pathway through which these compounds act to protect RGC, thus identifying a novel drug/drug target combination for neuroprotection. We have also developed a microparticle ocular drug delivery system that, following intravitreal administration, allows slow release and sustained localized delivery to the eye, without causing inflammation. In this application, we are combining two of these neuroprotective drugs with our microparticle delivery system to develop a new therapeutic for the treatment of glaucoma.
In Aim 1, we will formulate and characterize microparticles that release the neuroprotective drugs continuously for up to 6 months to reduce the required injection frequency to 2-3 injections per year.
In Aim 2, we will test whether the drug-releasing microparticles promote RGC survival and function in the mouse optic nerve crush and bead-induced glaucoma models. A drug dose escalation study will be performed and function of the optic nerve in transmitting visual stimulation from the eye to the brain will be assessed by optokinetic responses (OKR).
In Aim 3, we will evaluate the intraocular pharmacokinetics in the rabbit eye for 6 months and perform preliminary safety analyses following intravitreal administration of microparticles. Safety evaluations will include fundus exams, IOP, and retinal morphology analyses as a preliminary evaluation of the long-term effects of drug exposure in the eye. The demonstration of efficacy in rodent models of neurodegeneration, including the verification of function of the protected RGCs, along with long-term drug release and no overt toxicity in the rabbit eye, would provide evidence of the therapeutic potential of our neuroprotective drug delivery strategy for the treatment of glaucoma.

Public Health Relevance

Glaucoma is a leading cause of blindness, affecting over 70 million people worldwide. Glaucoma is caused by the loss of retinal ganglion cells (RGC), which can continue despite clinical treatment to reduce intraocular pressure (IOP). We identified novel neuroprotective drugs that prevent RGC loss even when IOP is elevated, and developed a sustained-release, ocular drug delivery system. We expect our system to be synergistic with current IOP-lowering glaucoma therapies, resulting in an improved treatment for glaucoma.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY026578-04
Application #
9647453
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Liberman, Ellen S
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205