Glaucoma is a neurodegenerative disease of the eye with an estimated prevalence of 80 million patients
worldwide by 2020, at least 6 to 8 million becoming bilaterally blind. Elevated intraocular pressure (IOP)
causing axonal degeneration of the optic nerve and progressive loss of retinal ganglion cells (RGCs)
which are the characteristic hallmarks of glaucoma. Clinically, the only method of slowing glaucomatous
vision loss is to reduce intraocular pressure (IOP), which is partially effective and doesn’t address
susceptibility to RGC degeneration. Current therapy for glaucoma includes use of prostaglandin analogs
based IOP lowering agents, however, about 10% of glaucoma patients don’t respond to these therapies.
Brimonidine, an a2 agonist, eye-drop lowers IOP and is also neuroprotective, however it causes many
side effects such as allergic reactions and corneal disorders. Along with IOP, age related decline in anti-
oxidant enzymes in ocular tissues contributes to the death of both RGCs and trabecular meshwork (TM)
cells, which is not addressed by available treatments. The nitric oxide (NO) system could potentially be
targeted to enhance the aqueous outflow by relaxing the trabecular meshwork (TM) cells to lower IOP.
Here, we propose to develop a robust hybrid NO donating and SOD mimetic compound encapsulated in
PLGA nanoparticle which will prolong the duration of lowering IOP and also have neuroprotective effects.
We have synthesized a novel bi-functional hybrid compound SA-2 with NO donor and SOD mimetic
functional groups. Our preliminary results demonstrated that, a single eye drop of PLGA encapsulated
SA-2 nanoparticles (SA-2-NPs) lowered IOP by 50% in a mouse glaucoma model. Additionally,
compound SA-2 is highly neuroprotective both in ex vivo hypoxic insult of adult rat retinal explants and
in in vivo mouse optic nerve crush model via intravitreal injection. Our goals are 1) to optimize the dose
via toxicokinetic study of SA-2-NPs and determine the efficacy to lower IOP in two animal models: a
mouse model of ocular hypertension (OHTN) induced by Ad5.TGFß2 and in normotensive monkey eyes.
2) To delineate the biochemical mechanisms through which compound SA-2 protects both human TM
cells and RGCs from glaucomatous changes. 3) To assess the topically administered SA-2-NPs for their
ability to prevent RGC death in two models: a mouse model of optic nerve crush (traumatic injury) and a
mouse model of ocular hypertension (chronic injury). Successful completion of the above proposed
studies will provide information on the maximum effective dose of and frequency of dosing of SA-2-NPs
that will be further evaluated in laser induced OHTN monkey model as our future goal and eventually will
progress to human clinical trials. The results will have a major impact in the field with implications for
developing novel non-prostaglandin therapeutics that have both IOP lowering and neuroprotective