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Principal Investigator: Suchismita Acharya
Organization: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
Fiscal Year: 2023
Award: $370,000
Funding agency: National Eye Institute
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 α2 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.TGFβ2 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
effects.
Terms: <21+ years old><3-mononitrotyrosine><3-nitrotyrosine><Active Oxygen><Address><Adult><Adult Human><Affect><African Green Monkey><After Care><After-Treatment><Aftercare><Allergic Reaction><Animal Model><Animal Models and Related Studies><Anterior><Antioxidants><Apoptotic><Aqueous Humor><Autoregulation><Bilateral><Bioavailability><Biochemical><Biological Availability><Blindness><Body Tissues><Bone-Derived Transforming Growth Factor><Brimodine><Cell Body><Cell Death><Cell Protection><Cell Survival><Cell Viability><Cell-Extracellular Matrix><Cells><Cessation of life><Characteristics><Chlorocebus aethiops><Chlorocebus sabaeus><Chronic><Clinical><Clinical Trials><Collaborations><Common Rat Strains><Corneal Diseases><Corneal Disorder><Cranial Nerve II><Cytoprotection><Death><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Disease><Disorder><Doppler OCT><Dose><Drug Kinetics><ECM><Electroretinography><Encapsulated><Endogenous Nitrate Vasodilator><Endothelium-Derived Nitric Oxide><Esters><Extracellular Matrix><Eye><Eye Drops><Eye diseases><Eyeball><Eyedrops><FDA approved><Formulation><Free Radicals><Frequencies><Future><Gene Expression><Glaucoma><Global Change><Goals><Green Monkey><Homeostasis><Human><Hybrids><Hypoxia><Hypoxic><Injury><Intraocular Fluid><Intraocular Pressure><Laser Electromagnetic><Laser Radiation><Lasers><Latanoprost><Lipid Peroxidation><Measures><Mediating><Mercaptans><Mercapto Compounds><Methods><Mice><Mice Mammals><Milk Growth Factor><Modeling><Modern Man><Monkeys><Mononitrogen Monoxide><Murine><Mus><NO3-><Nature><Nerve Crush><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Nitrates><Nitric Oxide><Nitric Oxide Donors><Nitrogen Monoxide><Nitrogen Protoxide><OCT Tomography><Ocular Hypertension><Ocular Tension><Optic Nerve><Optical Coherence Tomography><Oxygen Deficiency><Oxygen Radicals><PG Analogs><POAG><Pathology><Pathway interactions><Patients><Pattern><Persons><Pharmacokinetics><Physiologic Availability><Physiologic Intraocular Pressure><Physiological Homeostasis><Platelet Transforming Growth Factor><Posterior Eye Segment><Posterior eyeball segment structure><Predisposition><Prevalence><Primary Open Angle Glaucoma><Pro-Oxidants><Production><Prostaglandin Analogs><RNA Seq><RNA sequencing><RNAseq><Rat><Rats Mammals><Rattus><Reactive Oxygen Species><Regulation><Relaxation><Retina><Retinal Ganglion Cells><Rodent><Rodent Model><Rodentia><Rodents Mammals><Route><Safety><Second Cranial Nerve><Sulfhydryl Compounds><Susceptibility><Suspension substance><Suspensions><Synthetic Prostaglandins><System><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Therapeutic><Thiols><Tissues><Topical Drug Administration><Topical application><Toxicokinetics><Trabecular Meshwork><Trabecular meshwork structure><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Traumatic injury><Venous Blood Pressure><Venous Pressure><Venous Pressure level><administer topically><adulthood><age dependent><age related><alpha 2 agonist><anti-oxidant><anti-oxidant enzyme><antioxidant enzyme><apply topically><aqueous><axon degeneration><axonal degeneration><blind><brimonidine><bromoxidine><cornea disorder><cytoprotective><degenerative axon><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><deliver topically><delivery vector><delivery vehicle><determine efficacy><drug release profile><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><electroretinogram><endothelial cell derived relaxing factor><evaluate efficacy><examine efficacy><eye disorder><eye toxicity><functional group><glaucomatous><in vivo><injuries><intra-ocular pressure><intravitreal injection><mimetics><model of animal><mouse model><murine model><nano particle><nano polymer><nano-sized particle><nanoparticle><nanoparticle drug><nanopolymer><nanosized particle><necrocytosis><neurodegenerative illness><neuroprotection><neuroprotective><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><nitrate><nitrotyrosine><normotensive><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ocular disease><ocular disorder><ocular hypertensive><ocular toxicity><ophthalmopathy><optical Doppler tomography><optical coherence Doppler tomography><pathway><patient population><post treatment><preservation><pressure><prevent><preventing><retinal ganglion><retinal ganglion cell degeneration><retinal toxicity><safety assessment><side effect><small molecule><stem><sulfhydryl group><topical administration><topical delivery><topical drug application><topical treatment><topically administered><topically applied><topically delivered><topically treated><transcriptome sequencing><transcriptomic sequencing><treat topically><treatment effect><vision loss><visual loss><α2 agonist>