Glaucoma, the leading cause of irreversible blindness in the world; currently affects more than 3 million in theU.S. and is projected to increase to ~6.3 million by 2050. The four major types of adult-onset glaucoma all leadto vision loss through a final common pathway of retinal ganglion cell (RGC) dysfunction and/or death. Thecurrent standard of care includes treatment with IOP-lowering eye drops, all of which have limited efficacy.Specifically, IOP reduction does not fully prevent RGC death and resulting visual field loss in many glaucomapatients. In our previous NIH-funded studies, we identified both a novel IOP-lowering drug target, the calciumchannel, voltage-dependent, α2δ1subunit (aka CACNA2D1) and a selective CACNA2D1 blocker,pregabalin (PRG), that lowers IOP. Lastly, we developed a topical extended release PRG microemulsion (ME)that increases drug entry into the eye, resulting in higher efficacy and duration of action. Our most recentstudies have uncovered an unanticipated additional treatment benefit of PRG, namely its additional localizationto, and neuroprotection of, RGCs and optic nerve (ON) as we have demonstrated in an animal model of normaltension glaucoma. Thus, PRG ME could be the first glaucoma therapy to both lower IOP and have direct,neuroprotective effects on RGCs and their axons. This current SBIR Phase I application is designed tovalidate our new findings regarding the neuroprotective effects of our PRG ME, and to establish its mechanismof action. Our central hypothesis is that our PRG ME will lower IOP with improved efficacy, as well as maintainthe health of RGCs, a field of use for which there is currently no FDA-approved drug. This hypothesis issupported by our data showing that CACNA2D1 is located in RGCs and ON and that topical administration ofour extended-release bioadhesive ME promotes delivery of PRG to the retina. Overall strengths of this projectinclude: 1) a strong and experienced interdisciplinary OculoTherapy team; 2) engineering of an innovativedelivery strategy using an extended-release formulation; 3) the use of a highly promising FDA-approved drugthat will be repurposed as a glaucoma therapeutic; and 4) the discovery that the drug may have multiple sites ofaction within the eye that collectively provide IOP lowering through direct interactions with the ciliary bodyand/or outflow structures as well as direct RGC neuroprotection that is independent of its IOP-loweringcapability. In this Phase I SBIR proposal, we will provide proof of concept and address key feasibility questionsby establishing neuroprotective efficacy and mechanism of action of our PRG ME. This treatment strategy willreduce the burden to the patient and lead to better visual outcomes for glaucoma patients. To address ourobjective, we propose the following Aims: Aim 1: We test the hypothesis that PRG is a neuroprotectant forRGCs and the ON using once daily dosing. Aim 2: We test the hypothesis that PRG plays a direct role in RGChealth by regulating the concentration of intracellular calcium (Ca2+).
Public Health Relevance Statement: All currently FDA-approved glaucoma medications are designed to lower IOP, yet IOP reduction alone does
not fully prevent RGC death, optic nerve damage and resulting visual field loss in many glaucoma patients in
spite of treatment. Our data suggests that: a) one druggable target, CACNA2D1, is localized to anterior
chamber structurces where it regulates IOP, and also to RGCs and the ON, where it affects overall neuronal
viability; and b) our proposed topically applied drug, PRG ME, binds to both targets to decrease IOP and
provide neuroprotection. In this Phase I SBIR proposal, we will determine neuroprotective efficacy and
mechanism of action of PRG ME with the aim of establishing PRG ME as the first glaucoma therapy to both
lower IOP and have direct, neuroprotective effects on RGCs and their axons.
Project Terms: Adult ; 21+ years old ; Adult Human ; adulthood ; Affect ; anterior chamber ; Axon ; Calcium ; Calcium Channel ; Calcium Channel Antagonist Receptor ; Calcium Channel Blocker Receptors ; Calcium Ion Channels ; VDCC ; Voltage-Dependent Calcium Channels ; Cell Death ; necrocytosis ; Ciliary Body ; Cessation of life ; Death ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Engineering ; Exhibits ; Eye ; Eyeball ; Eyedrops ; Eye Drops ; Glaucoma ; glaucomatous ; Goals ; Grant ; Health ; Physiologic Intraocular Pressure ; Intraocular Pressure ; Ocular Tension ; intra-ocular pressure ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Longevity ; Length of Life ; life span ; lifespan ; Movement ; body movement ; United States National Institutes of Health ; NIH ; National Institutes of Health ; Nerve Fibers ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Optic Nerve ; Cranial Nerve II ; Second Cranial Nerve ; Patients ; Play ; Research ; Retina ; Retinal Ganglion Cells ; retinal ganglion ; Risk Factors ; Role ; social role ; Testing ; United States ; Vision ; Sight ; visual function ; Visual Fields ; eye field ; base ; improved ; Anterior ; Site ; Phase ; Visual ; high intraocular pressure ; high intra-ocular pressure ; Neuroprotective Agents ; Neuroprotectants ; Neuroprotective Drugs ; Funding ; Functional disorder ; Dysfunction ; Physiopathology ; pathophysiology ; Therapeutic ; Hour ; System ; vision loss ; visual loss ; Blindness ; Drug Formulations ; meetings ; experience ; voltage ; neuroprotection ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; 3-isobutyl GABA ; pregabalin ; Structure ; novel ; Topical Drug Administration ; administer topically ; apply topically ; deliver topically ; topical administration ; topical delivery ; topical drug application ; topical treatment ; topically administered ; topically applied ; topically delivered ; topically treated ; treat topically ; Topical application ; Property ; Molecular Interaction ; Binding ; preventing ; prevent ; Address ; Dose ; Data ; Preclinical Models ; Pre-Clinical Model ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Pathway interactions ; pathway ; design ; designing ; Outcome ; innovation ; innovate ; innovative ; FDA approved ; standard of care ; treatment strategy ; phase 1 study ; Phase I Study ; Drug Targeting ; genetic approach ; genetic strategy ; Formulation ; preservation ; druggable target ; nerve damage ;
