Glaucoma is one of the leading causes of irreversible blindness worldwide. In the USA, glaucoma is projected to increase from 2.7 million in 2010 to 6.3 million by 2050. Glaucoma is characterized by progressive degeneration of retinal ganglion cells with corresponding irreversible deficits in visual function, and in a majority of patients, elevation in intraocular pressure (IOP). While current medication therapies target reduction in IOP, so far, a clinically effective treatment that exerts both ocular hypotensive and retinal neuroprotective actions remain elusive, prompting intense search for potential therapeutic options. There is evidence that hydrogen sulfide (H2S), a colorless odoriferous gas, attenuates IOP in normotensive rabbits and exerts neuroprotection in retinal neurons, suggesting a potential superior application in management of glaucoma. However, the full clinical potential of H2S cannot be realized without an efficient method for its delivery into ocular tissues. Indeed, the convenient and conventional topical ocular delivery approaches (e.g. solutions, suspensions, emulsions, ointments, etc) are not appropriate because ocular surface is predominantly aqueous, and most H2S- donors release the gas in aqueous medium. Additionally, it cannot provide a low sustained level of H2S, a critical requisite for therapeutic application. The main objective of this proposal, therefore, is to design a novel drug delivery system capable of supplying H2S into the anterior uvea and retina at a sustained rate. We hypothesize that subconjunctival injection of a novel GYY4137 (H2S donor)-loaded microparticle-based in situ gelling delivery system can release H2S at a sustained rate with corresponding reduction in IOP in the anterior segment and protection of retinal neurons in the posterior segment. There is evidence that some subconjunctivally administered drugs can gain access to the posterior segment of the eye, in vivo. Thus, due to its gaseous nature, it is conceivable that H2S released on subconjunctival administration can simultaneously gain access into the anterior segment for reduction of IOP and the posterior segment for retinal neuroprotection. Experiments in this project have therefore been designed to address the following questions: (a) Can GYY4137 loaded microparticle-based, in situ gel forming delivery system sustain H2S in the anterior and posterior segments within a pharmacological range? (b) What are the release and distribution profiles of H2S from the novel formulation in ocular tissues, in vitro and in vivo? (c) Can the novel formulation induce and sustain a reduction in IOP and mitigate retinal neurodegeneration following subconjunctival injection? We anticipate that satisfactory completion of these aims will not only demonstrate the potential application of H2S in ocular therapy and reveal strategies to overcome barriers to delivery of a wide range of H2S-donors to ocular tissues.
|Effective start/end date||3/1/22 → 2/29/24|
- National Eye Institute: $436,500.00
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