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Michael Byrne, Melissa Maxwell, Richard Looby, Katherine Holton, James Cardia, Lyn Libertine, Pamela A Pavco, Karen Bulock; sd-rxRNA®: Self-Delivering RNAi Compounds Show Potential for Corneal Indications Following Topical Application. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1280.
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© ARVO (1962-2015); The Authors (2016-present)
sd-rxRNA® are stable oligonucleotides that have features of RNAi and antisense and result in spontaneous cellular uptake. When dosed by intravitreal injection sd-rxRNAs are taken up by all cell layers of the retina within 24 hours and result in dose-dependent, target-specific mRNA reduction for as long 3 weeks. RXI-109 is an sd-rxRNA, targeting connective tissue growth factor (CTGF), being evaluated in a Phase 1/2 clinical trial for subretinal fibrosis associated with wet AMD. When RXI-109 is dosed by intravitreal injection to non-human primate, dose-dependent protein reduction is noted in the retina and the cornea for at least 1 week. Current ocular clinical focus is to reduce the progression of scarring in the back of the eye. Scarring is also a major concern for many front of the eye indications, specifically those involving the cornea.Here we present new data highlighting topical delivery of sd-rxRNA to the cornea, administered as eye drops or formulated in a thermo-reversible gel, in the presence of an epithelial injury.
An 8 mm epithelial wound was created on the cornea of rabbits. sd-rxRNA was dosed topically 4 times a day for 1 day as eye drops or in a thermo-reversible gel. A second group of animals with an intact epithelial layer of the cornea were exposed to the same dosing regimen. At 24 and 48 hours post application, whole eyes were processed for histological evaluation of cornea cellular uptake of sd-rxRNA.
Macroscopically, compound was visible in the cornea in the injured cornea group at 24 hours post dose. The intensity was less at 48 hours. Microscopically, fluorescent sd-rxRNA was visible through all layers of the cornea in the presence of an epithelial injury at 24 hours when formulated in the thermo-reversible gel, and through the majority of layers when administered as drops. Cellular delivery continued to be detectable at 48 hours. No cellular uptake was visible in the cornea when the epithelial layer was intact.
sd-rxRNA compounds are stable compounds requiring no additional delivery vehicle to be taken up by cells. RXI-109, a CTGF-targeting sd-rxRNA being developed to reduce scarring, is in a Phase 1/2 clinical trial for subretinal fibrosis associated with late-stage wet AMD. Here we provide evidence of the potential of the sd-rxRNA platform for development of topical therapeutics for front of the eye indications.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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