Thursday, April 21, 2016 8:01:36 PM
Program Number: 1280 Poster Board Number: D0228
Presentation Time: 3:15 PM–5:00 PM
sd-rxRNA®: Self-Delivering RNAi Compounds Show Potential
for Corneal Indications Following Topical Application
Michael Byrne, Melissa Maxwell, Richard Looby, Katherine Holton,
James Cardia, Lyn Libertine, Pamela A. Pavco, Karen Bulock.
OPHTHALMOLOGY, RXi Pharmaceuticals, Marlborough, MA.
Purpose: 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 thermoreversible
gel, in the presence of an epithelial injury.
Methods: 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.
Results: 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.
Conclusions: 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.
Commercial Relationships: Michael Byrne, RXi Pharmaceuticals;
Melissa Maxwell, RXi Pharmaceuticals; Richard Looby, RXi
Pharmaceuticals; Katherine Holton, RXi Pharmaceuticals;
James Cardia, RXi Pharmaceuticals; Lyn Libertine, RXi
Pharmaceuticals; Pamela A. Pavco, RXi Pharmaceuticals;
Karen Bulock, RXi Pharmaceuticals
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