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Geoffrey Lewis, Michael Byrne, Steven Fisher, James Cardia, Lakshmipathi Pandarinathan, Karen Bulock, Lyn Libertine, Pamela Pavco; Novel Anti-CTGF RNAi Therapy for Treatment of Proliferative Vitreoretinopathy (PVR) and other Ocular Disorders. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6262. doi: https://doi.org/.
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Proliferative vitreoretinopathy (PVR) remains a serious medical problem despite advances in vitreoretinal surgery. Connective tissue growth factor (CTGF) is over expressed in human PVR and is believed to play a key role in development of ocular fibrosis. We have developed a new class of stable, self-delivering RNAi compounds (sd-rxRNA®) that incorporate features of both RNAi and antisense and results in spontaneous cellular uptake. Intradermal injection of the CTGF-targeting sd-rxRNA RXI-109 results in robust, dose-dependent, long-lasting reduction of CTGF in a rodent model of dermal wound healing. Silencing of CTGF also impacts myofibroblast differentiation and collagen deposition, both key markers of fibrosis. Previously we established mRNA silencing of CTGF in rodent retina following intravitreal injection of a CTGF-targeting sd-rxRNA. Here we have evaluated the tissue distribution pattern of RXI-109 in vivo in a model of retinal detachment.
Preliminary studies of control sd-rxRNAs in the mouse eye resulted in a statistically significant reduction of target mRNA levels in the retina for up to 21 days. Additionally, a CTGF-targeting sd-rxRNA administered by single intravitreal injection to Brown Norway rats resulted in a significant reduction of CTGF mRNA levels 48 h post injection relative to a control, non-targeting sd-rxRNA (52%, p<0.01). Here, intravitreal administration of RXI-109 in the presence and absence of retinal detachment was performed and the tissue distribution of the drug was evaluated.
Treatment with RXI-109 resulted in detectable uptake by cells of all layers of the retina through 14 days in the presence of a retinal detachment. Interestingly, RXI-109 was also taken up by Müller cells, a key cell type involved in retinal scarring.
In the rat model of retinal detachment, sd-rxRNA is detected in all cell layers of the retina and is taken up by cell types known to be important for retinal scarring. This result, along with our previous report of specific and extended silencing of retinal genes by sd-rxRNA, supports the potential use of an anti-CTGF treatment for PVR and other retinopathies, including those resulting from neovascularization. Our next step is to evaluate the ability of RXI-109 to reduce CTGF mRNA levels in vivo in the retinal detachment model and to assess the effect of RXI-109 on scar formation.
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