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Michael J. Byrne, Glenna Ford, James Cardia, Lakshmipathi Pandarinathan, Karen Bulock, Lyn Libertine, Kevin Fettes, Pamela Pavco, Anastasia Khvorova; Novel Anti-CTGF RNAi Therapy for Treatment of Proliferative Vitreoretinopathy (PVR) and other Ocular Disorders. Invest. Ophthalmol. Vis. Sci. 2012;53(14):897. 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-rxRNATM) that incorporate features of RNAi and antisense and results in spontaneous cellular uptake. Intradermal injection of one such compound, 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. To determine if a CTGF sd-rxRNA could be used as potential therapy to reduce or inhibit the ocular fibrosis, we have carried out studies to establish mRNA silencing of CTGF in rodent retina following intravitreal injection.
Preliminary studies of control sd-rxRNAs in the eye have resulted in a statistically significant reduction of target mRNA levels in the retina for up to 21 days. Here, 5 ul of a CTGF sd-rxRNA was administered by single intravitreal injection to Brown Norway rats. A non-targeting control (NTC), an sd-rxRNA directed against a different target or PBS was injected into the contralateral eye of each animal as a control. mRNA levels were evaluated by qPCR 48 h post injection.
Treatment with sd-rxRNA targeting CTGF resulted in a significant reduction of CTGF mRNA levels 48 h post injection relative to NTC (52%, p<0.01). The association of CTGF with VEGF has been reported to be important in retinopathy therefore, levels of VEGF mRNA were also quantified and found to be reduced (40%, p<0.05) in concert with the reduction of CTGF.
Results presented show that targeting CTGF with sd-rxRNA not only reduces CTGF mRNA levels, but as a consequence also significantly reduces VEGF mRNA levels. 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 test the efficacy of an anti-CTGF sd-rxRNA in an in vivo model of retinal detachment.
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