RXI-109 Treatment for Proliferative Vitreoretinopathy (PVR) and other Ocular Disorders

Abstract

Purpose: 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 are spontaneously taken up by cells. 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 evaluated the tissue distribution pattern of fluorescently-tagged RXI-109 in vivo in a rat model of retinal detachment and established uptake throughout the retina in both the presence and absence of retinal detachment. Here we extend these findings by evaluating the in vivo expression profile of CTGF mRNA in detached rat retina over time to determine the optimal time for dosing for future studies.

Methods: Retinal detachments were created in rat eyes on day 0. Retinas were collected on days 1, 3 and 14 post detachment and CTGF mRNA levels were determined by qPCR to establish the typical expression level of CTGF mRNA following retinal detachment.

Results: Following retinal detachment in rat, retinal CTGF mRNA levels were found to increase by 1.3-fold at day 3 and by 1.8-fold 14 days post detachment relative to undetached retina in the contralateral eyes. These data indicate that CTGF is elevated for at least 2 weeks following retinal detachment.

Conclusions: In the rat model of retinal detachment CTGF mRNA levels are upregulated over time. Ongoing studies are focusing on the impact that treatment with RXI-109 has on CTGF mRNA levels post detachment. RXI-109 was administered by intravitreal injection at the time of detachment and CTGF mRNA levels are being evaluated by qPCR. The current results, 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. Future studies will focus on optimizing dose level of RXI-109, evaluating duration of effect and determining if RXI-109 can prevent subsequent scarring and/or detachment in a rat model of PVR.

Keywords: 655 proliferative vitreoretinopathy • 533 gene/expression