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Corrie L Gallant-Behm, Stephanie Propp, Aimee Jackson; Inhibition of ocular fibrosis with a miR-29b mimic. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5316.
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Corneal and retinal fibrosis lead to vision loss following ocular injury (e.g., corneal damage and retinal detachment) or as a result of progressive disease (e.g., FECD and diabetic retinopathy). Few to no therapies are currently available to prevent or treat ocular fibrosis and this is therefore an area of high unmet medical need. miR-29b is a potent anti-fibrotic microRNA that inhibits the expression of collagens and other extracellular matrix molecules. miR-29 is expressed at abnormally low levels in numerous fibrotic conditions, and addition of exogenous miR-29 has been shown to prevent fibrosis in the lung, skin and other organs. This study investigated the anti-fibrotic effects of a miR-29b mimic in the eye.
An oligonucleotide mimic of miR-29b, MRG-201, was administered topically to the rat cornea in the context of an alkali burn, via intravitreal injection in naïve rats and in a rabbit model of proliferative vitreoretinopathy (PVR), or via active transfection into human retinal pigment epithelial (RPE) cells. Uptake/distribution of a FITC labeled oligo was assessed by confocal microscopy. Pharmacokinetics was assessed by quantitative RT-PCR (qRT-PCR) from whole tissue homogenates over time. Pharmacodynamic activity was assessed by measuring repression of miR-29 target gene expression in cells or tissue using qRT-PCR.
FITC-MRG-201 was readily taken up into the cornea in the context of an alkali burn and into all layers of the retina including the RPE layer after intravitreal injection. PK analysis indicates that dosing into the closed compartment of the eye leads to relatively long tissue exposure in the retina. In vitro, MRG-201 inhibited expression of multiple collagens in both primary RPE cells and iPS-derived RPE cells in the presence and absence of TGF-b1 stimulation. In vivo, MRG-201 inhibited expression of multiple miR-29 target genes (e.g. COL1A1, COL1A2) in a rabbit model of PVR.
MRG-201 represents a potential new therapeutic for prevention of both corneal and retinal fibrosis. MRG-201 is taken up into the relevant cell types in both tissues, and reduces expression of multiple collagens and other miR-29 target genes in vitro and in vivo. These findings suggest that MRG-201 or other miR-29 mimics may function as effective therapeutics to inhibit either corneal or retinal fibrosis. Additional PK/PD/efficacy studies in vivo are currently underway.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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