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Erica L Fletcher, Alice A Brandli, Roy Kong, Fay Khong, Darren J. Kelly; The protective effect of OCX063 on reducing neovascularization and lesion size in a mouse model of choroidal neovascularization.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1982. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Vision loss in wet age-related macular degeneration (AMD) is caused by aberrant blood vessel growth and fibrosis in the choroid. Wet AMD is currently treated by intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors. These anti-VEGFs agents, however, are not effective in all patients. Hence, there is a need for novel drugs that reduce neovascularization, and choroidal fibrosis. We investigated the effect of OCX063 in an experimental model of choroidal neovascularization (CNV).
CNV lesions were induced in 8 week old female BL6 mice (n= 10 eyes/group) using laser photocoagulation (350 mW). Animals were intravitreal injected with either 0.5 uL of OCX063 (50 uM) or PBS immediately following lasering (acute) or at 7 days (long-term). Leakage was assessed using fluorescence angiography and total lesion size was quantified using image J at 7 days or 30 days and animals were euthanized at 7 days or at 30 days and the eyes were removed, fixed and stained using trichrome. The CNV lesion height/choroid height ratio was measured in image J. mRNA expression and gene ontology (GO) analysis study was also undertaken. RNA was extracted from the RPE, 7 days after laser. mRNA expression levels were compared using angiogenesis and fibrosis qPCR arrays. Significantly expressed genes relative to control (p< 0.05, fold change (FC) ± 1.5) underwent overrepresentation testing on the panther GO platform.
CNV lesions outcomes were reduced in OCX063 treated mice relative to PBS treated mice in the acute and long-term experiments. The total leakage area (Pixels, 7 days; 5.7 x 104 vs. 2.8 x 104, 30 days; 2.3 x 104 vs. 1.4 x 104, p< 0.05) and the CNV lesion size (B/C ratio, 7 days; 5.5 vs. 3.5 (p< 0.01), 30 days; 3.6 vs. 2.6 (p< 0.05)) was significantly reduced. Gene expression changes showed that OCX063 significantly reduced (p< 0.05) the mRNA expression of CNV-promoting genes; Timp1 (-1.6 FC), Cxcl11 (-1.5 FC), and Thbs1 (-1.3 FC). Over-enrichment testing revealed TGF-beta pathways were being regulated by OCX063, indicating that OCX063 may be acting as an anti-fibrotic.
OCX063 reduced CNV lesion size and leakage at 7 days and 30 days. OCX063 may provide an alternative treatment to wet AMD patients especially those that do not respond to anti-VEGF therapies.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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