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xilun Anthony wang, Michael Foley, Gene Venables, Erica L Fletcher; Inhibition of the chemokine receptor CXCR4 reduces pathology in a laser induced mouse model of choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2259.
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© ARVO (1962-2015); The Authors (2016-present)
Age related macular degeneration (AMD) is treated with a range of anti-VEGF inhibitors. Although these treatments have had a profound effect on the acute pathology, in the longer term, vision loss continues for many patients. New drugs are needed to effectively treat wet AMD. One approach is to target cytokine signalling, which has been implicated in the development of neovascularization pathology. The central aim of this project was to evaluate the role of the chemokine receptor CXCR4 in a mouse model of choroidal neovasculariation (CNV).
CNV lesions were induced in 8 week old female BL6 mice (n= 10 eyes/group) using laser photocoagulation (Micron III, 532nm, 350 mW). Animals were intravitreal injected with either a single domain like antibody known as an i-body targeting CXCR4 (AD-114 12µg/ml), a negative control i-body (AD-21H5 12µg/mL) or vehicle (PBS). Leakage was assessed using fluorescence angiography and lesion size was quantified using image J at 7 days and the eyes were removed, fixed and stained using Masson’s trichrome stain. The CNV lesion height/choroid height ratio was measured in image J. mRNA expression and a gene ontology (GO) study was also undertaken. RNA was extracted from the retina and RPE, 7 days after laser. mRNA expression levels were compared using qPCR arrays (84 fibrosis-associated genes). Significantly expressed genes relative to control (p< 0.05, fold change ±1.5) underwent overrepresentation testing on the Panther GO platform to identify any potential gene networks modified by CXCR4 inhibiting i-bodies.
The size of the lasered lesions was reduced with the addition of the anti-CXCR4 i-body AD-114 relative to the negative control i-body or PBS treated mice. The total leakage area (µm2; 1.82 vs. 5.06, p<0.0001) and the CNV lesion size (B/C ratio; 2.0 vs. 4.3 p<0.0001) were significantly reduced at 7 days. Gene expression changes showed that AD-114 significantly altered (p<0.05) the mRNA expression of cytokine genes (IL13, IL1b) and pro-fibrotic genes. Gene ontological analysis confirmed these findings, with the cytokine signaling pathways found to be overrepresented.
Inhibition of CXCR4 reduced neovascularization pathology following laser photocoagulation. These results suggest an alternative treatment mechanism targeting the chemokine receptor CXCR4 using i-body AD-114 may reduce ocular pathology of CNV.
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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