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Norihiro Nagai, Kanako Izumi-Nagai, Scott J. Robbie, James W. Bainbridge, Peter S. Adamson, Yin-shan Ng, David T. Shima; Novel Ccr3 Antagonists Are Effective Mono- And Combination Inhibitors Of Cnv Growth And Vascular Permeability. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1670.
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© ARVO (1962-2015); The Authors (2016-present)
We explored the functional role of CCR3 in laser-induced and spontaneous choroidal neovascularisation.
A novel model of spontaneous CNV and laser-induced CNV models were used for assessing the novel CCR3 antagonists. CCR3 ligands, receptors, and leukocytes were analysed by immunostaining. Pharmacological blockade of mouse CCR3 was performed by using the CCR3 antagonist GW766994, and in the primate laser-induced CNV model, a second antagonist, GW782415 was used. Systemic and topical routes of administration were explored. CNV number, area and permeability were evaluated by fluorescein angiography and immunostaining in the mouse, and by fluorescein angiography in the primate.
In rodent studies, CNV was associated with increased expression of CCR3, and both the number and size of spontaneous CNV were significantly reduced in a dose-dependent manner by a systemic CCR3 antagonist. Similarly, oral dosing with CCR3 antagonist dose-dependently reduced laser-induced CNV development. Furthermore, topical administration of the CCR3 antagonist was also effective in reducing spontaneous CNV area and number, with efficacy comparable to that of the systemic CCR3 antagonist. Combination treatment with systemic anti-VEGFR2 antibody and CCR3 antagonist resulted in an additive effect in reducing CNV number, area, and permeability. In the primate, oral dosing of the CCR3 antagonist GW782415 resulted in a significant suppression of grade IV CNV lesions 16, 24 and 30 days following laser photocoagulation.
We have demonstrated a direct functional role of CCR3 in the development and hyper-permeability of CNV, and also the additive therapeutic effect of a CCR3 antagonist in combination with VEGFR2 blockade. Our data suggest that CCR3 signalling may be an attractive therapeutic target for neovascular AMD and is distinct from the VEGF signalling pathway.
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