CCR3 is a target for age-related macular degeneration diagnosis and therapy

Abstract

Age-related macular degeneration (AMD), a leading cause of blindness worldwide, is as prevalent as cancer in industrialized nations. Most blindness in AMD results from invasion of the retina by choroidal neovascularization (CNV). We report that the eosinophil/mast cell chemokine receptor CCR3 is specifically expressed in CNV endothelial cells in humans with AMD, and that, despite the expression of its ligands eotaxin-1, -2, and -3, neither eosinophils nor mast cells are present in human CNV. Genetic or pharmacological targeting of CCR3 or eotaxins inhibited injury-induced CNV in mice. CNV suppression by CCR3 blockade was due to direct inhibition of endothelial cell proliferation, and was uncoupled from inflammation as it occurred in mice lacking eosinophils or mast cells and was independent of macrophage and neutrophil recruitment. CCR3 blockade was more effective at reducing CNV than vascular endothelial growth factor-A (VEGF-A) neutralization, which is currently in clinical use, and, unlike VEGF-A blockade, not toxic to the mouse retina. In vivo imaging with CCR3-targeting quantum dots located spontaneous CNV invisible to standard fluorescein angiography in mice before retinal invasion. CCR3 targeting might reduce vision loss due to AMD through early detection and therapeutic angioinhibition.

Novel CCR3 Antagonists Are Effective Mono- and Combination Inhibitors of Choroidal Neovascular Growth and Vascular Permeability

“…Others have also reported CCR3 expression in the vascular endothelial cells of CNV vessels as well as in choroidal endothelial cells and leukocytes, 9,14,15,30,31 but this is the first report of macrophages as a source of CCR3 ligands in CNV. Our findings support a possible mechanism of CCR3 activity in which the CNV neovessels, leukocytes, and likely the choroidal endothelial cells 9 express CCR3 and respond to CCR3 ligands that are produced in the subretinal space (eg, by recruited macrophages).…”

“…14 Mice deficient in the production of eosinophils or mast cells, the cells most closely associated with the expression of CCR3, were equally sensitive to the induction of CNV by laser injury and to the therapeutic benefits of CNV suppression by CCR3 blockage. 14 Here we focus on the effects of pharmacological CCR3 blockade in a mouse model of spontaneous CNV, a model that mimics disease progression in humans more closely than does laser-induced CNV, as well as in a primate model of CNV.…”

“…12 Significantly increased levels of CCL24/eotaxin-2, another natural ligand of CCR3, have been observed in the sera of patients with wet AMD compared with those in normal counterparts, and anti-VEGF treatment in these patients did not reduce the levels of CCL24. 13 Studies in mouse models have demonstrated therapeutic benefits of CCR3 blockade in treating laser-induced CNV, 14,15 and photocoagulation studies in mice with a homozygous genetic deficiency for either CCR3 or specific CCR3 ligands demonstrated significant CNV suppression in the mutant mice compared with that in wild-type controls. 14 Mice deficient in the production of eosinophils or mast cells, the cells most closely associated with the expression of CCR3, were equally sensitive to the induction of CNV by laser injury and to the therapeutic benefits of CNV suppression by CCR3 blockage.…”

“…13 Studies in mouse models have demonstrated therapeutic benefits of CCR3 blockade in treating laser-induced CNV, 14,15 and photocoagulation studies in mice with a homozygous genetic deficiency for either CCR3 or specific CCR3 ligands demonstrated significant CNV suppression in the mutant mice compared with that in wild-type controls. 14 Mice deficient in the production of eosinophils or mast cells, the cells most closely associated with the expression of CCR3, were equally sensitive to the induction of CNV by laser injury and to the therapeutic benefits of CNV suppression by CCR3 blockage. 14 Here we focus on the effects of pharmacological CCR3 blockade in a mouse model of spontaneous CNV, a model that mimics disease progression in humans more closely than does laser-induced CNV, as well as in a primate model of CNV.…”

Novel Retinal Imaging Technologies

“…King et al, [38] suggests that ROS a good early indicator of the changes of disease-related in the RPE. Takeda et al, [39] indicates that the C-C chemokine receptor 3 (CCR3) is a possible target for AMD diagnosis and therapy. CCR3 can play a role as a potentially important biomarker of CNV in AMD.…”