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

• Published in: Nature (London) Vol. 460; no. 7252; pp. 225 - 230
• Main Authors: Ambati, Jayakrishna, Takeda, Atsunobu, Baffi, Judit Z, Kleinman, Mark E, Cho, Won Gil, Nozaki, Miho, Yamada, Kiyoshi, Kaneko, Hiroki, Albuquerque, Romulo J. C, Dridi, Sami, Saito, Kuniharu, Raisler, Brian J, Budd, Steven J, Geisen, Pete, Munitz, Ariel, Ambati, Balamurali K, Green, Martha G, Ishibashi, Tatsuro, Wright, John D, Humbles, Alison A, Gerard, Craig J, Ogura, Yuichiro, Pan, Yuzhen, Smith, Justine R, Grisanti, Salvatore, Hartnett, M. Elizabeth, Rothenberg, Marc E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.07.2009; Nature Publishing Group
• Subjects: Animals; Care and treatment; Cell Movement; Cell Proliferation; Cells; Cells, Cultured; Chemokine CCL11 - antagonists & inhibitors; Chemokine CCL11 - metabolism; Chemokine CCL24 - antagonists & inhibitors; Chemokine CCL24 - metabolism; Chemokine CCL26; Chemokine receptors; Chemokines, CC - antagonists & inhibitors; Chemokines, CC - metabolism; Choroid - blood supply; Choroid - cytology; Choroid - metabolism; Choroidal Neovascularization - diagnosis; Choroidal Neovascularization - metabolism; Disease Models, Animal; Endothelial Cells - cytology; Endothelial Cells - metabolism; Genetic aspects; Humanities and Social Sciences; Humans; Inflammation; Leukocytes; Ligands; Macular degeneration; Macular Degeneration - diagnosis; Macular Degeneration - metabolism; Macular Degeneration - therapy; Mice; Mice, Inbred C57BL; multidisciplinary; Neutralization; Ophthalmology; Physiological aspects; Quantum Dots; Receptors, CCR3 - analysis; Receptors, CCR3 - antagonists & inhibitors; Receptors, CCR3 - genetics; Receptors, CCR3 - immunology; Receptors, CCR3 - metabolism; Retina - drug effects; Retina - pathology; Science; Science (multidisciplinary); Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - immunology; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature08151

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 neovascularisation (CNV). Here we show that the eosinophil/mast cell chemokine receptor CCR3 is specifically expressed in choroidal neovascular 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 because 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 in clinical use at present, and, unlike VEGF-A blockade, is 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. Early indicator of sight loss More than 30 million people worldwide are affected by age-related macular degeneration (AMD), the leading cause of blindness in the elderly. The standard treatments for the blinding neovascular form of the disease are anti-VEGF drugs — principally ranibizumab (Lucentis) and bevacizumab (Avastin) — but they improve vision in only a third of patients and there is concern about possible toxicity as VEGF plays an important role in normal retinal functioning. Now the identification of the cytokine receptor CCR3 as an early detection marker of the disease in a mouse model raises the possibility of early diagnosis, which would be an important contribution to improving clinical outcome. In addition, targeting CCR3 or its ligands, which inhibits the invasion of the retina by new blood vessels, may provide a safe alternative means of treatment. Age-related macular degeneration (AMD) is a major cause of blindness. Now, the eosinophil/mast cell chemokine receptor CCR3 is shown to be specifically expressed in choroidal neovascular endothelial cells in humans with AMD, and targeting CCR3 or its ligands in mice inhibits the choroidal neovascularization that underlies AMD. In the mouse model, CCR3 blockade was more effective and less toxic than VEGF-A neutralization, which is currently in clinical use.