CCR3: a molecular marker for neovascular AMD

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DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) affects as many Americans as all cancers combined and twice as many as Alzheimer's disease. The overwhelming cause of severe vision loss in AMD is choroidal neovascularization (CNV), the growth of abnormal blood vessels into the retina. Despite the use of recently approved molecular therapeutics targeting vascular endothelial growth factor (VEGF)-A, the majority of patients do not recover good, functional vision, and a significant fraction progress to legal blindness. This is due to the present inability to detect CNV before it invades the retina and causes structural and functional tissue damage. In new and exciting findings, we are reporting the discovery of the first molecular marker that is specific for human CNV (Takeda et al. Nature 2009): CCR3, a chemokine receptor best known for promoting eosinophil and mast cell trafficking, is expressed in human choroidal endothelial cells in vivo only in the setting of CNV due to AMD. Targeting CCR3 or its eotaxin ligands inhibited angiogenesis in vitro and in vivo, and was both superior to and safer than VEGF-A blockade. Non-invasive in vivo bioimaging using functionalized quantum dots targeting CCR3 detected CNV within the mouse choroid that had not yet invaded the retina and was invisible to fluorescein angiography. These findings define CCR3 as a novel specific molecular early diagnostic and therapeutic target in human CNV. In this proposal, we will define the biological relationships between the CCR3/eotaxin axis and aging, complement activation, and oxidative stress to decipher how these established AMD pathogenetic factors regulate the neovascular progression of disease. We will also create and optimize new fluorescent optical bioimaging CCR3-targeting probes that can detect intrachoroidal, "subclinical" CNV. These studies respond precisely to this Challenge Topic as they will illuminate how the immune system regulates this specific signature of the angiogenic switch in AMD, and innovatively exploit it to enable prevention of vision loss by coupling early detection with targeted therapy. As such, this proposal is perfectly aligned with the 5-year program goals of the NEI's Retinal Diseases strategic plan. It also advances the goals of the American Recovery and Reinvestment Act as it will, if funded, create or retain jobs for three individuals, and provide economic benefits to third- party suppliers and vendors. We are committed to complete the program by the determined October 2010 deadline, and are willing to complete quarterly reports pertaining to this project as outlined by NIH. PUBLIC HEALTH RELEVANCE: Choroidal neovascularization (CNV) is responsible for 90% of severe vision loss due to age- related macular degeneration (AMD), the leading cause of blindness among the elderly in the United States. Our recent discovery of CCR3 as the first molecule specifically expressed with human CNV and our exciting new finding that CCR3-targeting molecular imaging probes can detect CNV before retinal invasion support the investigation of CCR3 biology in AMD and optimization of bioimaging modalities. This proposal can transform the clinical practice paradigm by introducing an innovative bioimaging strategy that enables early detection of CNV for targeted therapy that can prevent vision loss. It also will advance the goals of the ARRA by creating or retaining multiple jobs and provide economic benefit to the University of Kentucky College of Medicine, which has consistently served the Commonwealth of Kentucky as a principal force for economic development, and third-party suppliers and vendors.