Multimodal Molecular Imaging of Choroidal Neovascularization

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PROJECT SUMMARY/ABSTRACT Wet age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. Choroidal neovascularization (CNV) is the leading cause of vision loss due to AMD. Although anti-vascular endothelial growth factor (VEGF) therapy has shown a great breakthrough in CNV treatment, persistent disease activity (PDA) is common. PDA has been demonstrated in 53% and 71% of patients treated monthly with ranibizumab and bevacizumab, respectively. 20% of patients become legally blind and another 30% suffer from some degree of vision loss after 5 years of anti-VEGF therapy. While AMD is a serious problem, one critical barrier limiting the ability to test novel therapies in preclinical settings is the lack of CNV animal models with PDA and the lack of methods for longitudinal monitoring of disease biomarkers and response to therapy. The goal of this project is to develop state-of-the-art multimodal molecular imaging for non-invasive and longitudinal assessment of the imaging biomarkers in a new CNV rabbit model with PDA to offer a platform technology for the development of novel therapeutics. We have developed a high resolution, multimodal ophthalmic imaging system incorporating photoacoustic microscopy (PAM), optical coherence tomography (OCT), and fluorescence microscopy (FM). Novel chain-like gold nanoparticle clusters have been developed and used to enhance molecular imaging and target integrins present in CNV. We have also developed a robust animal model of PDA using older rabbits that demonstrate minimal response to anti-VEGF therapy. Encouraged by these exciting preliminary results, we propose to further develop this platform molecular imaging technology for AMD with a central hypothesis that a multimodal molecular imaging system that can evaluate the CNV animal model could contribute to understanding the fundamental biology of AMD and the development of new pharmaceutical therapies to treat CNV. We will test our hypothesis with the following Specific Aims: Aim 1: Upgrade the multimodal PAM, OCT, and FM system for real-time imaging in rabbit eyes. Aim 2: Test the prediction that young rabbits with robust response to anti-VEGF demonstrate capillary CNV while older rabbits demonstrate arteriolar CNV that can be visualized with multimodal imaging. Aim 3: Test the prediction that the rabbit models of CNV in response to anti- VEGF can be visualized at a molecular level with multimodal imaging powered by ultraminiature chain-like gold nanoparticles. The results of this work will include concepts, tools, and strategies for future research across several disciplines: a) Fundamental biology of AMD to visualize and quantify, with high spatial and temporal resolution, functional and molecular changes in living animals. b) Strategies for testing and developing novel drugs and non-pharmaceutical therapies in large eye models, particularly for CNV with PDA. c) Improved prognostication research to enable real-time molecular biomarkers of treatment response.