Research Project
7404839
[unreadable] DESCRIPTION (provided by applicant): The objective of this proposal is to develop a service for the high-throughput drug screening of compounds to treat Age-Related Macular Degeneration (AMD). In our preliminary studies, we have identified a genetically-modified mouse (Vldlr-/-) that presents with symptoms nearly identical to AMD pathogenesis in humans. Based on the following observations, we hypothesize that Vldlr-/- mice is a good model for AMD 1) VLDLR variants have been recently shown to associate with AMD in human patients, suggesting that the pathogenesis of this model is relevant to human AMD. 2) This mouse model develops most phenotypes of human AMD, including retinal inflammation, photoreceptor degeneration, retinal vascular leakage and CNV. 3) Compared to the laser-induced neovascularization models, Vldlr-/- mice are a genetic model and the CNV is highly reproducible and easy to quantify. The CNV can be readily quantified by counting vessels penetrating the RPE on the surface of the RPE/choroid flat mount. 4) VEGF over-expression is a major causative factor in this model, similar to that in human AMD and suitable for the screening of new anti-VEGF drugs. 4) Compared to several other existing transgenic models of AMD, this model develops early onset AMD, which makes it a suitable model for screening new anti-CNV drugs. 5) Vldlr-/- mice are easy to breed and do not need additional genotyping, so that the costs of drug screening using this model is low. Retinal blood vessel formation is known to be mediated by the vascular endothelial growth factor (VEGF) protein, and current FDA approved treatments for AMD are inhibitors of this protein and its ability to signal. These drugs are a great advancement in the treatment of AMD, but they 1) fail to address the inflammatory nature of the disease; 2) are not effective in all AMD patients; 3) require monthly injections into the eye to deliver the drug; 4) can only be used once visual loss has already occurred. Therefore, more efficacious therapies are still needed to treat AMD, and numerous pharmaceutical companies are heavily engaged in the development of new AMD-therapeutics. Towards this end, suitable animal models are needed to rapidly screen and develop compounds that could be useful in treating AMD. The goal of our proposed research is to establish justification for the utilization of Vldlr-/- mice in AMD-drug screening. We plan to use several established anti-VEGF compounds to demonstrate a similar efficacy in preventing AMD-phenotypes with comparable compounds in Vldlr-/- mice. In this Phase I project, we will test the efficacy of these anti-VEGF compounds on retinal vascular leakage and choroidal neovascularization in this mouse model. If these VEGF-inhibitors are successful in alleviating the AMD-symptoms observed in Vldlr-/- mice, this will provide substantial evidence that these mice are an excellent model of AMD. Our company is actively engaged in providing contractual services to screen the efficacy of ophthalmic pharmaceutical compounds in our proprietary animal models of diabetes, and the completion of the studies described above would enable us to offer similar services for AMD-drug screening. PUBLIC HEALTH RELEVANCE: Age-Related Macular Degeneration (AMD) is the leading cause of blindness worldwide in patients over the age of 50. The development of therapies to treat AMD is heavily reliant on preclinical testing in animal models; however, no satisfactory animal models exist for AMD-drug screening. We have identified a mouse model for AMD, and the goal of this proposal is to justify the utilization of these mice in AMD-drug screening so that we may develop a high-throughput contract service for evaluating the efficacy of pharmaceuticals in development by various companies. [unreadable] [unreadable] [unreadable]
