New Thalidomide Analogs for Retinal Neovacularization

DESCRIPTION (provided by applicant): Diabetic retinopathy is a common complication of diabetes mellitus and a leading cause of blindness in the developed countries. There are two major pathological changes which impair vision in diabetic retinopathy: diabetic macular edema (DME) resulting from increased retinal vascular permeability and abnormal angiogenesis in the retina or retinal neovascularization (NV). Currently, there is no effective drug treatment for DME and retinal NV. Over-expression of vascular endothelial growth factor (VEGF) is believed to play a critical role in the development of DME and retinal NV. Thalidomide and its analogs have been shown to have anti-angiogenic activities and have been used for the treatments of multiple myenoma and several cancers. The application of thalidomide and its existing analogs in the treatment of retinal neovascular disorders is limited due to their weak anti-angiogenic activities. Novel compounds with improved anti-angiogenic activities are needed. Recently, our collaborator has synthesized a series of novel thalidomide analogs by substituting the glutaramide ring of thalidomide with an aromatic group. The in vitro assays have shown that three of these analogs have more potent anti-agiogenic activity than thalidomide and other existing analogs. We hypothesize that these analogs have therapeutic potential in the treatment of DME and retinal NV. This Phase I project will serve as a proof-of-concept study to confirm the anti-angiogenic effect of the three thalidomide analogs on retinal NV in a rat model of oxygen-induced retinopathy (OIR), a commonly used animal model of retinal NV. We will determine if these compounds can prevent the development of retinal NV and arrest its progression. As these compounds block the expression of HIF-1, a key transcription factor up-regulating VEGF expression, we hypothesize that they may also reduce vascular permeability in diabetic retina. The effect of these compounds on retinal vascular permeability will be determined in steptozotocin-induced diabetic rats. The effect of these compounds will be compared with that of thalidomide. These studies will not only reveal the therapeutic potenital of these compounds in the treatment of retinal NV and DME, but also determine if they are more potent than thalidomide. The Phase I project will lay a solid ground for the Phase II to investigate the mechanism, delivery routes, metabolism and toxicities of these compounds. Therefore, this project has potential to develop novel anti-angiogenic drugs with improved potency.