A Novel Thalidomide Analog for the Treatment of Diabetic Macular Edema

DESCRIPTION (provided by applicant): Retinal vascular leakage or breakdown of the blood-retina barrier (BRB) is an early feature of diabetic retinopathy (DR) and can lead to diabetic macular edema (DME), which is the single greatest cause of vision loss in diabetic patients. Currently, there is no effective drug treatment for DME. Although the pathogenesis of DR is uncertain, over-expression of vascular endothelial growth factor (VEGF) is believed to play a critical role in DME. Targeting VEGF or the VEGF signaling is believed to be a most promising strategy for pharmacological interventions of DME. Therefore, searching for and developing new drugs to block retinal vascular leakage via targeting VEGF or the VEGF receptor (VEGFR) have become a major incentive and research effort for the treatment of DME. Thalidomide and some of its existing analogs have displayed anti-angiogenic activities and have been used for the treatment of several inflammatory diseases and cancer. The application of thalidomide and its existing analogs in the treatment of retinal neovascular disorders is limited due to their weak anti-angiogenic activities. Recently, we have designed and synthesized a series of novel thalidomide analogs. In the Phase I studies, the in vitro assays have shown that three of these analogs, Compounds 1, 2 and 4, have potent anti-angiogenic activities. Moreover, these analogs block the expression of retinal vascular permeability factors, VEGF and hypoxia induced factor-1a (HIF-1a), a major transcription factor up-regulating VEGF expression in diabetic retina. We have evaluated the efficacies of these compounds on retinal vascular leakage and retinal neovascularization (NV) in two independent DR models. The results showed that Compound 4 has significantly more potent effects on reducing retinal vascular leakage when compared with thalidomide and the other two compounds. Based on these results, we hypothesize that Compound 4 is a promising drug candidate for the treatment of DME. The goal of this project is to develop a novel, more effective, less toxic thalidomide analog for clinical trials to treat DR and commercialization. In this Phase II project, we will further investigate its long-term efficacy, pharmacokinetics, toxicities and molecular mechanisms of action, to obtain essential data for FDA approval and commercialization of this new compound. This project has potential to develop a novel drug for treatment of DME. These Phase II studies represent an essential step in developing a new drug. Retinal vascular leakage or breakdown of the blood-retina barrier is an early feature of diabetic retinopathy and can leads to diabetic macular edema, which is the single greatest cause of vision loss in diabetic patients. Currently, there is no effective drug treatment for diabetic macular edema. The goal of this project is to develop a novel, more effective, less toxic thalidomide analog for clinical trials to treat diabetic macular edema. In Phase I, we have compared the efficacy of a series of newly synthesized analogs of thalidomide and identified a compound with the most potent effect on retinal vascular leakage. In this Phase II project, we will further investigate its long-term efficacy, pharmacokinetics, toxicities and molecular mechanisms of action, to obtain essential data for FDA approval and commercialization of this new compound.