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Wenbo Zhang, PhD
BASIC RESEARCH PROJECT
Department of Ophthalmology & Visual Sciences
University of Texas Medical Branch at Galveston
Dr. Zhang’s Research Project
Novel therapy for retinal neovascularization
Current Research Interests
Ischemic retinopathies (IRs) are caused by impaired retinal blood supply because of retinal vessel regression or vascular occlusion occurring in various diseases, such as diabetic retinopathy, retinopathy of prematurity, and retinal vascular occlusion. These conditions often result in irreversible vision loss due to the development and growth of abnormal new vessels after a period of retinal ischemia. This process is referred to as retinal neovascularization. These abnormal vessels are leaky and fragile, resulting in vitreous hemorrhage, epiretinal or subretinal fibrosis, and tractional retinal detachment. At present, therapies for retinal neovascularization are limited, not always effective, and have considerable side effects. The goal of this project is to develop a novel approach to selectively kill abnormal blood vessels in the retina without affecting normal blood vessels. Dr. Zhang will take advantage of his new discovery of cellular and molecular changes that accompany retinopathies in combination with drug repositioning to speed up the development of innovative therapeutic approaches to treat neovascularization in IRs.
Progress in 2016
Dr. Zhang has developed and synthesized 12 novel Epac inhibitors based on the structure of ESI-09. In a mouse model of ischemic retinopathy, Dr. Zhang showed that nanoparticle-formulated ESI-09 effectively eliminated abnormal vessels while promoting the physiological vascular repair. Additionally, his studies suggest that the adenosine A2A receptor may potentially serve as an upstream regulator of the cAMP/pac1 pathway. Since A2AR antagonist istradefylline has been used to treat Parkinson’s disease in Japan, he plans to further investigate the role of A2AR in activation of cAMP/Epac pathway and test whether A2AR antagonists can be used to safely and effectively prevent and eliminate neovascularization without inhibiting the process of vascular repair.
Plans for 2017
Dr. Zhang’s proposal is based on his exciting preliminary findings obtained during the RRF support in 2016 that the Adenosine A2A receptor/cAMP/Epac1 pathway may play a critical role in retinal vasculopathy in IR. He proposes to investigate the role of A2A receptor (A2AR) in activation of Epac pathway and conduct pre-clinical study to test whether blocking A2AR with potent A2AR antagonists can safely and effectively prevent and eliminate neovascularization without inhibiting the process of vascular repair. Aim 1) To test the hypothesis that A2AR mediates activation of the cAMP/Epac1 pathway in ischemic retinopathy; and 2) To investigate the effects of A2AR antagonists on retinal neovascularization and vascular repair in ischemic retinopathy.
Progress in 2015
Dr. Zhang’s results indicated that targeting Epac alone is sufficient to achieve his research goal to specifically eliminate retinal neovascularization while sparing or even accelerating normal vascular repair. He made some modifications of the original plan to only target Epac1 in retinal neovascularization but substantially extend his study to understand the actions of Epac1 in this process. In addition, he developed in vitro 3D angiogenesis assay that allows him to examine the anti-angiogenic effect of testing agents in a pathophysiological environment. With these modifications, he not only accomplished the goal of the project to develop novel and specific treatment for retinal neovascularization but also provided further insights of mechanisms by which activation of Epac1 induces retinal neovascularization. In addition, since the current formulation only contains Epac inhibitor, it would be easier to engage pharmaceutical companies in the future to develop anti-Epac therapy because it is extremely expensive for clinical trials if both Epac inhibitor and Fn14 inhibitor are included.
Dr. Zhang proposes to use the nanotechnology developed during 2014 funding to deliver drugs to inhibit Fn14 and/or Epac to selectively prevent and eliminate neovascularization without inhibiting the vascular repairing process. He will 1) generate FDA-approved biocompatible nanoparticles loaded with drugs to block Fn14 and Epac individually or simultaneously and demonstrate their efficacies in inhibiting angiogenesis using in vitro assays; 2) investigate the effects of these nanoparticles in treating retinal neovascularization using his established animal model of ischemic retinopathy.
Progress in 2014
The goal of this project is to develop a novel approach for topical delivery of anti-angiogenic drugs to selectively kill abnormal blood vessels in the retina without affecting normal blood vessels. Dr. Zhang found in 2014 that two proteins known as Fn14 and Epac1, which are highly expressed in endothelial cells of abnormal new blood vessels in retina, are involved in the process of retinal neovascularization. He determined whether blocking Fn14 can specifically eliminate retinal neovascularization and developed nanoparticles targeting Fn14 for the delivery of anti-neovascularization drug. He is testing the hypothesis that nanoparticles-mediated delivery of drugs to block Fn14 and Epac1 may allow for safe and effective treatment of retinal neovascularization without impairing normal vascular repair.