A Small Molecule Targeting Wnt Pathway for Treatment of Diabetic Retinopathy
DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness. This sight-threatening condition has become a public health challenge in the US. Currently, there is no FDA- approved drugfor DR. Laser photocoagulation has remained the gold standard for the treatment of DR over the past two decades. However, laser therapy is usually applied for proliferative DR and is an invasive procedure with considerable limitations and side effects. Research efforts have increasingly focused on the application of anti-vascular endothelial growth factor (VEGF) therapy for the treatment of DR. Recent clinical trials have shown that the therapy can slow or reverse the progression of DR, but many patients show only a partial response and the therapy results in adverse events. Due to the limited efficacy of both treatments, new drugs with higher efficacy are urgently needed to improve the management for DR. The Wnt pathway is involved in the multiple pathological processes, including angiogenesis, vascular permeability, inflammation and fibrosis, as it regulates many Wnt-responsive gene products which are known pathogenic factors in DR. Previous studies have shown that Wnt pathway is over-activated in the retinas of human patients with DR and in diabetic models. Further, blocking Wnt pathway by specific Wnt inhibitors down-regulated multiple pathogenic factors and ameliorated DR. These findings have established that the Wnt pathway over-activation induced by diabetes plays a key pathogenic role in DR. Thus, this pathway has become an attractive target of new drugs for the treatment of DR. Since Wnt inhibitors can simultaneously down-regulate multiple pathogenic factors, they should be more superior to anti-VEGFregents. In preliminary studies, we have screened over 100 novel, small molecule compounds to identify potent Wnt inhibitors by assessing their inhibitory effects on Wnt pathway and on retinal vascular endothelial cell growth. Compound E1086 was ultimatelyidentified as a leading compound for blocking Wnt pathway. Our data showed that E1086 attenuated the Wnt pathway activation because it blocked LRP6 phosphorylation, an essential step in Wnt pathway activation, and enhanced 2-catenin phosphorylation to lead to 2-catenin degradation. The compound also inhibited Wnt3a (a Wnt ligand)-induced expression of multiple pathogenic factors. Moreover, E1086 specifically inhibited the growth of retinal vascular endothelial cells. However, it did not significantly inhibit the growth of primary pericytes and fibroblasts. Based on these observations, we hypothesize that E1086 has great potential to become an effective drug for the treatment of DR since it can inhibit retinal angiogenesis, vascular permeability, inflammation and fibrosis through targeting an upstream pathway. This SBIR Phase I project will serve as a proof-of-concept study to investigate the effects of E1086 on the Wnt pathway activation, retinal vascular leakage and inflammation in a diabetic animal model.The program includes two specific aims. The Aim 1 will determine the effect of E1086 on the Wnt pathway activation. The study will clarity the in vivo mechanisms of action of E1086 and will provide new insights into the rationale for the efficacy of E1086.The Aim 2 will evaluate the efficacies of E1086 on retinal vascular leakage and inflammation. The establishment of efficacy profile will direct the future preclinical studies of E1086. Applying an innovative strategy, this project will develop a new therapy with more effective than current medications to cure DR. The proposed studies will lay a solid groundwork for future Phase II preclinical studies of E1086. PUBLIC HEALTH RELEVANCE: Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness. There is no FDA-approved pharmacotherapy for DR and the current treatments are not effective in all DR patients. New drugs with higher efficacy are urgently needed to improve the management of this disease. This project willdevelop a new therapeutics which disrupts the multiple pathological processes though targeting Wnt pathway to cure DR.
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