Developing a Novel Therapeutic for Diabetic Retinopathy by Targeting the Heparin-Binding Domain of VEGF: Anti-Inflammation and Protection of the Diabetic Retina
Abstract
Diabetic retinopathy is one of the most devastating complications of diabetes mellitus and the most frequent cause of new cases of blindness among working-age adults in the United States. Veterans are disproportionately affected by diabetes and therefore have an even higher incidence of diabetic retinopathy when compared to the general population. There is a growing body of scientific evidence suggesting that diabetic retinopathy is driven by vascular inflammation in the eye, which is at least in part induced by increased ocular levels of the multi-functional protein vascular endothelial growth factor (VEGF). Neutralization of VEGF is an approved treatment for diabetic retinopathy, but the long-term efficacy and safety of this strategy are of concern. VEGF has pathological effects, causing vascular inflammation and permeability in diabetic retinopathy, but it also has important beneficial functions in protecting the neural retina and retinal blood vessels exposed to stressful conditions. These beneficial functions could facilitate the healing and protection of the diabetic retina, and their inhibition might ultimately promote progression of diabetic retinopathy. Ideally, a VEGF inhibitor would block the pathogenic effects without disrupting the beneficial functions. The objective of this proposal is to investigate a novel anti-inflammatory therapy for diabetic retinopathy that specifically inhibits the pro-inflammatory activity of VEGF while preserving its beneficial functions. A recombinant portion of the VEGF molecule, the heparin-binding domain (HBD), was serendipitously found to inhibit vascular inflammation. The HBD has previously been implicated in modulating inflammation, but does not directly bind to VEGF receptors 1 and 2, which are known to mediate protective functions of VEGF. We therefore hypothesize that the purified HBD protein can inhibit pathological, pro-inflammatory function of VEGF without affecting its beneficial activities. To develop this purified HBD protein as a therapeutic for diabetic retinopathy, a more stable and likely more potent dimerized version of the HBD protein will first be engineered. The efficacy of the dimerized HBD and the HBD monomer in suppressing vascular inflammation and other vascular pathologies will be assessed in a mouse model of diabetic retinopathy. As a basis for further optimization, the mutated versions of the HBD will be generated in order to identify the structural components necessary for anti-inflammatory activity in vivo. Results from these experiments will provide proof-of-concept data supporting use of this novel HBD protein to suppress VEGF-induced vascular inflammation in diabetic retinopathy. The studies will also provide important insights into the mechanism of action of the HBD protein that could aid future development of a more effective therapeutic for treatment and possibly prevention of diabetic retinopathy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610144
Entities
People
- Yin Shan Ng
Organizations
- Schepens Eye Research Institute
- United States Army