Preventing and reversing blindness: COMP-ANG1 and endothelial progenitor cells as a novel therapeutic approach in diabetic retinopathy

Diabetes affects 25.8 million people in the United States and its prevalence is expected to triple in the next 20 years. Diabetic retinopathy (DR) affects nearly 30% of people with diabetes and is the leading cause of blindness in the working-age population. Current treatments for DR improve vision in only a minority of patients, and carry significant risks. This work advances a new approach that works by reversing retinal vascular damage and restoring normal perfusion to improve vision in this condition. Chapter 1 reviews the epidemiology, pathophysiology, and current standards of therapy for diabetic retinopathy. The roles of vascular maturation factor Angiopoietin-1 (Ang1) and its receptor Tie2 are introduced. Chapter 2 describes the development of an improved method for visualization of leukocytes in the diabetic mouse retina, which was critical for studies in this dissertation and broadly applicable to fields studying leukocyte endothelial interaction and inflammation. Chapter 3 focuses on the studies describing prevention of neurovascular dysfunction in diabetic retinopathy achieved by treating diabetic mice with gene therapy expressing COMP-Ang1. This chapter further details the studies performed to reverse diabetic retinopathy with a combination therapy consisting of endothelial colony-forming cells (ECFCs) and COMP-Ang1. We demonstrated that COMP-Ang1 enhanced the vasculogenic capabilities of ECFCs leading to increased integration into the diabetic retina and preservation of visual function in mice with advanced diabetic retinopathy. Chapter 4 represents my contributions toward the understanding of how targeting alternative VEGF receptor 2 splicing can suppress hemangiogenesis and lymphangiogenesis in the retina and choroid. This work was published in the FASEB journal in 2013. Chapter 5 describes my work published in PLoS ONE describing suppression of both tumor and ocular neovascularization, wherein we used morpholinos to increased soluble VEGF receptor 1. Chapter 6 concludes this work by recapping how the work accomplished in this dissertation built off of previous discoveries. The Appendix describes studies initiated to test the effects of COMP-Ang1 in an acute model of retinal ischemia, central retinal artery occlusion.