Discovery of a Novel Therapeutic Approach to Preventing Diabetic Eye Disease Based on Animal Models

VEGF (vascular endothelial growth factor) activation is now an established mechanism of high blood sugar-induced eye damage, leading to various forms of diabetic eye disease such as diabetic macular edema (DME). Seminal work by JDRF-supported and other investigators over the last two decades has led to the development and recent approval of Lucentis, an inhibitor of VEGF. However, other factors in addition to VEGF, and several pathways activated by these factors, render specific drugs such as Lucentis, effective in only about half of patients with DME. A group led by Dr. Antonetti provides evidence through genetic and other preclinical models of diabetes for the involvement of alternative eye damage-pathways controlled by an enzyme called aPKC. They demonstrated that this enzyme is both sufficient and required for VEGF-induced damage to blood vessels in the eye, and that specific and potent small-molecule inhibitors of this enzyme can prevent the process in the rat eye.

Ramifications for Individuals with T1D:

People with T1D are at risk for diabetic eye disease, including DME, which can cause significant loss of vision and, in extreme cases, even blindness. Laser therapy has been used as standard treatment for the past few decades and has dramatically helped to reduce blindness. However, laser therapy is not perfect, and though it can in many cases prevent people with DME from losing even more vision, it very rarely improves vision. Anti-VEGF therapies, such as the recently approved drug Lucentis, have been shown to preserve and even improve vision in those with DME. However, there remains a segment of individuals with diabetic eye disease that are unresponsive to conventional therapies that require different therapies potentially like the one discovered in this research.

JDRF Involvement:

Dr. Antonetti’s research was funded from a JDRF grant.

Investigators and Institutions:

Dr. David A. Antonetti and colleagues conducted this work at the Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA 17033, USA. He is now part of the Gardner Center of Excellence for Eye Research at the Kellogg Eye Center at the University of Michigan

Reference:

Titchenell PM, Lin CM, Keil JM, Sundstrom JM, Smith CD, Antonetti DA. 2012. Novel atypical PKC inhibitors prevent vascular endothelial growth factor-induced blood-retinal barrier dysfunction. Biochem J. 446(3):455-67.