A molecular pathological approach to therapy for diabetic retinopathy

In spite of the development of therapies such as retinal photocoagulation and vitreous surgery, diabetic retinopathy (DR) remains the leading cause of blindness in the developed countries. Vascular hyperpermeability is a crucial event in the pathogenesis of maculopathy and proliferative change, both of which have been documented and considered to be the cause of decreasing visual acuity in diabetic patients. The expression of vascular endothelial growth factor (VEGF), also known as vascular permeability factor, has been shown to be upregulated in eyes with background retinopathy, and VEGF has been shown to function as an indicator and promoter of DR. Consequently, blocking the expression of VEGF and its binding to receptors are the logical targets of therapies for DR of all stages, from early to progressive. We succeeded in blocking the action of VEGF, especially its role in vascular hyperpermeability, by blocking its binding to receptors, both in vitro and in vivo, using the VEGF-receptor KDR-specific cytosine-kinase inhibitor SU 5416 and the anti-rheumatic drug Bucillamine. Our results also demonstrate that the success of vitreous surgery, which can be useful in decreasing diabetic macular edema, is at least due in part to removal of VEGF and sources of expression of VEGF in the posterior vitreous membrane and inner limiting membrane. By elucidating the molecular mechanism for DR, we have helped to define better approaches to therapy for this condition.