Moving Past Anti-VEGF: Novel Therapies for Treating Diabetic Retinopathy

Abstract

Diabetic retinopathy is the leading cause of blindness in working age adults, and is projected to be a significant future health concern due to the rising incidence of diabetes. The recent advent of anti-vascular endothelial growth factor (VEGF) antibodies has revolutionized the treatment of diabetic retinopathy but a significant subset of patients fail to respond to treatment. Accumulating evidence indicates that inflammatory cytokines and chemokines other than VEGF may contribute to the disease process. The current review examines the presence of non-VEGF cytokines in the eyes of patients with diabetic retinopathy and highlights mechanistic pathways in relevant animal models. Finally, novel drug targets including components of the kinin-kallikrein system and emerging treatments such as anti-HPTP (human protein tyrosine phosphatase) β antibodies are discussed. Recognition of non-VEGF contributions to disease pathogenesis may lead to novel therapeutics to enhance existing treatments for patients who do not respond to anti-VEGF therapies.

Keywords: TNF-α; VEGF; angiopoietin; blood retinal barrier; corticosteroid; cytokine; diabetic macular edema; diabetic retinopathy; kinin-kallikrein system; renin-angiotensin system; vitreomacular adhesion.

Figure 1

Drug Targets in Trial for Diabetic Retinopathy. Currently, anti-VEGF has shown great effectiveness for many patients with DR. Targeting the Tie-2 receptor signaling through HPTPβ may provide additional benefit. A number of studies demonstrate evidence for inflammation that is targeted through a variety of potential interventions. Hemodynamic control through kallikrein inhibition to prevent kinin production or ACE inhibitors to control angiotensin may also provide potential therapeutic options. The relationship of these drug targets to disease progression is an area of active investigation.