Using the past to inform the future: anti-VEGF therapy as a road map to develop novel therapies for diabetic retinopathy

Abstract

Therapies targeting vascular endothelial growth factor (VEGF) are revolutionizing the treatment of diabetic retinopathy (DR) and diabetic macular edema (DME). In August 2012, ranibizumab, a monoclonal antibody fragment targeting VEGF designed for ocular use, became the first and only U.S. Food and Drug Administration-approved medical therapy for DME and the first approved treatment in over 25 years. This approval was based on strong preclinical data followed by numerous clinical trials that demonstrate an essential role of VEGF in vascular permeability and angiogenesis in both normal physiology and disease pathology. In this Perspective, we will examine the experimental studies and scientific data that aided in the success of the development of therapies targeting VEGF and consider how these approaches may inform the development of future therapeutics for diabetic eye disease. A multipoint model is proposed, based on well-established drug development principles, with the goal of improving the success of clinical drug development. This model suggests that to provide a validated preclinical target, investigators should demonstrate the following: the role of the target in normal physiology, a causal link to disease pathogenesis, correlation to human disease, and the ability to elicit clinically relevant improvements of disease phenotypes in animal models with multiple, chemically diverse interventions. This model will provide a framework to validate the current preclinical targets and identify novel targets to improve drug development success for DR.

FIG. 1.

Extracellular signaling implicated in the pathogenesis of DR. This cartoon illustration of the neurovascular retina provides a summary of the factors implicated in DR and highlighted in this Perspective. Receptors for permeabilizing factors, such as VEGF, are expressed on the endothelial cells. The factors may be secreted in a paracrine fashion by the surrounding glial cells or from microglia or inflammatory cells (not shown). Proangiogenic factors such as Ang2 contribute to pathological angiogenesis and vascular permeability along with VEGF. Inflammatory factors, such as TNF and CCL2, represent another class of factors that may contribute to the increased retinal vascular endothelial permeability. Wnt signaling during endothelial maturation promotes differentiation, while aberrant Wnt signaling increases vascular permeability. In proliferative DR, vascular hemorrhage and erythrocyte lysis increase extracellular carbonic anhydrase in the blood vessel lumen and activate the kinin-kallikrein system promoting vascular permeability. In addition, PDGF signaling in pericytes is imperative for pericyte survival, and hyperglycemia-induced defects in PDGFRβ signaling in pericytes lead to blood-retinal barrier dysfunction. BKR, bradykinin receptor.

FIG. 2.

Intracellular mechanisms of retinal vascular permeability in DR. Signaling mechanisms downstream of VEGF including PKCβ, Akt, and aPKC lead to retinal vascular permeability. VEGF activates PKCβ, which in turn phosphorylates the tight junction proteins occludin and induces the endocytosis of several tight junction–containing proteins leading to retinal vascular permeability. VEGF also activates eNOS and aPKC, which lead to barrier destabilization through currently unknown mechanisms. TNF is known to activate NF-κB and induce an inflammatory response leading to decreases in tight junction proteins ZO-1 and claudin-5. Importantly, aPKC contributes to the permeabilizing mechanisms of VEGF, CCL2, and TNF and represents a common signaling node for all three permeabilizing factors. PDK1, phosphoinositde-dependent kinase 1.