Diabetic retinopathy: a complex pathophysiology requiring novel therapeutic strategies

Abstract

Introduction: Diabetic retinopathy (DR) is the leading cause of vision loss in the working age population of the developed world. DR encompasses a complex pathology, and one that is reflected in the variety of currently available treatments, which include laser photocoagulation, glucocorticoids, vitrectomy and agents which neutralize vascular endothelial growth factor (VEGF). Whilst these options demonstrate modest clinical benefits, none is yet to fully attenuate clinical progression or reverse damage to the retina. This has led to an interest in developing novel therapies for the condition, such as mediators of angiopoietin signaling axes, immunosuppressants, nonsteroidal anti-inflammatory drugs (NSAIDs), oxidative stress inhibitors and vitriol viscosity inhibitors. Further, preclinical research suggests that gene therapy treatment for DR could provide significant benefits over existing treatments options.

Areas covered: Here we review the pathophysiology of DR and provide an overview of currently available treatments. We then outline recent advances made towards improved patient outcomes and highlight the potential of the gene therapy paradigm to revolutionize DR management.

Expert opinion: Whilst significant progress has been made towards our understanding of DR, further research is required to enable the development of a detailed spatiotemporal model of the disease. In addition, we hope that improvements in our knowledge of the condition facilitate therapeutic innovations that continue to address unmet medical need and improve patient outcomes, with a focus on the development of targeted medicines.

Keywords: Diabetic retinopathy; diabetic macular edema; neovascularization; neuronal apoptosis; vascular endothelial growth factor.

Figure 1.

Diabetes leads to hyperglycemic episodes which in turn impacts five key biochemical pathways: – polyol pathway activation; production of advanced glycation endproducts (AGEs); protein kinase C (PKC) activation; hexosamine pathway activation; and poly (ADP-ribose) polymerase upregulation. This in turn leads to oxidative stresses, resulting in mitochondrial dysfunction, deregulation of proinflammatory mediators and crucially, hypoxia. These effects cause apoptosis of vascular and neuronal cells and upregulation of VEGF expression, eventually leading to neurovascular dysregulation, and hyperpermeable blood vessels and/or neovascularization. Importantly, the generation of ROS and oxidative stress further exacerbates metabolic dysfunction, itself leading to elevated ROS production in a self-perpetuating positive feedback mechanism. In addition, the renin angiotensin aldosterone system is implicated in driving neurovascular dysfunction. Reproduced from Pharmacology & Therapeutics, Vol 173, Wang et al., Gene therapy for diabetic retinopathy: Are we ready to make the leap from bench to bedside?, Copyright 2017, with permission from Elsevier [7].

Figure 2.

The relationship between superoxide and ROS production and the key pathologic pathways of DR. This model demonstrates the centrality of oxidative stress to DR and has led some to purport superoxide production to be the ‘unifying mechanism’ in the complex pathology of DR. G6P = glucose-6-phosphate, F6P = fructose-6-phosphate, GA3P = glyceraldehyde-3-phosphate, 1,3-DPG = 1,3,-diphosphoglycerate, GS6P = glucosamine-6-phosphate, a-GP = alpha-glycerol-phosphate. Reproduced with permission from Springer Nature, Copyright 2001 [45].