Novel Therapeutics for Diabetic Retinopathy and Diabetic Macular Edema: A Pathophysiologic Perspective

Abstract

Diabetic retinopathy (DR) and diabetic macular edema (DME) are retinal complications of diabetes that can lead to loss of vision and impaired quality of life. The current gold standard therapies for treatment of DR and DME focus on advanced disease, are invasive, expensive, and can trigger adverse side-effects, necessitating the development of more effective, affordable, and accessible therapies that can target early stage disease. The pathogenesis and pathophysiology of DR is complex and multifactorial, involving the interplay between the effects of hyperglycemia, hyperlipidemia, hypoxia, and production of reactive oxygen species (ROS) in the promotion of neurovascular dysfunction and immune cell polarization to a proinflammatory state. The pathophysiology of DR provides several therapeutic targets that have the potential to attenuate disease progression. Current novel DR and DME therapies under investigation include erythropoietin-derived peptides, inducers of antioxidant gene expression, activators of nitric oxide/cyclic GMP signaling pathways, and manipulation of arginase activity. This review aims to aid understanding of DR and DME pathophysiology and explore novel therapies that capitalize on our knowledge of these diabetic retinal complications.

Do Nutrients and Nutraceuticals Play a Role in Diabetic Retinopathy? A Systematic Review

“…Despite chronic hyperglycaemia and long-term glucose control being the main determinant of this highly specific vascular injury related to DM, other extraocular factors, such as hypertension, dyslipidaemia, obesity, cigarette smoke, pregnancy, genetic and epigenetic susceptibility, contributes to the onset and course of DR [ 11 ]. Nevertheless, some diabetes patients without these traditional risk factors can likewise develop a retinal damage, suggesting the involvement of other pathogenetic elements [ 70 ]. Preclinical and clinical studies investigated whether nutraceuticals could influence the course of DR [ 23 , 24 ].…”

Targeting hypoxia-inducible factors with 32-134D safely and effectively treats diabetic eye disease in mice

“…Nonetheless, accumulation of HIF-1α and HIF-2α protein was observed in immunoblot assays of neurosensory retina lysates from STZ mice that were hyperglycemic ing a role for HIFs in the development of early NPDR or DME. In the absence of ischemia, the expression of VEGF in patients with DME is believed to be independent of hypoxia or HIFs and has instead been attributed to other causes including AGEs, oxidative stress, and neuroinflammation, independent of HIF accumulation (1,2). However, in addition to hypoxia, many inflammatory cytokines and growth factors previously implicated in diabetic eye disease (20) have also been shown to induce HIF activity in an oxygen-independent manner (21), often by mechanisms distinct from its canonical hypoxia-mediated regulation (22).…”

AAV-Based Strategies for Treatment of Retinal and Choroidal Vascular Diseases: Advances in Age-Related Macular Degeneration and Diabetic Retinopathy Therapies

“…DR is the most common complication of DM, estimated to be present in more than 103 million people worldwide, and ranking as one of the leading causes of preventable blindness in the working-age population [ 107 ]. In its severe stage, DR highly impacts the quality of life of patients due to its association with social isolation, reduced physical activity, and dependence on daily activities, resulting in a significant economic and healthcare burden [ 108 , 109 ]. The disease can be classified as non-proliferative (mild, moderate, severe, or very severe) or proliferative (early, high-risk, or severe), with the latter corresponding to the late stage, characterised by neovascularisation [ 109 ].…”