Antioxidant and Cytoprotective Potential of Erythropoietin in Mitigating Oxidative Stress-Induced Changes in the Retinal Pigment Epithelium

Abstract

Erythropoietin (EPO) protects cells by inhibiting apoptosis, oxidative stress and inflammation in several models of retinal degeneration. In this study, we demonstrate the effects of recombinant Adeno Associated Virus (AAV) vector-mediated delivery of a modified form of erythropoietin (EPO-R76E) in an established mouse model of dry-AMD in which retinal degeneration is induced by RPE oxidative stress. Experimental vector AAV-EPO-R76E and control vector AAV-GFP were packaged into serotype-1 (AAV1) to enable RPE selective expression. RPE oxidative stress-mediated retinal degeneration was induced by exon specific deletion of the protective enzyme MnSOD (encoded by Sod2) by cre/lox mechanism. Experimental mice received subretinal injection of AAV-EPO-R76E in the right eye and AAV-GFP in the left eye. Western blotting of RPE/Choroid protein samples from AAV-EPO-R76E injected eyes showed RPE specific exogenous protein expression. Retinal degeneration was monitored by electroretinography (ERG). EPO-R76E over-expression in RPE delayed the progressive retinal degeneration as measured by light microscopy in RPE specific Sod2 knockout mice. Delivery of EPO-R76E vector can be used as a tool to prevent retinal degeneration induced by RPE oxidative stress as seen in this mouse model.

Cell and molecular targeted therapies for diabetic retinopathy

“…The research landscape continues to evolve, with promising new avenues, such as gene and cell therapies, which may offer new avenues for managing diabetic eye disease. Gene therapy for diabetic retina employs gene-specific targeted therapy, which is split into two categories based on the pathophysiology of the disease (226): therapies that target pre-existing neovascularization such as the use of sFlt-1, a soluble splice variant of the VEGF receptor 1 (VEGFR-1 or Flt-1), that acts as a decoy VEGF receptor and vascular hyperpermeability (227), and therapies that try to prevent damage to retinal blood vessels such as pigment epithelium-derived factor (PEDF) (192), angiogenin (193), and glial fibrillary acidic protein (GFAP) (228) and those that protect neurons such as the AAV vectors encoding brain-derived neurotrophic factor (BDNF) (229) and erythropoietin (EPO) (230). Some research suggests that modulating ANGPTL4 expression through gene therapy could help stabilize blood vessels and reduce vascular leakage in DR (194).…”