Systemic but not intraocular Epo Gene Transfer Protects the Retina from Light-and Genetic-Induced Degeneration

Abstract

Molecules with neurotrophic activity are being evaluated for treatment of retinitis pigmentosa in animal models. In particular, great interest has been focused recently on erythropoietin (Epo). Evidence of its neurotrophic activity comes mainly from data demonstrating photoreceptor protection in a rodent light-damage model through systemic administration of a recombinant form of this hormone. Our goal was to test whether Epo retinal gene transfer can rescue or delay photoreceptor cell death. We delivered adeno-associated viral vectors encoding Epo intraocularly and, for comparison, intramuscularly to one light-induced and two genetic models of retinal degeneration. Intraocular Epo gene transfer resulted in sustained hormone expression in the eye, which was undetectable systemically. In contrast, Epo intramuscular gene transfer resulted in hormone secretion in the circulation, which was not detected in ocular fluids. The protein secreted from muscle and retina is of the same molecular weight as a commercial recombinant human Epo. Interestingly, following systemic but not intraocular Epo delivery, morphological photoreceptor protection was observed in the light-damage and rds/peripherin (Prph2) models of retinal degeneration. In the light-damage model, the morphological rescue was accompanied by a significant electrophysiological improvement of photoreceptor function. In contrast, no photoreceptor rescue was observed following Epo gene transfer in the rd10 model. This suggests that different apoptotic mechanisms, with varying sensitivities to Epo, occur in different retinal degeneration models. In conclusion, our data support Epo as a neuroprotective agent in some, but not all, retinal degenerations. Further, rescue is observed in specific models after systemic but not intraocular Epo gene transfer.

Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy

“…Activation of HIF under hyperoxic conditions caused an upregulation of proangiogenic molecules Epo and VEGF that likely prevent vascular loss, ischemia, and subsequent proliferative retinopathy. Previous studies have demonstrated a deficiency of Epo during phase I of retinopathy and a protective effect in terms of vascular and neuronal survival after Epo supplementation early in phase I of the disease (16) or in other models of oxygen-induced retinal degeneration (17). Under normal O 2 tension, HIF-␣ subunits are rapidly degraded via PHD-dependent interactions with the von Hippel-Lindau protein, which is a component of the E3 ubiquitin ligase complex, resulting in degradation of the complex (10).…”

Revisiting the role of erythropoietin for treatment of ocular disorders

“…Several distinguished investigations addressed the properties of the EPO to mediate protection against retinal damage through anti-apoptotic, 29,30 anti-oxidant, 22 and antiinflammatory 26,31 actions in hypoxia-, light-, and geneticinduced models. 5,8,12,15 Furthermore, Chung et al 20 reported on his finding for the expression of EPO and Figure 2 The role of erythropoietin in eye development via anti-apoptotic action. Binding of EPO/EPOR induces JAK2 phosphorylation, dimerization, and subsequently, activation of several tyrosine residues forming docking site for STAT, NF-κB, PI3-K/Akt, and MAPK.…”

“…2,13,14,98,99 Based on the positive pre-clinical outcomes with various animal models, 5,8,12,15 EPO may offer a promising future therapy for treatment of many common ocular disorders plaguing us today such as DR, retinal detachment, glaucoma, retinopathy of prematurity, AMD, and optic neuritis. Current clinical trials are using established recombinant EPO such as epoietin alfa 100,101 and darbepoietin, 100,102 which do not specifically target to correct nerve circuitry activity in the eye.…”

“…1 However, ample studies have evinced the presence of EPO protein and its receptors in extra-hematopoietic tissues including the retina tissue. 2,3 In adults, there is a wide distribution of EPO and EPO receptors (EPOR) reported on the human retinal tissue [4][5][6][7] and retinal pigment epithelium (RPE) 4 (Figure 1). According to Grimm et al, 8 EPOR expression was initially found to localize on the inner segments and synaptic terminals of the photoreceptors.…”

Safety and efficacy of intravitreal injection of recombinant erythropoietin for protection of photoreceptor cells in a rat model of retinal detachment

“…1 An increasing number of studies have demonstrated the neuroprotective effects of EPO and its receptor, by anti-apoptotic mechanisms. Several studies have indicated that EPO can protect photoreceptor cells from the effects of lightinduced and hereditary retinal dystrophy; [2][3][4][5] protect retinal neurons from ischemiareperfusion injury, 6 and retinal ganglion cells after acute and chronic ocular hypertension; [7][8][9] promote ganglion cell survival and axonal regeneration after optic nerve transection; [10][11][12] attenuate inflammation in multiple sclerosis optic neuritis; 13,14 reduce the permeability of the retinal barrier and protect retinal neurons in diabetic retinopathy; [15][16][17][18] relieve diabetic macular edema; 19 enhance the stability of hypoxic retinal vessels; 20,21 and has a neuroprotective role in pigment epithelial cells subjected to photo-oxidative damage. 22 EPO exerts its biological effects through interaction with EPO receptor (EPOR).…”