Erythropoietin Receptor Signaling Supports Retinal Function after Vascular Injury

Bretz, Colin A.; Simmons, Aaron B.; Kunz, Eric; Ramshekar, Aniket; Kennedy, Carson; Cardenas, Ivan A; Hartnett, M. Elizabeth

doi:10.1016/j.ajpath.2019.11.009

Cited by 14 publications

(12 citation statements)

References 44 publications

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“…EPO signaling increases choroidal macrophages and cytokine expression and exacerbates choroidal neovascularization, conditions associated with the advanced wet-form of AMD [73]. EPO receptor signaling supports retinal function after vascular injury [74], but its pro-angiogenic properties may limit the usefulness of unregulated EPO expression as a therapy for dry AMD. We plan to determine if EPO-R76E stimulated choroidal neovascularization (CNV) using the laser-induced CNV model.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium

et al. 2021

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Erythropoietin (EPO) plays an important role in erythropoiesis by its action in blocking apoptosis of progenitor cells and protects both photoreceptors and retinal ganglion cells from induced or inherited degeneration. A modified form of EPO, EPO-R76E has attenuated erythropoietic activity but is effective in inhibiting apoptosis, oxidative stress, and inflammation in several models of retinal degeneration. In this study, we used recombinant Adeno Associated Virus (AAV) to provide long-term sustained delivery of EPO-R76E and demonstrated its effects in a mouse model of dry-AMD in which retinal degeneration is induced by oxidative stress in the retinal pigment epithelial (RPE) cells. 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 EPO expression. Retinal function was monitored by electroretinography (ERG). EPO-R76E over-expression in RPE delayed the 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, which is implicated as a potential cause of Age-Related Macular Degeneration.

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Section: Discussionmentioning

confidence: 99%

Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium

et al. 2021

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“…The effect of cibinetide in retinal function may possibly relate to its apparent neuroprotective effects [ 11 , 27 , 28 ]. Neuroprotective effects in the retina in experimental diabetic retinopathy models have also been observed with EPO [ 29 , 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

A Phase 2 Clinical Trial on the Use of Cibinetide for the Treatment of Diabetic Macular Edema

Lois

Gardner

McFarland

et al. 2020

JCM

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Purpose: Evaluating the effects of cibinetide in diabetic macular edema (DME). Methods: Phase 2 trial. Naïve patients with >400 µm central retinal thickness (CRT) DME in one/both eyes were recruited (May 2016–April 2017) at the Belfast Health and Social Care Trust. The study eye was that with best vision and lowest CRT. Patients self-administered cibinetide 4 mg/day subcutaneously for 12 weeks. Primary and secondary outcomes: mean change from baseline to week 12 in best corrected visual acuity (BCVA), CRT, central retinal sensitivity, tear production, patient-reported outcomes, adverse events and antibodies to cibinetide. Descriptive statistics were used; exploratory analyses focused on non-study eyes, diabetic control, serum cytokines and albuminuria. Results: Nine patients were recruited; eight completed the study. There was no improvement in mean change baseline-week 12 in BCVA (−2.9 + 5.0), CRT (10 + 94.6 microns), central retinal sensitivity (−0.53 + 1.9 dB) or tear production (−0.13 + 7.7 mm), but there was an improvement in National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite scores (2.7 + 3.1). Some participants experienced improvements in CRT, tear production, diabetic control and albuminuria. No serious adverse events/reactions or anti-cibinetide antibodies were seen. Conclusions: The cibinetide 12-week course was safe. Improvements in NEI VFQ-25 scores, CRT, tear production, diabetic control and albuminuria, observed in some participants, warrant further investigation. Trial Registration: EudraCT number: 2015-001940-12. ISRCTN16962255—registration date 25.06.15.

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“…Although multicenter clinical trials and meta-analysis testing exogenous EPO in premature infants did not find evidence of neuroprotection or worsened severity of ROP [ 21 , 22 , 23 ], another study suggests that EPO is beneficial to the preterm infant without affecting ROP [ 24 ]. Other studies, particularly preclinical data, suggest EPO does affect ROP pathophysiology [ 25 , 26 , 27 , 28 , 29 ]. This article will review the role of NOXs in physiologic and pathologic angiogenesis from studies over the past five years and dissect the role of EPO in ROP development and in reducing oxidative stress in angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Erythropoietin, and Their Interactions in Angiogenesis: Implications in Retinopathy of Prematurity

Cung

Wang

Hartnett

2022

Cells

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Retinopathy of prematurity (ROP) is a leading cause of vision impairment and blindness in premature infants. Oxidative stress is implicated in its pathophysiology. NADPH oxidase (NOX), a major enzyme responsible for reactive oxygen species (ROS) generation in endothelial cells, has been studied for its involvement in physiologic and pathologic angiogenesis. Erythropoietin (EPO) has gained interest recently due to its tissue protective and angiogenic effects, and it has been shown to act as an antioxidant. In this review, we summarize studies performed over the last five years regarding the role of various NOXs in physiologic and pathologic angiogenesis. We also discuss the effect of EPO in tissue and vasoprotection, and the intersection of EPO and NOX-mediated oxidative stress in angiogenesis and the pathophysiology of ROP.

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Erythropoietin Receptor Signaling Supports Retinal Function after Vascular Injury

Cited by 14 publications

References 44 publications

Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium

Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium

A Phase 2 Clinical Trial on the Use of Cibinetide for the Treatment of Diabetic Macular Edema

The Effects of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Erythropoietin, and Their Interactions in Angiogenesis: Implications in Retinopathy of Prematurity

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