Systemic AAV-Mediated Gene Therapy Using Epo-R76E to Protect Retinal Ganglion Cells from Optic Nerve Injury and Disease
type: CreativeWork
description: Neuroprotection is a strategy to prevent or reduce neuronal cell death regardless of the underlying cause. Erythropoietin (EPO) exhibits neuroprotective effects in a variety of in vitro and in vivo models of neuronal cell death although its classical function is the regulation of red blood cell production. EPO crosses the blood brain barrier and therefore can be delivered systemically. However, long term treatment with exogenous EPO causes over stimulation of the erythropoietic pathway which can be lethal. The erythropoietic and neuroprotective pathways are regulated by different receptors; further, it is possible to modify EPO to primarily, if not solely, activate the receptor responsible for neuroprotection. An example of this is a novel form of EPO that we developed by altering a single amino acid, arginine to glutamate, at position 76 (EPO‑R76E). The present study uses recombinant adeno-associated virus (rAAV) gene therapy and systemic delivery of EPO‑R76E to assess treatment potential for degenerating neurons in an induced model of neurodegeneration and a spontaneous model of glaucoma. Optic nerve crush is a model of retinal ganglion cell (RGC) death. Crushing the optic nerve causes the axons to undergo Wallerian degeneration and apoptotic loss of retinal ganglion cells over time. This pattern of cell death is very similar to that observed in glaucoma. The BALB/cByJ mouse strain is highly susceptible to optic nerve crush and therefore was selected to examine the potential effects of EPO‑R76E as a neuroprotectant. Mice received a single intramuscular injection of rAAV carrying either Epo or EpoR76E. Upon reaching peak gene expression (30 days), mice were subjected to optic nerve crush. Neuronal cell death was examined in both the ganglion cell layer and the optic nerve. Treatment with either Epo vector resulted in a significantly greater amount of cells at the ganglion cell layer compared to crushed controls but had no effect on axon number. The observed protect…
abstract: Neuroprotection is a strategy to prevent or reduce neuronal cell death regardless of the underlying cause. Erythropoietin (EPO) exhibits neuroprotective effects in a variety of in vitro and in vivo models of neuronal cell death although its classical function is the regulation of red blood cell production. EPO crosses the blood brain barrier and therefore can be delivered systemically. However, long term treatment with exogenous EPO causes over stimulation of the erythropoietic pathway which can be lethal. The erythropoietic and neuroprotective pathways are regulated by different receptors; further, it is possible to modify EPO to primarily, if not solely, activate the receptor responsible for neuroprotection. An example of this is a novel form of EPO that we developed by altering a single amino acid, arginine to glutamate, at position 76 (EPO‑R76E). The present study uses recombinant adeno-associated virus (rAAV) gene therapy and systemic delivery of EPO‑R76E to assess treatment potential for degenerating neurons in an induced model of neurodegeneration and a spontaneous model of glaucoma. Optic nerve crush is a model of retinal ganglion cell (RGC) death. Crushing the optic nerve causes the axons to undergo Wallerian degeneration and apoptotic loss of retinal ganglion cells over time. This pattern of cell death is very similar to that observed in glaucoma. The BALB/cByJ mouse strain is highly susceptible to optic nerve crush and therefore was selected to examine the potential effects of EPO‑R76E as a neuroprotectant. Mice received a single intramuscular injection of rAAV carrying either Epo or EpoR76E. Upon reaching peak gene expression (30 days), mice were subjected to optic nerve crush. Neuronal cell death was examined in both the ganglion cell layer and the optic nerve. Treatment with either Epo vector resulted in a significantly greater amount of cells at the ganglion cell layer compared to crushed controls but had no effect on axon number. The observed protect…
author: Sullivan, Timothy A.
keywords: Adeno-associated virus, DBA/2J mouse, Erythropoietin, Gene therapy, Glaucoma, Optic nerve crush, Medical Pharmacology, Medicine and Health Sciences
date published: 2011-05-01T07:00:00Z
date modified: 2026-07-24T05:00:23Z
provider: University of Tennessee Health Science Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Tennessee Health Science Center