Systemic Adeno-Associated Virus-Mediated Gene Therapy Preserves Retinal Ganglion Cells and Visual Function in DBA/2J Glaucomatous Mice

A slow progressive death of neurons is the hallmark of neurodegenerative diseases, such as glaucoma. A therapeutic candidate, erythropoietin (EPO), has shown promise in many models of these diseases; however, it also causes polycythemia, a potentially lethal side effect. We have developed a novel mu...

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Veröffentlicht in:Human gene therapy 2011-10, Vol.22 (10), p.1191-1200
Hauptverfasser: SULLIVAN, Timothy A, GEISERT, Eldon E, HINES-BEARD, Jessica, REX, Tonia S
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container_end_page 1200
container_issue 10
container_start_page 1191
container_title Human gene therapy
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creator SULLIVAN, Timothy A
GEISERT, Eldon E
HINES-BEARD, Jessica
REX, Tonia S
description A slow progressive death of neurons is the hallmark of neurodegenerative diseases, such as glaucoma. A therapeutic candidate, erythropoietin (EPO), has shown promise in many models of these diseases; however, it also causes polycythemia, a potentially lethal side effect. We have developed a novel mutant form of EPO that is neuroprotective but no longer erythropoietic by altering a single amino acid (arginine to glutamate at position 76; R76E). We hypothesized that a single intramuscular injection of recombinant adeno-associated virus carrying EpoR76E (rAAV2/5.CMV.EpoR76E) would protect retinal ganglion cells in a mouse model of glaucoma without inducing polycythemia. This systemic treatment not only protected the retinal ganglion cell somata located within the retina; it also preserved axonal projections within the optic nerve, while maintaining the hematocrit within normal limits. The rescued retinal ganglion cells retained their visual function demonstrated by flash visual evoked potentials. To our knowledge, this is the first demonstration of a therapy that protects neurons from death and prevents loss of visual function from the slow neurodegenerative effects of glaucoma. Because of its broad range of cellular targets, EpoR76E is likely to be successful in treating other neurodegenerative diseases as well.
doi_str_mv 10.1089/hum.2011.052
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A therapeutic candidate, erythropoietin (EPO), has shown promise in many models of these diseases; however, it also causes polycythemia, a potentially lethal side effect. We have developed a novel mutant form of EPO that is neuroprotective but no longer erythropoietic by altering a single amino acid (arginine to glutamate at position 76; R76E). We hypothesized that a single intramuscular injection of recombinant adeno-associated virus carrying EpoR76E (rAAV2/5.CMV.EpoR76E) would protect retinal ganglion cells in a mouse model of glaucoma without inducing polycythemia. This systemic treatment not only protected the retinal ganglion cell somata located within the retina; it also preserved axonal projections within the optic nerve, while maintaining the hematocrit within normal limits. The rescued retinal ganglion cells retained their visual function demonstrated by flash visual evoked potentials. To our knowledge, this is the first demonstration of a therapy that protects neurons from death and prevents loss of visual function from the slow neurodegenerative effects of glaucoma. Because of its broad range of cellular targets, EpoR76E is likely to be successful in treating other neurodegenerative diseases as well.</description><identifier>ISSN: 1043-0342</identifier><identifier>EISSN: 1557-7422</identifier><identifier>DOI: 10.1089/hum.2011.052</identifier><identifier>PMID: 21542676</identifier><identifier>CODEN: HGTHE3</identifier><language>eng</language><publisher>Larchmont, NY: Liebert</publisher><subject>Adeno-associated virus ; Analysis of Variance ; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; Animals ; Applied cell therapy and gene therapy ; Axons - drug effects ; Biological and medical sciences ; Biotechnology ; Care and treatment ; Dependovirus ; Dependoviruses ; Enzyme-Linked Immunosorbent Assay ; Erythropoietin ; Erythropoietin - administration &amp; dosage ; Erythropoietin - genetics ; Erythropoietin - pharmacology ; Evoked Potentials, Visual - physiology ; Fundamental and applied biological sciences. Psychology ; Gene therapy ; Genetic Therapy - methods ; Genetic Vectors - administration &amp; dosage ; Genetic Vectors - genetics ; Genetic Vectors - pharmacology ; Glaucoma ; Glaucoma - genetics ; Glaucoma - therapy ; Health aspects ; Health. Pharmaceutical industry ; Hematocrit ; Immunohistochemistry ; Industrial applications and implications. Economical aspects ; Injections, Intramuscular ; Macaca mulatta - genetics ; Medical sciences ; Mice ; Mice, Inbred DBA ; Mutation, Missense - genetics ; Optic Nerve - drug effects ; Optic Nerve - pathology ; Physiological aspects ; Retinal Ganglion Cells - drug effects ; Transfusions. Complications. Transfusion reactions. 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A therapeutic candidate, erythropoietin (EPO), has shown promise in many models of these diseases; however, it also causes polycythemia, a potentially lethal side effect. We have developed a novel mutant form of EPO that is neuroprotective but no longer erythropoietic by altering a single amino acid (arginine to glutamate at position 76; R76E). We hypothesized that a single intramuscular injection of recombinant adeno-associated virus carrying EpoR76E (rAAV2/5.CMV.EpoR76E) would protect retinal ganglion cells in a mouse model of glaucoma without inducing polycythemia. This systemic treatment not only protected the retinal ganglion cell somata located within the retina; it also preserved axonal projections within the optic nerve, while maintaining the hematocrit within normal limits. The rescued retinal ganglion cells retained their visual function demonstrated by flash visual evoked potentials. To our knowledge, this is the first demonstration of a therapy that protects neurons from death and prevents loss of visual function from the slow neurodegenerative effects of glaucoma. Because of its broad range of cellular targets, EpoR76E is likely to be successful in treating other neurodegenerative diseases as well.</description><subject>Adeno-associated virus</subject><subject>Analysis of Variance</subject><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</subject><subject>Animals</subject><subject>Applied cell therapy and gene therapy</subject><subject>Axons - drug effects</subject><subject>Biological and medical sciences</subject><subject>Biotechnology</subject><subject>Care and treatment</subject><subject>Dependovirus</subject><subject>Dependoviruses</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Erythropoietin</subject><subject>Erythropoietin - administration &amp; dosage</subject><subject>Erythropoietin - genetics</subject><subject>Erythropoietin - pharmacology</subject><subject>Evoked Potentials, Visual - physiology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene therapy</subject><subject>Genetic Therapy - methods</subject><subject>Genetic Vectors - administration &amp; dosage</subject><subject>Genetic Vectors - genetics</subject><subject>Genetic Vectors - pharmacology</subject><subject>Glaucoma</subject><subject>Glaucoma - genetics</subject><subject>Glaucoma - therapy</subject><subject>Health aspects</subject><subject>Health. Pharmaceutical industry</subject><subject>Hematocrit</subject><subject>Immunohistochemistry</subject><subject>Industrial applications and implications. Economical aspects</subject><subject>Injections, Intramuscular</subject><subject>Macaca mulatta - genetics</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred DBA</subject><subject>Mutation, Missense - genetics</subject><subject>Optic Nerve - drug effects</subject><subject>Optic Nerve - pathology</subject><subject>Physiological aspects</subject><subject>Retinal Ganglion Cells - drug effects</subject><subject>Transfusions. Complications. Transfusion reactions. 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subjects Adeno-associated virus
Analysis of Variance
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Applied cell therapy and gene therapy
Axons - drug effects
Biological and medical sciences
Biotechnology
Care and treatment
Dependovirus
Dependoviruses
Enzyme-Linked Immunosorbent Assay
Erythropoietin
Erythropoietin - administration & dosage
Erythropoietin - genetics
Erythropoietin - pharmacology
Evoked Potentials, Visual - physiology
Fundamental and applied biological sciences. Psychology
Gene therapy
Genetic Therapy - methods
Genetic Vectors - administration & dosage
Genetic Vectors - genetics
Genetic Vectors - pharmacology
Glaucoma
Glaucoma - genetics
Glaucoma - therapy
Health aspects
Health. Pharmaceutical industry
Hematocrit
Immunohistochemistry
Industrial applications and implications. Economical aspects
Injections, Intramuscular
Macaca mulatta - genetics
Medical sciences
Mice
Mice, Inbred DBA
Mutation, Missense - genetics
Optic Nerve - drug effects
Optic Nerve - pathology
Physiological aspects
Retinal Ganglion Cells - drug effects
Transfusions. Complications. Transfusion reactions. Cell and gene therapy
Vision, Ocular - drug effects
title Systemic Adeno-Associated Virus-Mediated Gene Therapy Preserves Retinal Ganglion Cells and Visual Function in DBA/2J Glaucomatous Mice
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