Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium
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 ef...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-05-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/10/6/842 |
| _version_ | 1797532762513604608 |
|---|---|
| author | Manas R. Biswal Zhaoyao Wang Ryan J. Paulson Rukshana R. Uddin Yao Tong Ping Zhu Hong Li Alfred S. Lewin |
| author_facet | Manas R. Biswal Zhaoyao Wang Ryan J. Paulson Rukshana R. Uddin Yao Tong Ping Zhu Hong Li Alfred S. Lewin |
| author_sort | Manas R. Biswal |
| collection | DOAJ |
| description | 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 <i>Sod2</i>) 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 <i>Sod2</i> 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. |
| first_indexed | 2024-03-10T11:04:55Z |
| format | Article |
| id | doaj.art-e9e523031615417a904875ba17e0dfb5 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T11:04:55Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-e9e523031615417a904875ba17e0dfb52023-11-21T21:15:47ZengMDPI AGAntioxidants2076-39212021-05-0110684210.3390/antiox10060842Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment EpitheliumManas R. Biswal0Zhaoyao Wang1Ryan J. Paulson2Rukshana R. Uddin3Yao Tong4Ping Zhu5Hong Li6Alfred S. Lewin7Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USADepartment of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USADepartment of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Ophthalmology, University of Florida College of Medicine, Gainesville, FL 32610, USADepartment of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USAErythropoietin (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 <i>Sod2</i>) 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 <i>Sod2</i> 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.https://www.mdpi.com/2076-3921/10/6/842age related macular degenerationoxidative stressMnSODRPEretinal degenerationerythropoietin |
| spellingShingle | Manas R. Biswal Zhaoyao Wang Ryan J. Paulson Rukshana R. Uddin Yao Tong Ping Zhu Hong Li Alfred S. Lewin Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium Antioxidants age related macular degeneration oxidative stress MnSOD RPE retinal degeneration erythropoietin |
| title | Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium |
| title_full | Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium |
| title_fullStr | Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium |
| title_full_unstemmed | Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium |
| title_short | Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium |
| title_sort | erythropoietin gene therapy delays retinal degeneration resulting from oxidative stress in the retinal pigment epithelium |
| topic | age related macular degeneration oxidative stress MnSOD RPE retinal degeneration erythropoietin |
| url | https://www.mdpi.com/2076-3921/10/6/842 |
| work_keys_str_mv | AT manasrbiswal erythropoietingenetherapydelaysretinaldegenerationresultingfromoxidativestressintheretinalpigmentepithelium AT zhaoyaowang erythropoietingenetherapydelaysretinaldegenerationresultingfromoxidativestressintheretinalpigmentepithelium AT ryanjpaulson erythropoietingenetherapydelaysretinaldegenerationresultingfromoxidativestressintheretinalpigmentepithelium AT rukshanaruddin erythropoietingenetherapydelaysretinaldegenerationresultingfromoxidativestressintheretinalpigmentepithelium AT yaotong erythropoietingenetherapydelaysretinaldegenerationresultingfromoxidativestressintheretinalpigmentepithelium AT pingzhu erythropoietingenetherapydelaysretinaldegenerationresultingfromoxidativestressintheretinalpigmentepithelium AT hongli erythropoietingenetherapydelaysretinaldegenerationresultingfromoxidativestressintheretinalpigmentepithelium AT alfredslewin erythropoietingenetherapydelaysretinaldegenerationresultingfromoxidativestressintheretinalpigmentepithelium |