Erythropoietin Gene Therapy Delays Retinal Degeneration Resulting from Oxidative Stress in the Retinal Pigment Epithelium
| Autor: | Alfred S. Lewin, Zhaoyao Wang, Ryan J Paulson, Ping Zhu, Yao Tong, Hong Li, Rukshana R Uddin, Manas R. Biswal |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Retinal degeneration MnSOD Physiology age related macular degeneration Clinical Biochemistry RM1-950 medicine.disease_cause Biochemistry Retinal ganglion 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine oxidative stress Molecular Biology Retinal pigment epithelium medicine.diagnostic_test business.industry Communication animal model Retinal AAV Cell Biology Macular degeneration medicine.disease gene therapy eye diseases Cell biology 030104 developmental biology medicine.anatomical_structure chemistry ERG Knockout mouse 030221 ophthalmology & optometry retinal degeneration Therapeutics. Pharmacology sense organs RPE erythropoietin business Oxidative stress Electroretinography |
| Zdroj: | Antioxidants Antioxidants, Vol 10, Iss 842, p 842 (2021) |
| ISSN: | 2076-3921 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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