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A novel bispecific molecule delivered by recombinant AAV2 suppresses ocular inflammation and choroidal neovascularization
Elevated vascular endothelial growth factor (VEGF) and complement activation are implicated in the pathogenesis of different ocular diseases. The objective of this study was to investigate the hypothesis that dual inhibition of both VEGF and complement activation would confer better protection again...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543459/ https://www.ncbi.nlm.nih.gov/pubmed/28332318 http://dx.doi.org/10.1111/jcmm.13086 |
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author | Li, Yiming Zhu, Ping Verma, Amrisha Prasad, Tuhina Deng, Hongxin Yu, Dechao Li, Qiuhong |
author_facet | Li, Yiming Zhu, Ping Verma, Amrisha Prasad, Tuhina Deng, Hongxin Yu, Dechao Li, Qiuhong |
author_sort | Li, Yiming |
collection | PubMed |
description | Elevated vascular endothelial growth factor (VEGF) and complement activation are implicated in the pathogenesis of different ocular diseases. The objective of this study was to investigate the hypothesis that dual inhibition of both VEGF and complement activation would confer better protection against ocular inflammation and neovascularization. In this study, we engineered a secreted chimeric VEGF inhibitor domain (VID), a complement inhibitor domain (CID) and a dual inhibitor (ACVP1). Vectors expressing these three inhibitors were constructed and packaged into AAV2 (sextY‐F) particles. The expression and secretion of the proteins were validated by Western blot. The effects of these inhibitors expressed from AAV2 vectors were examined in endotoxin‐induced uveitis (EIU), experimental autoimmune uveoretinitis (EAU) and choroidal neovascularization (CNV) mouse models. The AAV2 vectors expressing the CID‐ and ACVP1‐attenuated inflammation in EIU and EAU model, whereas the vector expressing VID showed improved retinal structure damaged by EAU, but not affect the infiltration of inflammatory cells in EAU or EIU eyes. Both VID and CID vectors improved laser‐induced retinal and choroid/RPE injuries and CNV, whereas ACVP1 vector provided significantly better protection. Our results suggest that gene therapy targeting VEGF and complement components could provide an innovative and long‐term strategy for ocular inflammatory and neovascular diseases. |
format | Online Article Text |
id | pubmed-5543459 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-55434592017-08-09 A novel bispecific molecule delivered by recombinant AAV2 suppresses ocular inflammation and choroidal neovascularization Li, Yiming Zhu, Ping Verma, Amrisha Prasad, Tuhina Deng, Hongxin Yu, Dechao Li, Qiuhong J Cell Mol Med Original Articles Elevated vascular endothelial growth factor (VEGF) and complement activation are implicated in the pathogenesis of different ocular diseases. The objective of this study was to investigate the hypothesis that dual inhibition of both VEGF and complement activation would confer better protection against ocular inflammation and neovascularization. In this study, we engineered a secreted chimeric VEGF inhibitor domain (VID), a complement inhibitor domain (CID) and a dual inhibitor (ACVP1). Vectors expressing these three inhibitors were constructed and packaged into AAV2 (sextY‐F) particles. The expression and secretion of the proteins were validated by Western blot. The effects of these inhibitors expressed from AAV2 vectors were examined in endotoxin‐induced uveitis (EIU), experimental autoimmune uveoretinitis (EAU) and choroidal neovascularization (CNV) mouse models. The AAV2 vectors expressing the CID‐ and ACVP1‐attenuated inflammation in EIU and EAU model, whereas the vector expressing VID showed improved retinal structure damaged by EAU, but not affect the infiltration of inflammatory cells in EAU or EIU eyes. Both VID and CID vectors improved laser‐induced retinal and choroid/RPE injuries and CNV, whereas ACVP1 vector provided significantly better protection. Our results suggest that gene therapy targeting VEGF and complement components could provide an innovative and long‐term strategy for ocular inflammatory and neovascular diseases. John Wiley and Sons Inc. 2017-03-22 2017-08 /pmc/articles/PMC5543459/ /pubmed/28332318 http://dx.doi.org/10.1111/jcmm.13086 Text en © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Li, Yiming Zhu, Ping Verma, Amrisha Prasad, Tuhina Deng, Hongxin Yu, Dechao Li, Qiuhong A novel bispecific molecule delivered by recombinant AAV2 suppresses ocular inflammation and choroidal neovascularization |
title | A novel bispecific molecule delivered by recombinant AAV2 suppresses ocular inflammation and choroidal neovascularization |
title_full | A novel bispecific molecule delivered by recombinant AAV2 suppresses ocular inflammation and choroidal neovascularization |
title_fullStr | A novel bispecific molecule delivered by recombinant AAV2 suppresses ocular inflammation and choroidal neovascularization |
title_full_unstemmed | A novel bispecific molecule delivered by recombinant AAV2 suppresses ocular inflammation and choroidal neovascularization |
title_short | A novel bispecific molecule delivered by recombinant AAV2 suppresses ocular inflammation and choroidal neovascularization |
title_sort | novel bispecific molecule delivered by recombinant aav2 suppresses ocular inflammation and choroidal neovascularization |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543459/ https://www.ncbi.nlm.nih.gov/pubmed/28332318 http://dx.doi.org/10.1111/jcmm.13086 |
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