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Nme(2)Cas9‐mediated therapeutic editing in inhibiting angiogenesis after wet age‐related macular degeneration onset

BACKGROUND: Age‐related macular degeneration (AMD), particularly wet AMD characterised by choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. The hypoxia‐inducible factor‐1α (HIF‐1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway contribu...

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Autores principales: Hu, Sihui, Chen, Yuxi, Xie, Dongchun, Xu, Kan, Fu, Yunzhao, Chi, Wei, Liu, Haiying, Huang, Junjiu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440058/
https://www.ncbi.nlm.nih.gov/pubmed/37598400
http://dx.doi.org/10.1002/ctm2.1383
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author Hu, Sihui
Chen, Yuxi
Xie, Dongchun
Xu, Kan
Fu, Yunzhao
Chi, Wei
Liu, Haiying
Huang, Junjiu
author_facet Hu, Sihui
Chen, Yuxi
Xie, Dongchun
Xu, Kan
Fu, Yunzhao
Chi, Wei
Liu, Haiying
Huang, Junjiu
author_sort Hu, Sihui
collection PubMed
description BACKGROUND: Age‐related macular degeneration (AMD), particularly wet AMD characterised by choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. The hypoxia‐inducible factor‐1α (HIF‐1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway contributes to CNV pathogenesis. Previous gene editing research indicated that disrupting these genes in retinal pigment epithelial cells could have a preventive effect on CNV progression. However, no studies have yet been conducted using gene editing to disrupt VEGF signalling after CNV induction for therapeutic validation, which is critical to the clinical application of wet AMD gene editing therapies. METHOD: Here, we employed the single‐adeno‐associated virus‐mediated Nme(2)Cas9 to disrupt key molecules in VEGF signalling, Hif1α, Vegfa and Vegfr2 after inducing CNV and estimated their therapeutic effects. RESULTS: We found that Nme(2)Cas9 made efficient editing in target genes up to 71.8% post 11 days in vivo. And only Nme(2)Cas9‐Vegfa treatment during the early stage of CNV development reduced the CNV lesion area by 49.5%, compared to the negative control, while Nme(2)Cas9‐Hif1α or Nme(2)Cas9‐Vegfr2 treatment did not show therapeutic effect. Besides, no off‐target effects were observed in Nme(2)Cas9‐mediated gene editing in vivo. CONCLUSIONS: This study provides proof‐of‐concept possibility of employing Nme(2)Cas9 for potential anti‐angiogenesis therapy in wet AMD.
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spelling pubmed-104400582023-08-21 Nme(2)Cas9‐mediated therapeutic editing in inhibiting angiogenesis after wet age‐related macular degeneration onset Hu, Sihui Chen, Yuxi Xie, Dongchun Xu, Kan Fu, Yunzhao Chi, Wei Liu, Haiying Huang, Junjiu Clin Transl Med Research Articles BACKGROUND: Age‐related macular degeneration (AMD), particularly wet AMD characterised by choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. The hypoxia‐inducible factor‐1α (HIF‐1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway contributes to CNV pathogenesis. Previous gene editing research indicated that disrupting these genes in retinal pigment epithelial cells could have a preventive effect on CNV progression. However, no studies have yet been conducted using gene editing to disrupt VEGF signalling after CNV induction for therapeutic validation, which is critical to the clinical application of wet AMD gene editing therapies. METHOD: Here, we employed the single‐adeno‐associated virus‐mediated Nme(2)Cas9 to disrupt key molecules in VEGF signalling, Hif1α, Vegfa and Vegfr2 after inducing CNV and estimated their therapeutic effects. RESULTS: We found that Nme(2)Cas9 made efficient editing in target genes up to 71.8% post 11 days in vivo. And only Nme(2)Cas9‐Vegfa treatment during the early stage of CNV development reduced the CNV lesion area by 49.5%, compared to the negative control, while Nme(2)Cas9‐Hif1α or Nme(2)Cas9‐Vegfr2 treatment did not show therapeutic effect. Besides, no off‐target effects were observed in Nme(2)Cas9‐mediated gene editing in vivo. CONCLUSIONS: This study provides proof‐of‐concept possibility of employing Nme(2)Cas9 for potential anti‐angiogenesis therapy in wet AMD. John Wiley and Sons Inc. 2023-08-20 /pmc/articles/PMC10440058/ /pubmed/37598400 http://dx.doi.org/10.1002/ctm2.1383 Text en © 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Hu, Sihui
Chen, Yuxi
Xie, Dongchun
Xu, Kan
Fu, Yunzhao
Chi, Wei
Liu, Haiying
Huang, Junjiu
Nme(2)Cas9‐mediated therapeutic editing in inhibiting angiogenesis after wet age‐related macular degeneration onset
title Nme(2)Cas9‐mediated therapeutic editing in inhibiting angiogenesis after wet age‐related macular degeneration onset
title_full Nme(2)Cas9‐mediated therapeutic editing in inhibiting angiogenesis after wet age‐related macular degeneration onset
title_fullStr Nme(2)Cas9‐mediated therapeutic editing in inhibiting angiogenesis after wet age‐related macular degeneration onset
title_full_unstemmed Nme(2)Cas9‐mediated therapeutic editing in inhibiting angiogenesis after wet age‐related macular degeneration onset
title_short Nme(2)Cas9‐mediated therapeutic editing in inhibiting angiogenesis after wet age‐related macular degeneration onset
title_sort nme(2)cas9‐mediated therapeutic editing in inhibiting angiogenesis after wet age‐related macular degeneration onset
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440058/
https://www.ncbi.nlm.nih.gov/pubmed/37598400
http://dx.doi.org/10.1002/ctm2.1383
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