Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degeneration
Inhibition of vascular endothelial growth factor (VEGF) is the standard therapy for neovascular age-related macular degeneration (nAMD). However, anti-VEGF agents used in the clinic require repeated injections, causing adverse effects. Gene therapy could provide sustained anti-VEGF levels after a si...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-03-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050122000031 |
| _version_ | 1819349548028395520 |
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| author | Kaiqin She Jing Su Qingnan Wang Yi Liu Xiaomei Zhong Xiu Jin Qinyu Zhao Jianlu Xiao Ruiting Li Hongxin Deng Fang Lu Yang Yang Yuquan Wei |
| author_facet | Kaiqin She Jing Su Qingnan Wang Yi Liu Xiaomei Zhong Xiu Jin Qinyu Zhao Jianlu Xiao Ruiting Li Hongxin Deng Fang Lu Yang Yang Yuquan Wei |
| author_sort | Kaiqin She |
| collection | DOAJ |
| description | Inhibition of vascular endothelial growth factor (VEGF) is the standard therapy for neovascular age-related macular degeneration (nAMD). However, anti-VEGF agents used in the clinic require repeated injections, causing adverse effects. Gene therapy could provide sustained anti-VEGF levels after a single injection, thereby drastically decreasing the treatment burden and improving visual outcomes. In this study, we developed a novel VEGF Trap, nVEGFi, containing domains 1 and 2 of VEGFR1 and domain 3 of VEGFR2 fused to the Fc portion of human IgG. The nVEGFi had a higher expression level than aflibercept under the same expression cassettes of adeno-associated virus (AAV)8 in vitro and in vivo. nVEGFi was found to be noninferior to aflibercept in binding and blocking VEGF in vitro. AAV8-mediated expression of nVEGFi was maintained for at least 12 weeks by subretinal delivery in C57BL/6J mice. In a mouse laser-induced choroidal neovascularization (CNV) model, 4 × 108 genome copies of AAV8-nVEGFi exhibited a significantly increased reduction in the CNV area compared with AAV8-aflibercept (78.1% vs. 63.9%, p < 0.05), while causing no structural or functional changes to the retina. In conclusion, this preclinical study showed that subretinal injection of AAV8-nVEGFi was long lasting, well tolerated, and effective for nAMD treatment, supporting future translation to the clinic. |
| first_indexed | 2024-12-24T19:02:16Z |
| format | Article |
| id | doaj.art-d6915cfab3f34df6834ede0be746c902 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-24T19:02:16Z |
| publishDate | 2022-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-d6915cfab3f34df6834ede0be746c9022022-12-21T16:43:11ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012022-03-0124210221Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degenerationKaiqin She0Jing Su1Qingnan Wang2Yi Liu3Xiaomei Zhong4Xiu Jin5Qinyu Zhao6Jianlu Xiao7Ruiting Li8Hongxin Deng9Fang Lu10Yang Yang11Yuquan Wei12Department of Ophthalmology, West China Hospital, Sichuan University, No.37, Guoxue Xiang, Chengdu, Sichuan 610041, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, ChinaDepartment of Ophthalmology, West China Hospital, Sichuan University, No.37, Guoxue Xiang, Chengdu, Sichuan 610041, China; Corresponding author: Department of Ophthalmology, West China Hospital, Sichuan University, No.37, Guoxue Xiang, Chengdu, Sichuan 610041, China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China; Corresponding author: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, China.State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 1, Ke-yuan Road 4, Gao-peng Street, Chengdu, Sichuan 610041, ChinaInhibition of vascular endothelial growth factor (VEGF) is the standard therapy for neovascular age-related macular degeneration (nAMD). However, anti-VEGF agents used in the clinic require repeated injections, causing adverse effects. Gene therapy could provide sustained anti-VEGF levels after a single injection, thereby drastically decreasing the treatment burden and improving visual outcomes. In this study, we developed a novel VEGF Trap, nVEGFi, containing domains 1 and 2 of VEGFR1 and domain 3 of VEGFR2 fused to the Fc portion of human IgG. The nVEGFi had a higher expression level than aflibercept under the same expression cassettes of adeno-associated virus (AAV)8 in vitro and in vivo. nVEGFi was found to be noninferior to aflibercept in binding and blocking VEGF in vitro. AAV8-mediated expression of nVEGFi was maintained for at least 12 weeks by subretinal delivery in C57BL/6J mice. In a mouse laser-induced choroidal neovascularization (CNV) model, 4 × 108 genome copies of AAV8-nVEGFi exhibited a significantly increased reduction in the CNV area compared with AAV8-aflibercept (78.1% vs. 63.9%, p < 0.05), while causing no structural or functional changes to the retina. In conclusion, this preclinical study showed that subretinal injection of AAV8-nVEGFi was long lasting, well tolerated, and effective for nAMD treatment, supporting future translation to the clinic.http://www.sciencedirect.com/science/article/pii/S2329050122000031neovascular age-related macular degenerationanti-vascular endothelial growth factorchoroidal neovascularizationVEGF trapgene therapyadeno-associated virus |
| spellingShingle | Kaiqin She Jing Su Qingnan Wang Yi Liu Xiaomei Zhong Xiu Jin Qinyu Zhao Jianlu Xiao Ruiting Li Hongxin Deng Fang Lu Yang Yang Yuquan Wei Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degeneration Molecular Therapy: Methods & Clinical Development neovascular age-related macular degeneration anti-vascular endothelial growth factor choroidal neovascularization VEGF trap gene therapy adeno-associated virus |
| title | Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degeneration |
| title_full | Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degeneration |
| title_fullStr | Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degeneration |
| title_full_unstemmed | Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degeneration |
| title_short | Delivery of nVEGFi using AAV8 for the treatment of neovascular age-related macular degeneration |
| title_sort | delivery of nvegfi using aav8 for the treatment of neovascular age related macular degeneration |
| topic | neovascular age-related macular degeneration anti-vascular endothelial growth factor choroidal neovascularization VEGF trap gene therapy adeno-associated virus |
| url | http://www.sciencedirect.com/science/article/pii/S2329050122000031 |
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