An Engineered Intravitreal Injection Retinal-Pigment-Epithelium-Tropic Adeno-Associated Virus Vector Expressing a Bispecific Antibody Binding VEGF-A and ANG-2 Rescues Neovascular Age-Related Macular Degeneration in Animal Models and Patients
Antiangiogenesis gene therapy based on adeno-associated virus (AAV) vectors represents a promising advancement in the treatment of neovascular age-related macular degeneration (nAMD), providing an alternative to antibody-based therapies. However, the development of a safe and effective AAV vector ca...
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American Association for the Advancement of Science (AAAS)
2025-01-01
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| Series: | Research |
| Online Access: | https://spj.science.org/doi/10.34133/research.0717 |
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| author | Yuan Cai Yonghao Gu Jie Zhang Ying Zhu Zhen Ma Qin He Yongjia Sun Mengmeng Yuan Xiaojun Li Kai Zhu Bolong Miao Jin Zhao Juan Liu Min Tang Dali Tong Lixia Feng Ming Ma Guisheng Zhong Zilong Qiu Tian Xue |
| author_facet | Yuan Cai Yonghao Gu Jie Zhang Ying Zhu Zhen Ma Qin He Yongjia Sun Mengmeng Yuan Xiaojun Li Kai Zhu Bolong Miao Jin Zhao Juan Liu Min Tang Dali Tong Lixia Feng Ming Ma Guisheng Zhong Zilong Qiu Tian Xue |
| author_sort | Yuan Cai |
| collection | DOAJ |
| description | Antiangiogenesis gene therapy based on adeno-associated virus (AAV) vectors represents a promising advancement in the treatment of neovascular age-related macular degeneration (nAMD), providing an alternative to antibody-based therapies. However, the development of a safe and effective AAV vector capable of precisely targeting neovascularization and choroidal leakage remains a critical unmet need. In the present study, we engineered a novel intravitreally administered AAV vector with retinal-pigment-epithelium (RPE)-specific tropism. This vector demonstrated robust and localized gene expression in RPE cells while maintaining a favorable safety profile. The RPE-tropic AAV vector delivered a dual-acting antibody against vascular endothelial growth factor (VEGF) and angiopoietin-2 (ANG-2), exhibiting strong therapeutic efficacy and tolerability in both rodent and nonhuman primate choroidal neovascularization models. Based on the promising preclinical data, a single-center, single-arm, investigator-initiated trial (ChiCTR2400085329) was conducted to assess its safety and efficacy in patients with nAMD. The RPE-tropic AAV vector expressing anti-VEGF-A and anti-ANG-2 effectively alleviated disease progression and was well tolerated in the clinical setting. These findings highlight the potential of this engineered AAV-RPE capsid as a versatile platform for gene therapy, not only for nAMD but also for other ocular diseases involving RPE cells. |
| format | Article |
| id | doaj-art-5a528aebc28846cc9a0cca352121b264 |
| institution | DOAJ |
| issn | 2639-5274 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | Article |
| series | Research |
| spelling | doaj-art-5a528aebc28846cc9a0cca352121b2642025-08-20T03:21:32ZengAmerican Association for the Advancement of Science (AAAS)Research2639-52742025-01-01810.34133/research.0717An Engineered Intravitreal Injection Retinal-Pigment-Epithelium-Tropic Adeno-Associated Virus Vector Expressing a Bispecific Antibody Binding VEGF-A and ANG-2 Rescues Neovascular Age-Related Macular Degeneration in Animal Models and PatientsYuan Cai0Yonghao Gu1Jie Zhang2Ying Zhu3Zhen Ma4Qin He5Yongjia Sun6Mengmeng Yuan7Xiaojun Li8Kai Zhu9Bolong Miao10Jin Zhao11Juan Liu12Min Tang13Dali Tong14Lixia Feng15Ming Ma16Guisheng Zhong17Zilong Qiu18Tian Xue19First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.Starrygene Therapeutics Company Limited, Hefei 230031, China.Starrygene Therapeutics Company Limited, Hefei 230031, China.Starrygene Therapeutics Company Limited, Hefei 230031, China.First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.Starrygene Therapeutics Company Limited, Hefei 230031, China.First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.Starrygene Therapeutics Company Limited, Hefei 230031, China.Starrygene Therapeutics Company Limited, Hefei 230031, China.Starrygene Therapeutics Company Limited, Hefei 230031, China.Starrygene Therapeutics Company Limited, Hefei 230031, China.First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China.First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.iHuman Institute, ShanghaiTech University, Shanghai 201210, China.Starrygene Therapeutics Company Limited, Hefei 230031, China.First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.Antiangiogenesis gene therapy based on adeno-associated virus (AAV) vectors represents a promising advancement in the treatment of neovascular age-related macular degeneration (nAMD), providing an alternative to antibody-based therapies. However, the development of a safe and effective AAV vector capable of precisely targeting neovascularization and choroidal leakage remains a critical unmet need. In the present study, we engineered a novel intravitreally administered AAV vector with retinal-pigment-epithelium (RPE)-specific tropism. This vector demonstrated robust and localized gene expression in RPE cells while maintaining a favorable safety profile. The RPE-tropic AAV vector delivered a dual-acting antibody against vascular endothelial growth factor (VEGF) and angiopoietin-2 (ANG-2), exhibiting strong therapeutic efficacy and tolerability in both rodent and nonhuman primate choroidal neovascularization models. Based on the promising preclinical data, a single-center, single-arm, investigator-initiated trial (ChiCTR2400085329) was conducted to assess its safety and efficacy in patients with nAMD. The RPE-tropic AAV vector expressing anti-VEGF-A and anti-ANG-2 effectively alleviated disease progression and was well tolerated in the clinical setting. These findings highlight the potential of this engineered AAV-RPE capsid as a versatile platform for gene therapy, not only for nAMD but also for other ocular diseases involving RPE cells.https://spj.science.org/doi/10.34133/research.0717 |
| spellingShingle | Yuan Cai Yonghao Gu Jie Zhang Ying Zhu Zhen Ma Qin He Yongjia Sun Mengmeng Yuan Xiaojun Li Kai Zhu Bolong Miao Jin Zhao Juan Liu Min Tang Dali Tong Lixia Feng Ming Ma Guisheng Zhong Zilong Qiu Tian Xue An Engineered Intravitreal Injection Retinal-Pigment-Epithelium-Tropic Adeno-Associated Virus Vector Expressing a Bispecific Antibody Binding VEGF-A and ANG-2 Rescues Neovascular Age-Related Macular Degeneration in Animal Models and Patients Research |
| title | An Engineered Intravitreal Injection Retinal-Pigment-Epithelium-Tropic Adeno-Associated Virus Vector Expressing a Bispecific Antibody Binding VEGF-A and ANG-2 Rescues Neovascular Age-Related Macular Degeneration in Animal Models and Patients |
| title_full | An Engineered Intravitreal Injection Retinal-Pigment-Epithelium-Tropic Adeno-Associated Virus Vector Expressing a Bispecific Antibody Binding VEGF-A and ANG-2 Rescues Neovascular Age-Related Macular Degeneration in Animal Models and Patients |
| title_fullStr | An Engineered Intravitreal Injection Retinal-Pigment-Epithelium-Tropic Adeno-Associated Virus Vector Expressing a Bispecific Antibody Binding VEGF-A and ANG-2 Rescues Neovascular Age-Related Macular Degeneration in Animal Models and Patients |
| title_full_unstemmed | An Engineered Intravitreal Injection Retinal-Pigment-Epithelium-Tropic Adeno-Associated Virus Vector Expressing a Bispecific Antibody Binding VEGF-A and ANG-2 Rescues Neovascular Age-Related Macular Degeneration in Animal Models and Patients |
| title_short | An Engineered Intravitreal Injection Retinal-Pigment-Epithelium-Tropic Adeno-Associated Virus Vector Expressing a Bispecific Antibody Binding VEGF-A and ANG-2 Rescues Neovascular Age-Related Macular Degeneration in Animal Models and Patients |
| title_sort | engineered intravitreal injection retinal pigment epithelium tropic adeno associated virus vector expressing a bispecific antibody binding vegf a and ang 2 rescues neovascular age related macular degeneration in animal models and patients |
| url | https://spj.science.org/doi/10.34133/research.0717 |
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