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Liu Z, Zhang H, Jia H, Wang H, Huang Z, Tang Y, Wang Z, Hu J, Zhao X, Li T, Sun X. The clinical safety landscape for ocular AAV gene therapies: A systematic review and meta-analysis. iScience 2025; 28:112265. [PMID: 40248125 PMCID: PMC12005934 DOI: 10.1016/j.isci.2025.112265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 01/23/2025] [Accepted: 03/18/2025] [Indexed: 04/19/2025] Open
Abstract
Adeno-associated virus (AAV) gene therapy is a promising approach for treating ocular monogenic or acquired diseases, though immunogenicity and safety remain critical considerations. We conducted a systematic review of 120 trials and 32 publications to assess immune responses across different delivery routes. Intravitreal administration was associated with higher rates of anterior uveitis (43.06% vs. 10.22%) and intermediate/posterior uveitis (40.36% vs. 6.18%) compared to subretinal delivery. Engineered AAV capsids, used exclusively in intravitreal studies, showed no significant difference in either type of uveitis incidence compared to natural serotypes. Prophylactic immunosuppression (PI) did not affect ocular or systemic immune responses in subretinal delivery, but significantly reduced systemic immune responses in intravitreal administration. These findings underscore the potential of PI to mitigate systemic immune responses in intravitreal AAV therapy. This review should help guide the choice of routes of administration and immunosuppression strategies, and highlights current trends in ocular AAV gene therapy.
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Affiliation(s)
- Zishi Liu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
| | - Haoliang Zhang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
| | - Huixun Jia
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
- Shanghai Gene Therapy Center, Shanghai, China
| | - Hong Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
| | - Zhonghe Huang
- Qingdao University School of Mathematics and Statistics, Qingdao, China
| | - Yuhao Tang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
| | - Zilin Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
| | - Jing Hu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
| | - Xiaohuan Zhao
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
| | - Tong Li
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
- Shanghai Gene Therapy Center, Shanghai, China
| | - Xiaodong Sun
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
- Shanghai Gene Therapy Center, Shanghai, China
- Shanghai Key Laboratory of Fundus Diseases, Shanghai, China
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Ramamoorthi K, Curtis D, Asuri P. Advances in homology directed genetic engineering of human pluripotent and adult stem cells. World J Stem Cells 2013; 5:98-105. [PMID: 24179598 PMCID: PMC3812527 DOI: 10.4252/wjsc.v5.i4.98] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Revised: 09/06/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
The ability to introduce precise genomic modifications in human cells has profound implications for both basic and applied research in stem cells, ranging from identification of genes regulating stem cell self-renewal and multilineage differentiation to therapeutic gene correction and creation of in vitro models of human diseases. However, the overall efficiency of this process is challenged by several factors including inefficient gene delivery into stem cells and low rates of homology directed site-specific targeting. Recent studies report the development of novel techniques to improve gene targeting efficiencies in human stem cells; these methods include molecular engineering of viral vectors to efficiently deliver episomal genetic sequences that can participate in homology directed targeting, as well as the design of synthetic proteins that can introduce double-stranded breaks in DNA to initiate such recombination events. This review focuses on the potential of these new technologies to precisely alter the human stem cell genome and also highlights the possibilities offered by the combination of these complementary strategies.
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