Corydon Thomas J, Bek Toke
Department of Biomedicine, Hoegh Guldbergs Gade 10, Aarhus University, 8000, Aarhus C, Denmark; Department of Ophthalmology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark.
Department of Ophthalmology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark.
Prog Retin Eye Res. 2025 Jan;104:101323. doi: 10.1016/j.preteyeres.2024.101323. Epub 2024 Dec 11.
Anti-vascular endothelial growth factor (VEGF) therapies have revolutionized the treatment of neovascular age-related macular degeneration (nAMD) and other retinal diseases. However, the necessity for repeated intravitreal injections and the observation of variable treatment responses calls for new treatment modalities where fewer and more effective interventions can result in a clinical effect. Gene therapy might be such an alternative, and therefore the development and clinical application of gene therapy aimed at modifying gene expression has received considerable attention. The article reviews current knowledge of the background, pathophysiological mechanisms, technologies, limitations, and future directions for gene therapy aimed at modifying the synthesis of compounds involved in acquired and senescent retinal disease. The authors have contributed to the field by developing gene therapy to reduce the expression of vascular endothelial growth factor (VEGF), as well as multiple gene therapy for simultaneous downregulation of the synthesis of VEGF and upregulation of pigment epithelium-derived factor (PEDF) using adeno-associated virus (AAV) vectors. It is suggested that such multi-target gene therapy might be included in future treatments of retinal diseases where the underlying mechanisms are complex and cannot be attributed to one specific mediator. Such diseases might include dry AMD (dAMD) with geographic atrophy, but also diabetic macular edema (DME) and retinal vein occlusion (RVO). Gene therapy can be expected to be most beneficial for the patients in need of multiple intra-vitreal injections and in whom the therapeutic response is insufficient. It is concluded, that in parallel with basic research, there is a need for clinical studies aimed at identifying factors that can be used to identify patients who will benefit from gene therapy already at the time of diagnosis of the retinal disease.
抗血管内皮生长因子（VEGF）疗法彻底改变了新生血管性年龄相关性黄斑变性（nAMD）及其他视网膜疾病的治疗方式。然而，由于需要反复进行玻璃体内注射，且观察到治疗反应存在差异，因此需要新的治疗模式，即采用更少且更有效的干预措施就能产生临床效果。基因治疗可能是一种选择，因此旨在改变基因表达的基因治疗的开发和临床应用受到了广泛关注。本文综述了旨在改变与获得性和衰老性视网膜疾病相关化合物合成的基因治疗的背景、病理生理机制、技术、局限性及未来方向的现有知识。作者通过开发基因治疗来降低血管内皮生长因子（VEGF）的表达，以及利用腺相关病毒（AAV）载体同时下调VEGF合成和上调色素上皮衍生因子（PEDF）的多基因治疗，为该领域做出了贡献。有人认为，这种多靶点基因治疗可能会被纳入未来视网膜疾病的治疗中，这些疾病的潜在机制复杂，不能归因于一种特定的介质。此类疾病可能包括伴有地图样萎缩的干性年龄相关性黄斑变性（dAMD），还有糖尿病性黄斑水肿（DME）和视网膜静脉阻塞（RVO）。基因治疗预计对需要多次玻璃体内注射且治疗反应不足的患者最为有益。结论是，在进行基础研究的同时，需要开展临床研究，以确定在视网膜疾病诊断时可用于识别将从基因治疗中获益的患者的因素。
