Mishra Manish, Cashman Siobhan M, Kumar-Singh Rajendra
Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA, 02111, USA.
Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA, 02111, USA.
Exp Eye Res. 2025 Mar;252:110258. doi: 10.1016/j.exer.2025.110258. Epub 2025 Jan 28.
Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly. The exudative or wet form of AMD is caused by choroidal neovascularization (CNV) and subsequently a macular edema. Wet AMD can be effectively treated with anti-vascular endothelial growth factor (VEGF) therapies. However, despite treatment, more than half of patients continue to lose vision due to a lack of compliance with frequent intravitreal injections, failure to adequately respond to anti-VEGF therapy and emergence of fibrotic scars underneath the retina. In this study we investigated the use of our retinal penetrating AAV for delivery of human decorin (AAV-IKV-Decorin) in a murine model of laser induced CNV. Our results indicate that following a single intravitreal injection, decorin is highly expressed in the outer retina of AAV-IKV-Decorin injected mice and such mice exhibit significantly less neovascularization in laser induced CNV relative to mice injected with an AAV-IKV-Aflibercept, an AAV expressing an anti-VEGF. AAV-IKV-Decorin also significantly inhibited fibrosis, reduced inflammatory markers and increased autophagy.
年龄相关性黄斑变性（AMD）是老年人失明的最常见原因。渗出性或湿性AMD由脉络膜新生血管（CNV）引起，随后导致黄斑水肿。湿性AMD可以通过抗血管内皮生长因子（VEGF）疗法有效治疗。然而，尽管进行了治疗，但超过一半的患者由于未遵守频繁的玻璃体内注射、对抗VEGF治疗反应不足以及视网膜下出现纤维化瘢痕而继续丧失视力。在本研究中，我们在激光诱导的CNV小鼠模型中研究了使用我们的视网膜穿透性腺相关病毒（AAV）递送人核心蛋白聚糖（AAV-IKV-核心蛋白聚糖）。我们的结果表明，在单次玻璃体内注射后，核心蛋白聚糖在注射AAV-IKV-核心蛋白聚糖的小鼠的外视网膜中高度表达，并且相对于注射表达抗VEGF的AAV-IKV-阿柏西普的小鼠，此类小鼠在激光诱导的CNV中表现出明显更少的新生血管形成。AAV-IKV-核心蛋白聚糖还显著抑制纤维化、降低炎症标志物并增加自噬。
