Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach and der Riß, Germany.
Invest Ophthalmol Vis Sci. 2022 Jul 8;63(8):14. doi: 10.1167/iovs.63.8.14.
Semaphorin 3A (Sema3A) is a promising therapeutic target for macular edema in age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion (RVO). Anti-vascular endothelial growth factors (anti-VEGFs) are the current standard of care for many retinal diseases. This study investigated the Sema3A neutralizing antibody BI-X and/or anti-VEGF therapy (aflibercept) in an RVO mouse model. Treatment efficacy was examined and grouped by timing subsequent to the RVO mouse model induction: efficacy against the onset of intraretinal edema 1 day postinduction and protective effects at 7 days postinduction.
We examined the changes in expression of Sema3A in the retina of an RVO mouse model. In addition, changes in expression of tumor necrosis factor (TNF)-α and semaphorin-related proteins (neuropilin-1 and plexin A1) in the retina upon treatment were analyzed by Western blotting. The effects of BI-X and/or aflibercept were evaluated using measures of retinal edema, blood flow, and thinning of the inner nuclear layer.
Induction of vein occlusion in the RVO mouse model significantly increased Sema3A expression in the retina, particularly in the inner nuclear layer. BI-X was effective as a monotherapy and in combination with anti-VEGF therapy, demonstrating a beneficial effect on intraretinal edema and retinal blood flow. Moreover, in the RVO mouse model, BI-X monotherapy normalized the changes in expression of TNF-α and semaphorin-related proteins.
These findings support targeting Sema3A to treat intraretinal edema and retinal ischemia.
信号素 3A（Sema3A）是治疗年龄相关性黄斑变性、糖尿病视网膜病变和视网膜静脉阻塞（RVO）引起的黄斑水肿的有前途的治疗靶点。抗血管内皮生长因子（anti-VEGF）是许多视网膜疾病的当前标准治疗方法。本研究在 RVO 小鼠模型中研究了 Sema3A 中和抗体 BI-X 和/或抗 VEGF 治疗（阿柏西普）。通过在 RVO 小鼠模型诱导后的时间进行治疗效果检查和分组：对 1 天诱导后视网膜内水肿的疗效和 7 天诱导后的保护作用。
我们研究了 RVO 小鼠模型中 Sema3A 在视网膜中的表达变化。此外，通过 Western blot 分析了 TNF-α和信号素相关蛋白（神经纤毛蛋白-1 和丛蛋白 A1）在视网膜中治疗时的表达变化。通过评估视网膜水肿、血流和内核层变薄来评估 BI-X 和/或阿柏西普的作用。
RVO 小鼠模型中静脉阻塞的诱导显著增加了视网膜中 Sema3A 的表达，特别是在内核层。BI-X 作为单一疗法和与抗 VEGF 治疗联合使用均有效，对视网膜内水肿和视网膜血流具有有益作用。此外，在 RVO 小鼠模型中，BI-X 单药治疗可使 TNF-α和信号素相关蛋白的表达变化正常化。
这些发现支持针对 Sema3A 治疗视网膜内水肿和视网膜缺血。
