Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (L.T., R.A.B., N.Z.) and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (S.L., G.H.).
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (L.T., R.A.B., N.Z.) and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (S.L., G.H.)
J Pharmacol Exp Ther. 2023 Jun;385(3):214-221. doi: 10.1124/jpet.122.001473. Epub 2023 Mar 30.
Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults. Despite an established standard of care for advanced forms of DR, some patients continue to lose vision after treatment. This may be due to the development of diabetic macular ischemia (DMI), which has no approved treatment. Neuropilin-1 (Nrp-1) is a coreceptor with two ligand-binding domains, with semaphorin-3A (Sema3A) binding to the A-domain and vascular endothelial growth factor-A (VEGF-A) binding to the B-domain. Sema3A directs a subset of neuronal growth cones as well as blood vessel growth by repulsion; when bound to Nrp-1, VEGF-A mediates vascular permeability and angiogenesis. Modulating Nrp-1 could therefore address multiple complications arising from DR, such as diabetic macular edema (DME) and DMI. BI-Y is a monoclonal antibody that binds to the Nrp-1 A-domain, antagonizing the effects of the ligand Sema3A and inhibiting VEGF-A-induced vascular permeability. This series of in vitro and in vivo studies examined the binding kinetics of BI-Y to Nrp-1 with and without VEGF-A, the effect of BI-Y on Sema3A-induced cytoskeletal collapse, the effect of BI-Y on VEGF- A-induced angiogenesis, neovascularization, cell integrity loss and permeability, and retinal revascularization. The data show that BI-Y binds to Nrp-1 and inhibits Sema3A-induced cytoskeletal collapse in vitro, may enhance revascularization of ischemic areas in an oxygen-induced retinopathy mouse model, and prevents VEGF-A-induced retinal hyperpermeability in rats. However, BI-Y does not interfere with VEGF-A-dependent choroidal neovascularization. These results support further investigation of BI-Y as a potential treatment for DMI and DME. SIGNIFICANCE STATEMENT: Diabetic macular ischemia (DMI) is a complication of diabetic retinopathy (DR) with no approved pharmacological treatment. Diabetic macular edema (DME) commonly co-occurs with DMI in patients with DR. This series of preclinical studies in mouse and rat models shows that neuropilin-1 antagonist BI-Y may enhance the revascularization of ischemic areas and prevents vascular endothelial growth factor-A (VEGF-A)-induced retinal hyperpermeability without affecting VEGF-A-dependent choroidal neovascularization; thus, BI-Y may be of interest as a potential treatment for patients with DR.
糖尿病性视网膜病变（DR）是导致工作年龄成年人视力丧失的主要原因。尽管已经有了治疗晚期 DR 的标准方法，但有些患者在治疗后仍会失明。这可能是由于发生了糖尿病性黄斑缺血（DMI），而目前尚无针对这种疾病的治疗方法。神经纤毛蛋白-1（Nrp-1）是一种具有两个配体结合结构域的核心受体，其中信号素-3A（Sema3A）结合 A 结构域，血管内皮生长因子-A（VEGF-A）结合 B 结构域。Sema3A 通过排斥作用指导一部分神经元生长锥和血管生长；当与 Nrp-1 结合时，VEGF-A 介导血管通透性和血管生成。因此，调节 Nrp-1 可能会解决 DR 引起的多种并发症，如糖尿病性黄斑水肿（DME）和 DMI。BI-Y 是一种单克隆抗体，与 Nrp-1 的 A 结构域结合，拮抗配体 Sema3A 的作用，并抑制 VEGF-A 诱导的血管通透性。本系列体外和体内研究检测了 BI-Y 与 VEGF-A 结合和不结合时与 Nrp-1 的结合动力学、BI-Y 对 Sema3A 诱导的细胞骨架崩溃的影响、BI-Y 对 VEGF-A 诱导的血管生成、新生血管形成、细胞完整性丧失和通透性以及视网膜再血管化的影响。数据表明，BI-Y 与 Nrp-1 结合并抑制体外 Sema3A 诱导的细胞骨架崩溃，可能增强氧诱导的视网膜病变小鼠模型中缺血区的再血管化，并防止大鼠中 VEGF-A 诱导的视网膜高通透性。然而，BI-Y 不干扰 VEGF-A 依赖性脉络膜新生血管形成。这些结果支持进一步研究 BI-Y 作为治疗 DMI 和 DME 的潜在药物。意义声明：糖尿病性黄斑缺血（DMI）是糖尿病性视网膜病变（DR）的一种并发症，目前尚无批准的药物治疗方法。糖尿病性黄斑水肿（DME）在 DR 患者中常与 DMI 同时发生。本系列在小鼠和大鼠模型中的临床前研究表明，神经纤毛蛋白-1 拮抗剂 BI-Y 可能增强缺血区的再血管化，并防止血管内皮生长因子-A（VEGF-A）诱导的视网膜高通透性，而不影响 VEGF-A 依赖性脉络膜新生血管形成；因此，BI-Y 可能是治疗 DR 患者的一种有前途的治疗方法。
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