Sivaprasad Sobha, Cheung Chui Ming Gemmy, Gliem Martin, Wykoff Charles C, Zippel Nina, Ishida Susumu, Dong Nguyen Quan
National Institute of Health Research Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust, London, UK.
University College London Institute of Ophthalmology, London, UK.
Eye (Lond). 2025 Jul 9. doi: 10.1038/s41433-025-03835-w.
Diabetic retinopathy (DR) is a leading cause of acquired blindness. Retinal non-perfusion (RNP) is associated with DR worsening and vision loss. There are no treatments available that specifically address RNP in DR. The semaphorin 3A (Sema3A)/neuropilin 1 (Nrp1) pathway may be involved in RNP progression in DR. In DR, capillary dropout leads to RNP, subsequent hypoxia and ischaemia. Upon chronic hypoxia, retinal cells produce various factors, including vascular endothelial growth factor (VEGF) and Sema3A. While VEGF promotes the growth of new vessels, elevated Sema3A forms a chemical barrier in the retina that directs new blood vessels away from the ischaemic retina. The imbalance of VEGF and Sema3A in DR is believed to dysregulate physiological revascularisation in the retina and may guide blood vessels away from ischaemic regions into the vitreous cavity, causing the pathological neovascularisation typically found in advanced DR. Approved treatments can improve DR severity, but do not appear to improve the underlying RNP. This may lead to a high treatment burden over time and a risk for disease worsening once therapy is stopped, as the underlying disease may progress despite treatment. Therapeutic agents targeting the Sema3A/Nrp1 pathway may have the potential to improve RNP as a core pathophysiologic aspect of DR. This potential disease-modifying effect may sustainably improve DR and preserve the patient's visual function and quality of life. This review summarises Sema3A/Nrp1 pathway involvement in DR and RNP and its role as a potential target to treat DR in the context of current treatment options.
糖尿病视网膜病变（DR）是后天性失明的主要原因。视网膜无灌注（RNP）与DR病情恶化和视力丧失有关。目前尚无专门针对DR中RNP的治疗方法。信号素3A（Sema3A）/神经纤毛蛋白1（Nrp1）通路可能参与DR中RNP的进展。在DR中，毛细血管闭塞导致RNP，随后出现缺氧和缺血。在慢性缺氧时，视网膜细胞会产生各种因子，包括血管内皮生长因子（VEGF）和Sema3A。虽然VEGF促进新血管生长，但升高的Sema3A在视网膜中形成化学屏障，引导新血管远离缺血性视网膜。DR中VEGF和Sema3A的失衡被认为会使视网膜中的生理性血管再生失调，并可能引导血管从缺血区域进入玻璃体腔，导致晚期DR中常见的病理性新生血管形成。已批准的治疗方法可以改善DR的严重程度，但似乎并不能改善潜在的RNP。随着时间的推移，这可能导致高治疗负担，并且一旦停止治疗，疾病就有恶化的风险，因为尽管进行了治疗，潜在疾病仍可能进展。靶向Sema3A/Nrp1通路的治疗药物可能有潜力改善RNP，这是DR的一个核心病理生理方面。这种潜在的疾病改善作用可能可持续地改善DR，并保留患者的视觉功能和生活质量。本综述总结了Sema3A/Nrp1通路在DR和RNP中的作用及其作为在当前治疗选择背景下治疗DR的潜在靶点的作用。
