New targets in diabetic retinopathy: addressing limitations of current treatments through the Sema3A/Nrp1 pathway

Abstract: 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. Method oF Literature Search: Background literature was searched in PubMed using search terms such as ‘diabetic retinopathy’, ‘diabetic macular ischemia’, ‘diabetic macular edema’, ‘semaphorin 3a’, ‘neuropilin 1’, ‘retinal non-perfusion’, ‘vascular perfusion’, ‘anti-VEGF’, ‘corticosteroid’ and ‘laser photocoagulation’. Selected articles in English included the following publication types: Clinical Study; Clinical Trial; Clinical Trial, Phase I; Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Clinical Trial Protocol; Controlled Clinical Trial; Meta-Analysis, Randomised Controlled Trial; Review; and Systematic Review. Reference lists from the selected articles were also reviewed, from which relevant articles were manually included into the final list, in addition to extensive general background reading about the topic. Additionally, ClinicalTrials.gov and Google searches were performed to identify upcoming trials of treatments in DR with the potential to improve RNP. Plain Language Summary: The retina is the light-sensing layer at the back of the eye. Damage to the retina can lead to eye diseases. Diabetes can cause reduced blood flow to the retina, damaging the retina and leading to vision loss. Eye disease is common in people with diabetes. This review discusses different drugs currently used to treat sight loss in people with diabetes. Taking some of these drugs can affect the quality of a person’s life. For example, the treatment may need to be given by regular injections into the eye and/or may have upsetting side effects. This review also talks about new drugs now being studied to improve blood flow to the retina and slow or stop sight loss in people with diabetes. Proteins called semaphorin 3A and neuropilin 1 regulate blood flow to the retina. New drugs have been made that work against these proteins. These drugs may help to increase blood flow to the retina. Several other drugs that may increase blood flow to the retina are also being studied in animals and humans.