Anti-VEGF Treatment for Diabetic Macular Oedema: Clinical and Laboratory Insights

Abstract

Diabetic retinopathy (DR) is a leading cause of vision impairment, characterised by vascular damage and neurodegeneration. Anti vascular endothelial growth factor (VEGF) drugs have revolutionised the management of the most common cause of vision impairment in DR, diabetic macular oedema (DMO). These drugs restore vision in DMO and induce regression of vascular changes in DR. Despite anti-VEGF therapy, a proportion of patients may have persistent DMO. The aim of the research presented in this thesis is to investigate the effect of switching therapy between two anti-VEGF drugs for persistent DMO and to assess the potential effects of anti-VEGF drugs in modulating neurodegeneration in DR through production of neurotrophic factors. In a prospective, single-arm, open-label clinical trial of patients with persistent DMO despite prior treatment with bevacizumab, there was a significant improvement in visual and anatomical outcomes when therapy was switched to aflibercept. Artifacts on automated optical coherence tomography calculations were increased in the presence of DMO. Peripheral ischaemia was associated with a poorer baseline vision and greater vision gain. Microperimetry outcomes correlated with objective and subjective vision outcomes. Diabetic conditions were simulated in vitro using ARPE-19 cell-line culture. There was downregulation of pigment epithelium derived factor (PEDF) expression in hypoxic states. In the absence of hypoxia, the addition of anti-VEGF drugs led to a significant downregulation of PEDF. Brain derived neurotrophic factor secretion was downregulated in high glucose states and upregulated in hypoxia. This thesis has addressed a number of key issues relating to persistent DMO, a management challenge with a poor evidence base. Further research is required into the identification of clinical and laboratory biomarkers to individualise pharmacotherapy and identify patients who may be poor and good responders to anti-VEGF therapy.