The pathogenic role of LRG1 in ocular neovascularisation: From discovery to targeted therapy

Abstract

SummaryWe have reported that the secreted glycoprotein, leucine‐rich alpha‐2‐glycoprotein 1 (LRG1), promotes neovascularisation in various models of ocular disease (Wang et al., Nature 2014; 499: 306–311). LRG1 is up‐regulated in many disease conditions and mediates its pro‐angiogenic effect by modifying the TGFß signalling network. Loss of LRG1, or blocking its biological activity, results in attenuation of neovascular complications in the rodent models of laser‐induced choroidal neovascularisation and oxygen‐induced retinopathy. Recently, we have observed that loss of LRG1 results in vessel normalisation, suggesting that in the pathological setting LRG1 corrupts the normal physiological angiogenic process. Early indications suggest that LRG1 interferes with vascular recruitment of pericytes resulting in failure of vessel maturation. These findings have important implications in diseases such as diabetic retinopathy where there is a need to promote a normal functioning vasculature. Consistent with the concept of LRG1 causing vascular dysfunction, we have additionally observed that loss of LRG1 reduces vascular permeability in ocular inflammation. Together these findings have led us to develop a humanised blocking antibody that will be taken into clinical trials for the treatment of wet age‐related macular degeneration. In this seminar I will present our work on LRG1 in ocular disease and describe the development of an anti‐LRG1 therapeutic for clinical use.