Abstract
Retinal and choroidal diseases are major causes of blindness and visual impairment in the developed world and on the rise due to an ageing population and diabetes epidemic. Standard of care is centred around blockade of vascular endothelial growth factor (VEGF), but despite having halved the number of patients losing sight, a high rate of patient non-response and loss of efficacy over time are key challenges. Dysregulation of vascular homoeostasis, coupled with fibrosis and inflammation, are major culprits driving sight-threatening eye diseases. Improving our knowledge of these pathological processes should inform the development of new drugs to address the current clinical challenges for patients. Leucine-rich α-2 glycoprotein 1 (LRG1) is an emerging key player in vascular dysfunction, inflammation and fibrosis. Under physiological conditions, LRG1 is constitutively expressed by the liver and granulocytes, but little is known about its normal biological function. In pathological scenarios, such as diabetic retinopathy (DR) and neovascular age-related macular degeneration (nvAMD), its expression is ectopically upregulated and it acquires a much better understood pathogenic role. Context-dependent modulation of the transforming growth-factor β (TGFβ) pathway is one of the main activities of LRG1, but additional roles have recently been emerging. This review aims to highlight the clinical and pre-clinical evidence for the pathogenic contribution of LRG1 to vascular retinopathies, as well as extrapolate from other diseases, functions which may be relevant to eye disease. Finally, we will provide a current update on the development of anti-LRG1 therapies for the treatment of nvAMD.
Highlights
There are currently 2 million people in the UK either legally blind or living with sight-threatening pathologies and this number is predicted to double by 2050
We describe the pre-clinical evidence for a pathogenic role of Leucine-rich α-2 glycoprotein 1 (LRG1) in diabetic retinopathy (DR) and neovascular age-related macular degeneration (nvAMD), and touch upon other ocular pathologies
That new vessel formation in the that LRG1 is produced by RPE cells undergoing transforming growth-factor β (TGFβ)-induced absence of LRG1 would be more likely to occur, as it does during trans-differentiation, and knocking-down Lrg1 abolishes this development, in a physiological manner
Summary
There are currently 2 million people in the UK either legally blind or living with sight-threatening pathologies and this number is predicted to double by 2050. The treatment of some retinopathies was, revolutionised by the approval in 2004 of Macugen (Eyetech Inc.), the first anti-VEGF agent and the first aptamer to be licensed for clinical use, and subsequent anti-VEGF drugs including Lucentis (Genentech), Eylea (Regeneron Pharmaceuticals) and Avastin (Genentech, off label), administered at slightly different dosage regimens (once a month, on average) by intra-vitreal (IVT) injection These agents have decreased the number of patients becoming legally blind by ~50% in nvAMD [9], by ~75% in DMO [10] and by ~50% in DR [11]. While this result is an enormous success and illustrates the value of targeting vessel leakage and angiogenesis to restore retinal function, it highlights that there remains a huge number of patients who do not benefit from anti-VEGF therapies, benefit suboptimally, or cease to respond [12]. Faricimab, a bispecific antibody targeting both VEGF and angiopoietin-2, has given promising results in phase III trials for DMO and nvAMD [16]
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