LRG1 a novel therapeutic target in eye disease
Pathogenic contribution of LRG1 to vascular retinopathies
Globally, 2.2 billion people are estimated to have a vision impairment. Eye diseases are on the rise due to an ageing population and an increase of diabetes. The classical therapy involves the blockage of vascular endothelial growth factor (VEGF). However, a high rate of patient non-response and loss of efficacy over time are major challenges.
Evaluating new treatments with better efficiency are moving forward. One novel therapeutic target is leucine-rich α-2 glycoprotein 1 (LRG1). It is an emerging key player in vascular dysfunction, inflammation, and fibrosis.
LRG1 as a novel therapeutic target in eye disease
The uncontrolled formation of new blood vessels in the eye (ocular angiogenesis) is one of the major causes of eye diseases and blindness.
The blood protein LRG1 plays a central role in the progression of eye diseases and is thus a promising novel therapeutic target.
In searching for mediators of vascular remodeling in the diseased and damaged retina, researchers discovered that leucine-rich α-2 glycoprotein 1 (LRG1) is a novel regulator of TGFß signaling. The study published in Nature in 2013 by Wang X et al., revealed that LRG1 is a novel regulator of angiogenesis that mediates its effect through modulating TGFβ signaling. The researchers showed that LRG1 expression in the retina is predominantly vascular and is increased during neovascular growth. Their study in mice supported the hypothesis that LRG1 is necessary for robust vascular growth and its inhibition has potential as a therapeutic target. Based on their studies, the authors suggested that LRG1 is not only a promising target for controlling pathogenic angiogenesis in eye diseases but could potentially also be used in other diseases such as cancer and atherosclerosis.
WHAT IS LRG1 (leucine-rich α-2 glycoprotein 1)
The mature 38,2 kDa glyocoprotein LRG contains 347 amino acids (Uniprot entry Leucine-rich alpha-2-glycoprotein). It belongs to the family of LRG proteins characterized through leucine-rich repeats in its amino acid sequence. LRG1 (also named LRG) is involved in protein-protein interactions, signal transduction, and development. Studies have shown that LRG plays a role in physiological processes of the nervous system including synapse formation and growth. It is also implied in cell proliferation, in immune responses, in cell migration, in neovascularization, and in apoptosis.
Alternative titles: LRG – OMIM Entry leucine-rich α-2 glycoprotein (LRG)
HOW CAN YOU MEASURE LRG1?
LRG1 can reliably be measured in human serum and plasma with the Biomedica LRG ELISA (cat. no. BI-LRG).
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Sample volume: 5µl
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Assay range: 2-64 ng/ml
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Easy protocol – day test
The validation of the LRG1 ELISA kit has been performed following international quality guidelines. Download the validation data here.
RELATED PUBLICATIONS
LRG1 as a novel therapeutic target in eye disease.
De Rossi G, Da Vitoria Lobo ME, Greenwood J, Moss SE. Eye (Lond). 2022 Feb;36(2):328-340. doi: 10.1038/s41433-021-01807-4. Epub 2022 Jan 5. Erratum in: Eye (Lond). 2022 Feb 28;: PMID: 34987199; PMCID: PMC8807626.
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..
LRG1 promotes angiogenesis by modulating endothelial TGF-β signalling.
Wang X, Abraham S, McKenzie JAG, Jeffs N, Swire M, Tripathi VB, Luhmann UFO, Lange CAK, Zhai Z, Arthur HM, Bainbridge J, Moss SE, Greenwood J.Nature. 2013 Jul 18;499(7458):306-11. doi: 10.1038/nature12345. PMID: 23868260; PMCID: PMC3836402.