Description
Neovascular age-related macular degeneration (nvAMD) is a leading cause of irreversible vision loss, with subretinal fibrosis representing a late and vision-threatening stage of disease progression. Although anti-VEGF therapies effectively suppress pathological neovascularisation and vascular leakage, they do not reliably prevent fibrotic scarring, and fibrosis can still develop despite repeated treatment. There are currently no approved therapies that directly target subretinal fibrosis, highlighting a major unmet clinical need.
Subretinal fibrosis is driven by the accumulation of extracellular matrix and contractile myofibroblast-like cells within choroidal neovascular membranes. These myofibroblasts may arise from multiple ocular cell populations, including retinal pigment epithelial cells, pericytes and other stromal cells, but the molecular signals that promote their emergence in nvAMD remain poorly understood.
Leucine-rich α-2 glycoprotein 1 (LRG1) is a secreted glycoprotein known to modulate TGF-β signalling and promote fibrosis in several organs, including the lung and kidney. Elevated LRG1 levels have been reported in ocular fluids and neovascular membranes from patients with nvAMD, suggesting that LRG1 may contribute to the local pro-fibrotic environment. We therefore investigated whether LRG1 acts as a pro-fibrotic factor in choroidal neovascularisation by promoting myofibroblast-like activation of ocular cells.
Using differentiated ARPE-19 cells cultured in Williams’ medium as a model of retinal pigment epithelium, we found that LRG1 increased the expression of pro-fibrotic markers, whereas undifferentiated ARPE-19 cells were unresponsive. LRG1 similarly enhanced fibrotic marker expression in human retinal pericytes. In parallel, we are using an ex vivo mouse choroid explant model in which sprouting CNV-like lesions develop progressive fibrotic features over time and respond to pro-fibrotic stimulation with TGF-β. This platform will enable us to define how LRG1 regulates fibrosis within sprouting neovascular lesions and assess its potential as a therapeutic target in nvAMD.
Lay Abstract
Neovascular age-related macular degeneration (nvAMD) is a leading cause of blindness in individuals over 50. nvAMD is characterised by the growth of abnormal blood vessels in the macula region resulting in rapid vision decline. The formation of scar tissue through the process called fibrosis marks the end phase of the disease resulting in irreversible vision loss. Current treatments primarily target abnormal vessel growth in patients but fail to address fibrosis and may even worsen it. The underlying mechanisms driving fibrosis in nvAMD remain largely unexplored, which impedes the development of effective treatments to preserve sight. Research from fibrosis in other organs such as the kidney and lung has identified the protein LRG1 to drive fibrosis. Emerging evidence from our preliminary studies suggests the protein may have a similar role in the eye. Preliminary data utilising human cells have demonstrated a pro-fibrotic effect of LRG1 in cells of the eye. In addition, mouse tissue will be utilised to promote the growth of new blood vessels in a model referred to as a sprouting assay. This model show increased fibrosis over time as a result of new vessel growth; providing a new way by which fibrosis and LRG1 can be investigated.
| Lay Title | Understanding and targeting fibrosis in Neovascular Age-Related Macular Degeneration |
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| Role | PhD Student |