LRG1 Expression Is Elevated in the Eyes of Patients with Neovascular Age-Related Macular Degeneration

Abstract

Leucine-rich a-2-glycoprotein 1 (LRG1) is a candidate therapeutic target for treating the neovascular form of age-related macular degeneration (nvAMD). In this study we examined the expression of LRG1 in eyes of nvAMD patients. Choroidal neovascular membranes (CNVMs) from patients who underwent submacular surgery for retinal pigment epithelium–choroid graft transplantation were collected from 5 nvAMD patients without any prior intravitreal anti-VEGF injection, and from six patients who received intravitreal anti-VEGF injections before surgery. As controls free of nvAMD, retina sections were obtained from the eyes resected from a patient with lacrimal sac tumor and from a patient with neuroblastoma. CNVMs were immunostained for CD34, LRG1, and α-smooth muscle actin (α-SMA). Aqueous humor samples were collected from 58 untreated-naïve nvAMD patients prior to the intravitreal injection of anti-VEGF and 51 age-matched cataract control patients, and LRG1 concentration was measured by ELISA. The level of LRG1 immunostaining is frequently high in both the endothelial cells of the blood vessels, and myofibroblasts in the surrounding tissue of CNVMs of treatment-naïve nvAMD patients. Furthermore, the average concentration of LRG1 was significantly higher in the aqueous humor of nvAMD patients than in controls. These observations provide a strong experimental basis and scientific rationale for the progression of a therapeutic anti-LRG1 monoclonal antibody into clinical trials with patients with nvAMD.

LRG1: an emerging player in disease pathogenesis

“…Abnormal levels of LRG1 in the skin of diabetic mice delay the closure of chronic wounds through the formation of NETs [ 56 ], whose dysregulated function is known to cause cell damage in a number of conditions including diabetes [ 66 ]. Similarly, LRG1 has been reported to promote fibrosis in lung [ 16 , 67 ], kidney [ 68 ], dermal [ 34 , 67 , 69 ], and ocular tissues [ 57 , 70 , 71 ]. In particular, aberrant LRG1 levels were shown to promote ECM deposition both directly, through transactivation of resident fibroblasts [ 16 , 68 , 70 ] and epithelial cells [ 57 , 71 ], and indirectly by disrupting the formation of functional vessels [ 34 ] and modulating neutrophil pro-fibrotic effects [ 57 ] (Fig.…”

“…Similarly, LRG1 has been reported to promote fibrosis in lung [ 16 , 67 ], kidney [ 68 ], dermal [ 34 , 67 , 69 ], and ocular tissues [ 57 , 70 , 71 ]. In particular, aberrant LRG1 levels were shown to promote ECM deposition both directly, through transactivation of resident fibroblasts [ 16 , 68 , 70 ] and epithelial cells [ 57 , 71 ], and indirectly by disrupting the formation of functional vessels [ 34 ] and modulating neutrophil pro-fibrotic effects [ 57 ] (Fig. 5 ).…”

“…In conditions of altered homeostasis that typically accompany disease, transcription of the Lrg1 gene has been reported to be highly upregulated in endothelial cells [ 4 , 70 , 73 – 75 ], several types of epithelial cells [ 15 , 17 , 26 , 28 , 68 , 76 ], fibroblasts [ 34 , 57 , 70 , 77 ] and myeloid cells [ 11 , 56 , 72 , 78 – 81 ] including microglia [ 82 ] (Fig. 5 ).…”

Immunosenescence in Choroidal Neovascularization (CNV)—Transcriptional Profiling of Naïve and CNV-Associated Retinal Myeloid Cells during Aging

“…Its relevance with respect to neovascular eye disease was first studied by Wang and colleagues, who showed that LRG1 mediates its angiogenic effects in murine models by modulating the TGF-beta signaling pathway in endothelial cells [50]. However, LRG1 has also come into focus in patients with neovascular AMD because elevated levels of LRG1 have been detected in the aqueous humor, vitreous, and CNV membranes of patients with nAMD [53][54][55]. This is of particular interest because the inhibition of LRG1 with a function-blocking antibody successfully inhibits laser-induced CNV in young mice [56], suggesting that anti-LRG1 therapy may be a promising therapeutic option for the treatment of nAMD.…”

Research Progress on Leucine-Rich Alpha-2 Glycoprotein 1: A Review

“…Protein expression of five genes, serpina3n (serine protease inhibitor A3N), lcn2 (lipocalin-2), ackr1 (atypical chemokine receptor 1), LRG1, and lamc3 (laminin subunit gamma 3), were validated at the level of the inner blood retinal barrier cells (Lipski et al, 2020). The level of LRG1 obtained from eyes in patients with neovascular agerelated macular degeneration were increased, which indicated the target therapeutic therapy of anti-LRG1 monoclonal antibody (Mundo et al, 2021). LRG1 activated NADPH oxidase four to promote the epithelial mesenchymal transition of retinal pigment epithelium cells, which explored the potential mechanism for subretinal fibrosis in the basic experiment (Zhou et al, 2021).…”