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Saadia Rashid, Zeljka Smit-McBride, David G. Telander, Allan A. Hunter, III, Lawrence S. Morse; Gene Profiling Of Retinal Gene Expression After Intravitreal Anti- Vegf Injections In Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3326.
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© ARVO (1962-2015); The Authors (2016-present)
To identify the extent of changes in gene expression changes affected by intravitreal injections of Lucentis, Avastin and Macugen in mice at the 1 week time point.
Intravitreal injections (1ul) of balanced salt solution (ctrl), Lucentis (10μg), Avastin (25μg) or Macugen (3μg), (n=4/group) were performed in anesthetized C57BL/6J mice. Eyes were harvested at 1wk, total RNA was isolated from neurosensory retina, and microarray analysis of 35,000 genes was performed using Affymetrix Mouse Genome 430 2.0. Data was analyzed using GeneSpring GX11 and Ingenuity Pathway Analysis software. Genes with greater than 1.5 fold change in expression compared to control were identified as signficant (p<0.01).
Lucentis and Macugen induced change in expression of nearly 400 genes and Avastin in 150 genes. Among inflammatory genes, Lucentis downregulated solute carrier family 7 (SLC7A2), sodium channel (SCN9A), and tachykinin 1 (TAC1). Avastin upregulated activin A receptor type 1 (ACVR1), member of Wnt signaling. Macugen upregulated serine peptidase inhibitor, an orthologue of human antichymotripsin (SERPINA3N). At p<0.01, all three anti-VEGF agents downregulated interleukin 17D, which stimulates VEGF production (Lucentis strongest at 2.7 folds decrease).Among angiogenesis genes, all 3 anti-VEGF reagents downregulated the axonal guidance/semaphorin receptor neuropilin (NRP1). NRP1 binds VEGF-A in endothelial cells promoting cell migration and angiogenesis. All 3 downregulated hypoxia inducible factor (HIF-1A) whose inhibition leads to decrease in tumor angiogenesis, and sphingosine-1-phosphate receptor 1 (S1PR1), which mediates endothelial cells angiogenic and vascular protective functions.Among glaucoma genes, all 3 anti-VEGF reagents upregulated the gene encoding WD repeat domain 36 (WDR 36) associated with open angle glaucoma by increasing ganglion cells susceptibility to apoptosis. Lucentis downregulated lysyl oxidase like- 1 (LOXL-1) gene, a risk factor for exfoliative glaucoma, and upregulated optineurin, associated with ganglion cell apoptosis in normal tension glaucoma. An opposite effect was seen with Avastin and Macugen, which upregulated LOXL 1 and downregulated optineurin.
Angiogenesis genes are downregulated by all 3 agents. Glaucoma genes are differentially affected. Certain inflammatory genes are downregulated by Lucentis and upregulated by Avastin and Macugen. Therefore Lucentis may have a stronger anti- inflammatory effect. Differential inflammatory gene expression induced by Lucentis, Avastin and Macugen may lead to clinical implications for AMD patient care.
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