Abstract
Neovascular AMD (nAMD) leads to vision loss and is a leading cause of visual impairment in the industrialised world. Current treatments that target blood vessel growth have not been able to treat subretinal fibrosis and nAMD patients continue to lose vision. The molecular mechanisms involved in the development of fibrotic lesions in nAMD are not well understood. The aim of this study was to further understand subretinal fibrosis in the laser photocoagulation model of choroidal neovascularization (CNV) by studying the whole transcriptome of the RPE/choroid following CNV and the application of an anti-fibrotic following CNV. Seven days after laser induced CNV, RPE and choroid tissue was separated and underwent RNAseq. Differential expression analysis and pathway analysis revealed an over representation of immune signalling and fibrotic associated pathways in CNV compared to control RPE/choroid tissue. Comparisons between the mouse CNV model to human CNV revealed an overlap in upregulated expression for immune genes (Ccl2, Ccl8 and Cxcl9) and extracellular matrix remodeling genes (Comp, Lrcc15, Fndc1 and Thbs2). Comparisons between the CNV model and other fibrosis models showed an overlap of over 60% of genes upregulated in either lung or kidney mouse models of fibrosis. Treatment of CNV using a novel cinnamoyl anthranilate anti-fibrotic (OCX063) in the laser induced CNV model was selected as this class of drugs have previously been shown to target fibrosis. CNV lesion leakage and fibrosis was found to be reduced using OCX063 and gene expression of genes within the TGF-beta signalling pathway. Our findings show the presence of fibrosis gene expression pathways present in the laser induced CNV mouse model and that anti-fibrotic treatments offer the potential to reduce subretinal fibrosis in AMD.
Highlights
Neovascular Age-related macular degeneration (AMD) leads to vision loss and is a leading cause of visual impairment in the industrialised world
Transcriptomic studies on RNA isolated from humans eyes of those with Neovascular AMD (nAMD) have confirmed the upregulation of a range of genes associated with the extracellular matrix d eposition[14,15]
We evaluated whether the differentially regulated genes identified following laser induced choroidal neovascularization (CNV) were similar to those altered in human nAMD tissue (RPE/Choroid)
Summary
Neovascular AMD (nAMD) leads to vision loss and is a leading cause of visual impairment in the industrialised world. Treatment of CNV using a novel cinnamoyl anthranilate antifibrotic (OCX063) in the laser induced CNV model was selected as this class of drugs have previously been shown to target fibrosis. Our findings show the presence of fibrosis gene expression pathways present in the laser induced CNV mouse model and that antifibrotic treatments offer the potential to reduce subretinal fibrosis in AMD. Lesions associated with nAMD consist of both a neovascular component as well as an extravascular component consisting of fibrotic tissue, RPE cells, fibroblasts, myofibroblasts and inflammatory cells[12,13]. Few studies have evaluated potential treatments of fibrosis in nAMD Cinnamoyl anthranilates such as tranilast are known to have a broad range of effects that may include effects on TGFβ signalling and extracellular matrix turnover[28]. What is not known is whether cinnamoyl anthranilates have potential to reduce fibrosis secondary to nAMD, and the mechanisms by which this might occur
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