Journal
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Volume 54, Issue 13, Pages 7836-7848Publisher
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.13-12494
Keywords
glaucoma pharmacology; extracellular matrix; lamina cribrosa; trabecular meshwork
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Funding
- Health Research Board Ireland [HRA POR_2010-129]
- International Glaucoma Association/United Kingdom
- Eire Glaucoma Society Award
- Health Research Board (HRB) [HRA-POR-2010-129] Funding Source: Health Research Board (HRB)
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PURPOSE. We have previously demonstrated elevated levels of connective tissue growth factor (CTGF/CCN2) in the aqueous humor (AqH) of pseudoexfoliation glaucoma (PXFG) patients when compared with cataract controls. Furthermore, there is a significant trabecular meshwork (TM) and lamina cribrosa (LC) fibrotic phenotype associated with glaucoma, possibly driven by CTGF. The purpose of this study was to investigate the potential of anti-CTGF immunotherapy in glaucoma. METHODS. Primary TM and LC cells were cultured from human donors with (GTM/GLC) and without (NTM/NLC) primary open angle glaucoma (POAG). Aqueous humor samples from PXFG, POAG, and control cataract patients were applied to N/GTM and N/GLC cells in the presence or absence of a therapeutic, humanized monoclonal anti-CTGF antibody FG-3019 (10 mu g/mL). Hydrogen peroxide (H2O2) was also used as a stimulus. Expression of fibrotic genes (fibronectin-1, fibrillin-1, CTGF, collagen type I alpha 1, and alpha-smooth muscle actin) was assessed by q-PCR. Protein expression of collagen 1A1 and alpha-smooth muscle actin was examined in N/G TM cells by SDS-PAGE. The modulatory effect of FG-3019 (10 mu g/mL) and IgG (10 mu g/mL) were also assessed. RESULTS. Treatment of cells with AqH from PXFG and POAG patients and H2O2 induced a significant (P < 0.05) increase in expression of profibrotic genes, which was significantly reduced by pretreatment with FG-3019 (P < 0.05). FG-3019 also reduced expression of alpha-smooth muscle actin and collagen 1A1 protein expression in N/GTM cells. CONCLUSIONS. FG-3019 is effective in blocking extracellular matrix production in TM and LC cells, thus supporting a role for the use of anti-CTGF immunotherapy in the treatment of glaucoma.
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