Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-00212-w
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Funding
- National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust
- UCL Institute of Ophthalmology
- UK Medical Research Council, Moorfields Trustees and Moorfields Eye Charity
- Freemasons Grand Charity
- Michael and Ilse Katz Foundation
- Helen Hamlyn Trust, Fight for Sight (UK)
- NIH [R01 AR066049]
- Francis Crick Institute, Cancer Research UK [FC001-190]
- UK Medical Research Council [FC001-190]
- Wellcome Trust [FC001-190]
- ERC Advanced Grant [268690]
- MRC [G0500927] Funding Source: UKRI
- Medical Research Council [G0500927] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10101] Funding Source: researchfish
- The Francis Crick Institute [10191, 10190] Funding Source: researchfish
- European Research Council (ERC) [268690] Funding Source: European Research Council (ERC)
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The myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway represents a promising therapeutic target to prevent fibrosis. We have tested the effects of new pharmacological inhibitors of MRTF/SRF signalling in a preclinical model of fibrosis. CCG-222740, a novel MRTF/SRF inhibitor, markedly decreased SRF reporter gene activity and showed a greater inhibitory effect on MRTF/SRF target genes than the previously described MRTF-A inhibitor CCG-203971. CCG-222740 was also five times more potent, with an IC50 of 5 mu M, in a fibroblast-mediated collagen contraction assay, was less cytotoxic, and a more potent inhibitor of alpha-smooth muscle actin protein expression than CCG-203971. Local delivery of CCG-222740 and CCG-203971 in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery increased the long-term success of the surgery by 67% (P < 0.0005) and 33% (P < 0.01), respectively, and significantly decreased fibrosis and scarring histologically. Unlike mitomycin-C, neither CCG-222740 nor CCG-203971 caused any detectable epithelial toxicity or systemic side effects with very low drug levels measured in the aqueous, vitreous, and serum. We conclude that inhibitors of MRTF/SRF-regulated gene transcription such as CCG-222740, potentially represent a new therapeutic strategy to prevent scar tissue formation in the eye and other tissues.
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