Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis

Abstract 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...

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Autores principales:	Cynthia Yu-Wai-Man, Bradley Spencer-Dene, Richard M. H. Lee, Kim Hutchings, Erika M. Lisabeth, Richard Treisman, Maryse Bailly, Scott D. Larsen, Richard R. Neubig, Peng T. Khaw
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d0d09e6ee5ac462a80dbec12fafe4e2c
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spelling	oai:doaj.org-article:d0d09e6ee5ac462a80dbec12fafe4e2c2021-12-02T11:40:20ZLocal delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis10.1038/s41598-017-00212-w2045-2322https://doaj.org/article/d0d09e6ee5ac462a80dbec12fafe4e2c2017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00212-whttps://doaj.org/toc/2045-2322Abstract 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 μM, 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.Cynthia Yu-Wai-ManBradley Spencer-DeneRichard M. H. LeeKim HutchingsErika M. LisabethRichard TreismanMaryse BaillyScott D. LarsenRichard R. NeubigPeng T. KhawNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cynthia Yu-Wai-Man Bradley Spencer-Dene Richard M. H. Lee Kim Hutchings Erika M. Lisabeth Richard Treisman Maryse Bailly Scott D. Larsen Richard R. Neubig Peng T. Khaw Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis
description	Abstract 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 μM, 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.
format	article
author	Cynthia Yu-Wai-Man Bradley Spencer-Dene Richard M. H. Lee Kim Hutchings Erika M. Lisabeth Richard Treisman Maryse Bailly Scott D. Larsen Richard R. Neubig Peng T. Khaw
author_facet	Cynthia Yu-Wai-Man Bradley Spencer-Dene Richard M. H. Lee Kim Hutchings Erika M. Lisabeth Richard Treisman Maryse Bailly Scott D. Larsen Richard R. Neubig Peng T. Khaw
author_sort	Cynthia Yu-Wai-Man
title	Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis
title_short	Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis
title_full	Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis
title_fullStr	Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis
title_full_unstemmed	Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis
title_sort	local delivery of novel mrtf/srf inhibitors prevents scar tissue formation in a preclinical model of fibrosis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d0d09e6ee5ac462a80dbec12fafe4e2c
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Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis

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