Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis.
Cynthia Yu-Wai-ManBradley Spencer-DeneRichard M H LeeKim HutchingsErika M LisabethRichard TreismanMaryse BaillyScott D LarsenRichard R NeubigPeng T KhawPublished in: Scientific reports (2017)
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.
Keyphrases
- transcription factor
- smooth muscle
- minimally invasive
- genome wide
- wound healing
- coronary artery bypass
- stem cells
- copy number
- mouse model
- cell therapy
- anti inflammatory
- ionic liquid
- coronary artery disease
- high throughput
- liver fibrosis
- mesenchymal stem cells
- atrial fibrillation
- surgical site infection
- electronic health record
- optical coherence tomography