September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Novel MRTF/SRF inhibitors prevent conjunctival scarring after glaucoma filtration surgery: An ex vivo and in vivo study
Author Affiliations & Notes
  • Cynthia Yu-Wai-Man
    National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom
  • Richard M H Lee
    National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom
  • Scott Larsen
    Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Michigan, United States
  • Richard Neubig
    Department of Pharmacology and Toxicology, Michigan State University, Michigan, United States
  • Peng Tee Khaw
    National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom
  • Footnotes
    Commercial Relationships   Cynthia Yu-Wai-Man, None; Richard Lee, None; Scott Larsen, None; Richard Neubig, None; Peng Khaw, None
  • Footnotes
    Support  The National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, the Medical Research Council, the Special Trustees of Moorfields Eye Hospital, the Freemasons Grand Charity, the Michael and Ilse Katz Foundation, the Helen Hamlyn Trust, and Fight for Sight (UK).
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2927. doi:
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    • Get Citation

      Cynthia Yu-Wai-Man, Richard M H Lee, Scott Larsen, Richard Neubig, Peng Tee Khaw; Novel MRTF/SRF inhibitors prevent conjunctival scarring after glaucoma filtration surgery: An ex vivo and in vivo study. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2927.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Post-surgical scarring remains the main cause of failure of glaucoma filtration surgery and current antimetabolites carry the risk of potentially blinding complications. There is increasing evidence that the Myocardin-related transcription factor/Serum response factor (MRTF/SRF) pathway plays a pivotal role in myofibroblast activation. We thus hypothesised that inhibiting the MRTF/SRF pathway would reduce scarring in an aggressive rabbit model of conjunctival fibrosis.

Methods : Ex vivo segments of rabbit conjunctiva were cultured in 100μM MRTF inhibitor 1 or PBS control and imaged for tissue area changes over 30 days. We validated our results using a randomised, prospective, masked-observer study of 24 New Zealand White female rabbits undergoing glaucoma filtration surgery. The animals received either intraoperative 0.2mg/ml mitomycin-C (MMC) [N=6] or postoperative subconjunctival injections of 100μM MRTF inhibitor 1 [N=6] or 100μM MRTF inhibitor 2 [N=6] or PBS [N=6]. Bleb morphology and intraocular pressure were recorded over 30 days. Tissue sections were immunohistochemically graded on day 30. We analysed our results using Kaplan-Meier curve Log-rank test and Student’s t-test.

Results : Ex vivo conjunctival tissue contraction was significantly reduced by 35%(day 6), 39%(day 15), 48%(day 21) and 68%(day 30) with inhibitor 1 compared to PBS (Fig 1). In vivo, bleb survival was significantly improved with inhibitor 1 (p=0.01) and inhibitor 2 (p=0.0005) compared to PBS (Fig 2). The mean day of bleb failure was 28.8 (range=24-30) for MMC, 28.5 (range=24-30) for inhibitor 2, 24.5 (range=15-30) for inhibitor 1, and 14 (range=12-18) for PBS. IOP also remained significantly lower with inhibitor 1 (p=0.027) and inhibitor 2 (p=0.0005) compared to PBS. MMC treatment led to thin avascular blebs with destruction of the epithelial layer. MRTF inhibitors however were not toxic and significantly reduced conjunctival scarring using H&E, picrosirius red, Gomori’s trichrome, and alpha-smooth muscle actin staining (p<0.05).

Conclusions : Novel MRTF inhibitors significantly improved bleb survival and prevented conjunctival scarring. MRTF inhibitor 2 had more potent anti-scarring effects than inhibitor 1. They were safe for subconjunctival delivery and less destructive to local tissue than MMC. MRTF inhibitors show potential as a novel class of anti-fibrotic agents in glaucoma filtration surgery.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

 

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