July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
INDUCIBLE MMP-3 EXPRESSION IN A STEROID-INDUCED MURINE MODEL OF GLAUCOMA
Author Affiliations & Notes
  • Jeffrey O'Callaghan
    Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
  • Paul S. Cassidy
    Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
  • Ester Reina-Torres
    Department of Bioengineering, Imperial College London, London, United Kingdom
  • Joseph Sherwood
    Department of Bioengineering, Imperial College London, London, United Kingdom
  • Marian M Humphries
    Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
  • Matthew Campbell
    Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
  • Colm J O'Brien
    Department of Ophthalmology, Mater Misericordiae University Hospital, Dublin, Ireland
  • Elke Lütjen-Drecoll
    Department of Anatomy II, University of Erlangen-Nurnberg, Erlangen, Germany
  • W Daniel Stamer
    Departments of Ophthalmology and Biomedical Engineering, Duke University, Durham, North Carolina, United States
  • Darryl R Overby
    Department of Bioengineering, Imperial College London, London, United Kingdom
  • Peter Humphries
    Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
  • Footnotes
    Commercial Relationships   Jeffrey O'Callaghan, None; Paul Cassidy, None; Ester Reina-Torres, None; Joseph Sherwood, None; Marian Humphries, None; Matthew Campbell, None; Colm O'Brien, None; Elke Lütjen-Drecoll, None; W Daniel Stamer, None; Darryl Overby, None; Peter Humphries, None
  • Footnotes
    Support  European Research Council [ERC-2012-AdG 322656-Oculus], Science Foundation Ireland [12/ERC/B2539].
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 3505. doi:
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      Jeffrey O'Callaghan, Paul S. Cassidy, Ester Reina-Torres, Joseph Sherwood, Marian M Humphries, Matthew Campbell, Colm J O'Brien, Elke Lütjen-Drecoll, W Daniel Stamer, Darryl R Overby, Peter Humphries; INDUCIBLE MMP-3 EXPRESSION IN A STEROID-INDUCED MURINE MODEL OF GLAUCOMA. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3505.

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

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Abstract

Purpose : We have previously reported on the efficacy of AAV-2/9-mediated expression of matrix metalloproteinase 3 (MMP-3) from the corneal endothelium, expressed both constitutively and induced by periodic topical administration of doxycycline in wild type mice (O’Callaghan et al. 2017, Hum. Mol. Genet.). MMP-3 secretion results in significantly increased outflow facility, with concomitant remodelling of the extracellular matrix and a reduction in intraocular pressure (IOP). We report here results obtained from using this approach in a widely accepted murine model of steroid-induced glaucoma.

Methods : Animals were intracamerally inoculated with inducible AAV-MMP-3 or contralateral AAV-eGFP as a control. 2 weeks later, animals were implanted with a micro-osmotic pump containing either cyclodextrin (vehicle control group) or dexamethasone (DEX) at 2 mg/kg/day for 4 weeks. Virus was activated by topical administration of doxycycline eye drops (0.2%) 2 weeks after micro pump implantation. Tonometric IOP readings were taken every week and facility was measured ex vivo using iPerfusion 2 weeks after induction.

Results : MMP-3 impeded the increase in IOP observed in response to systemically-administered DEX. For the DEX cohort: in eGFP injected eyes, IOP increased by 3.5 ± 1.9 mmHg (median ± median absolute deviation) (p=<0.001, N=14) over the 6 weeks, and in MMP-3 treated eyes, IOP increased by 2.1 ± 1.4 mmHg (p=0.008, N=14) over the same period. At the experimental endpoint, IOP had a median decrease of 1.9 ± 0.1 mmHg in the MMP-3 treated eyes as compared to eGFP treated eyes (p=0.002, N=14). No significant changes in IOP were observed between MMP-3 and eGFP-treated eyes in the control group (N=10). Facility in MMP-3 treated eyes was an average of 45% [18, 78%] (p=0.005, N=8) higher than in eGFP-injected eyes in the DEX cohort, and an average of 59% [26, 100%] greater in the control cohort (p=0.002, N=8). Electron microscopy showed a significant increase in optically empty spaces in MMP-3 treated eyes at the sub-endothelial region around the circumference of the Schlemm’s canal of 16% [5, 27%] (p=0.017, N=4).

Conclusions : Doxycycline-induced AAV-mediated expression of MMP-3 from the corneal endothelium significantly increases outflow facility and reduces IOP in hypertensive animals by degradation of ECM.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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