Therapeutic potential of AAV-mediated MMP-3 secretion from corneal endothelium in treating glaucoma

Jeffrey O'Callaghan, Darragh E. Crosbie, Paul S. Cassidy, Joseph M. Sherwood, Cassandra Flügel-Koch, Elke Lütjen-Drecoll, Marian M. Humphries, Ester Reina-Torres, Deborah Wallace, Anna Sophia Kiang, Matthew Campbell, W. Daniel Stamer, Darryl R. Overby, Colm O'Brien, Lawrence C.S. Tam, Peter Humphries

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Intraocular pressure (IOP) is maintained as a result of the balance between production of aqueous humour (AH) by the ciliary processes and hydrodynamic resistance to its outflow through the conventional outflow pathway comprising the trabecular meshwork (TM) and Schlemm's canal (SC). Elevated IOP, which can be caused by increased resistance to AH outflow, is a major risk factor for open-angle glaucoma. Matrix metalloproteinases (MMPs) contribute to conventional aqueous outflow homeostasis in their capacity to remodel extracellular matrices, which has a direct impact on aqueous outflow resistance and IOP. We observed decreased MMP-3 activity in human glaucomatous AH compared to age-matched normotensive control AH. Treatment with glaucomatous AH resulted in significantly increased transendothelial resistance of SC endothelial and TM cell monolayers and reduced monolayer permeability when compared to control AH, or supplemented treatment with exogenous MMP-3. Intracameral inoculation of AAV-2/9 containing a CMV-driven MMP-3 gene (AAV-MMP-3) into wild type mice resulted in efficient transduction of corneal endothelium and an increase in aqueous concentration and activity of MMP-3. Most importantly, AAV-mediated expression of MMP-3 increased outflow facility and decreased IOP, and controlled expression using an inducible promoter activated by topical administration of doxycycline achieved the same effect. Ultrastructural analysis of MMP-3 treated matrices by transmission electron microscopy revealed remodelling and degradation of core extracellular.

Original languageEnglish (US)
Article numberddx028
Pages (from-to)1230-1246
Number of pages17
JournalHuman molecular genetics
Volume26
Issue number7
DOIs
StatePublished - Apr 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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