Therapeutic potential of AAV-mediated MMP-3 secretion from corneal endothelium in treating glaucoma
O'Callaghan J, Crosbie DE, Cassidy PS, Sherwood JM, Flügel-Koch C, Lütjen-Drecoll E, Humphries MM, Reina-Torres E, Wallace D, Kiang AS, Campbell M, Stamer WD, Overby DR, O'Brien C, Tam LCS, Humphries P (2017)
Publication Type: Journal article
Publication year: 2017
Journal
Book Volume: 26
Pages Range: 1230-1246
Journal Issue: 7
DOI: 10.1093/hmg/ddx028
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 matrix components. These results indicate that periodic induction, via use of an eye drop, of AAV-mediated secretion of MMP-3 into AH could have therapeutic potential for those cases of glaucoma that are sub-optimally responsive to conventional pressure-reducing medications.
Authors with CRIS profile
Cassandra Flügel-Koch
Medizinische Fakultät
Elke Lütjen-Drecoll
Lehrstuhl für Funktionelle und Klinische Anatomie
Involved external institutions
Trinity College Dublin
Ireland (IE)
Imperial College London / The Imperial College of Science, Technology and Medicine
United Kingdom (GB)
University College Dublin (UCD)
Ireland (IE)
Duke University
United States (USA) (US)
Mater Misericordiae University Hospital (MMUH) / Ospidéal an Mater Misercordiae
Ireland (IE)
Ireland (IE)
Imperial College London / The Imperial College of Science, Technology and Medicine
United Kingdom (GB)
University College Dublin (UCD)
Ireland (IE)
Duke University
United States (USA) (US)
Mater Misericordiae University Hospital (MMUH) / Ospidéal an Mater Misercordiae
Ireland (IE)
How to cite
APA:
O'Callaghan, J., Crosbie, D.E., Cassidy, P.S., Sherwood, J.M., Flügel-Koch, C., Lütjen-Drecoll, E.,... Humphries, P. (2017). Therapeutic potential of AAV-mediated MMP-3 secretion from corneal endothelium in treating glaucoma. Human Molecular Genetics, 26(7), 1230-1246. https://dx.doi.org/10.1093/hmg/ddx028
MLA:
O'Callaghan, Jeffrey, et al. "Therapeutic potential of AAV-mediated MMP-3 secretion from corneal endothelium in treating glaucoma." Human Molecular Genetics 26.7 (2017): 1230-1246.
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