Therapeutic potential of AAV-mediated MMP-3 secretion from corneal endothelium in treating glaucoma.
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.
Ocular Genetics Unit, Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin, D2, Ireland.
Jeffrey
J
O'Callaghan
Ocular Genetics Unit, Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin, D2, Ireland.
Darragh E
DE
Crosbie
Ocular Genetics Unit, Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin, D2, Ireland.
Paul S
PS
Cassidy
Department of Bioengineering, Imperial College London, London, SW7 2BX, UK.
Joseph M
JM
Sherwood
Department of Anatomy II, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany.
Cassandra
C
Flügel-Koch
Department of Anatomy II, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany.
Elke
E
Lütjen-Drecoll
Ocular Genetics Unit, Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin, D2, Ireland.
Marian M
MM
Humphries
Ocular Genetics Unit, Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin, D2, Ireland.
Ester
E
Reina-Torres
Clinical Research Centre, UCD School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
Deborah
D
Wallace
Ocular Genetics Unit, Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin, D2, Ireland.
Anna-Sophia
AS
Kiang
Ocular Genetics Unit, Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin, D2, Ireland.
Matthew
M
Campbell
Departments of Ophthalmology and Biomedical Engineering, Duke University, Durham, NC, USA.
W Daniel
WD
Stamer
Department of Bioengineering, Imperial College London, London, SW7 2BX, UK.
Darryl R
DR
Overby
Department of Ophthalmology, Mater Misericordiae University Hospital, Dublin, D7, Ireland.
Colm
C
O'Brien
Ocular Genetics Unit, Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin, D2, Ireland.
Lawrence C S
LCS
Tam
Ocular Genetics Unit, Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin, D2, Ireland.
Peter
P
Humphries
D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004728:Endothelium, Corneal / Q000378:metabolism / Q000473:pathology; D005901:Glaucoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics* / Q000627:therapeutic use; D051379:Mice; D009883:Ophthalmic Solutions / Q000627:therapeutic use
D009883:Ophthalmic Solutions; D019278:Matrix Metalloproteinase 3