Therapeutic potential of AAV-mediated MMP-3 secretion from corneal endothelium in treating glaucoma
Autor: | Matthew Campbell, Joseph M. Sherwood, Elke Lütjen-Drecoll, Lawrence C. S. Tam, Cassandra Flügel-Koch, Colm O'Brien, Deborah Wallace, Anna-Sophia Kiang, Paul S. Cassidy, Ester Reina-Torres, Peter Humphries, Jeffrey O'Callaghan, Darryl R. Overby, W. Daniel Stamer, Marian M. Humphries, Darragh E. Crosbie |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Intraocular pressure genetic structures MATRIX METALLOPROTEINASES Glaucoma Pharmacology INDUCED OCULAR HYPERTENSION INTRAOCULAR-PRESSURE Mice 0302 clinical medicine AQUEOUS-HUMOR Genetics (clinical) Genetics & Heredity Endothelium Corneal 11 Medical And Health Sciences Articles General Medicine Anatomy CULTURED HUMAN Dependovirus medicine.anatomical_structure Matrix Metalloproteinase 3 OPEN-ANGLE GLAUCOMA Life Sciences & Biomedicine Biochemistry & Molecular Biology CELLS EXPRESS Corneal endothelium Endothelium Biology Aqueous Humor 03 medical and health sciences Ciliary processes OUTFLOW FACILITY Genetics medicine Extracellular Animals Humans Molecular Biology Intraocular Pressure Science & Technology Aqueous humour 06 Biological Sciences medicine.disease eye diseases HUMAN TRABECULAR MESHWORK Disease Models Animal 030104 developmental biology 030221 ophthalmology & optometry sense organs Trabecular meshwork Ophthalmic Solutions EXFOLIATION GLAUCOMA |
Zdroj: | Human Molecular Genetics |
ISSN: | 1460-2083 0964-6906 |
Popis: | 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. |
Databáze: | OpenAIRE |
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