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
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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