Inducible scAAV2.GRE.MMP1 lowers IOP long-term in a large animal model for steroid-induced glaucoma gene therapy

Current treatment of glaucoma relies on administration of daily drops or eye surgery. A gene therapy approach to treat steroid-induced glaucoma would bring a resolution to millions of people worldwide who depend on glucocorticoid therapy for a myriad of inflammatory disorders. Previously, we had cha...

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Bibliographic Details
Published in:Gene therapy 2016-05, Vol.23 (5), p.438-449
Main Authors: Borrás, T, Buie, L K, Spiga, M G
Format: Article
Language:English
Subjects:
Animal models
Animals
Care and treatment
Control
Dependovirus - genetics
Dependoviruses
Disease Models, Animal
Expression vectors
Eyes & eyesight
Fluprednisolone - administration & dosage
Fluprednisolone - analogs & derivatives
Gene therapy
Genetic Therapy
Genetic Vectors
Genomes
Glaucoma
Glaucoma - genetics
Glaucoma - therapy
Glucocorticoids
Glucocorticoids - genetics
Glucocorticoids - therapeutic use
Humans
Inflammatory diseases
Interstitial collagenase
Intraocular pressure
Intraocular Pressure - drug effects
Matrix Metalloproteinase 1 - genetics
Matrix Metalloproteinase 1 - therapeutic use
Methods
Ophthalmology
Patient outcomes
Sheep
Steroids
Toxicity
Trabecular Meshwork - drug effects
Trabecular Meshwork - pathology
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Description
Summary:Current treatment of glaucoma relies on administration of daily drops or eye surgery. A gene therapy approach to treat steroid-induced glaucoma would bring a resolution to millions of people worldwide who depend on glucocorticoid therapy for a myriad of inflammatory disorders. Previously, we had characterized a short-term Adh.GRE.MMP1 gene vector for the production of steroid-induced MMP1 in the trabecular meshwork and tested reduction of elevated intraocular pressure (IOP) in a sheep model. Here we conducted a trial transferring the same transgene cassette to a clinically safe vector (scAAV2), and extended the therapeutic outcome to longer periods of times. No evidence of ocular and/or systemic toxicity was observed. Viral genome distributions showed potential reinducible vector DNAs in the trabecular meshwork (0.4 v.g. per cell) and negligible copies in six major internal organs (0.00002-0.005 v.g. per cell). Histological sections confirmed successful transduction of scAAV2.GFP to the trabecular meshwork. Optimization of the sheep steroid-induced hypertensive model revealed that topical ophthalmic drug difluprednate 0.05% (durezol) induced the highest IOP elevation in the shortest time. This is the first efficacy/toxicity study of a feasible gene therapy treatment of steroid-induced hypertension using clinically accepted self-complementary adeno-associated vectors (scAAV) vectors in a large animal model.
ISSN:0969-7128
1476-5462
DOI:10.1038/gt.2016.14