title: Inducible scAAV2.GRE.MMP1 lowers IOP long-term in a large animal model for steroid-induced glaucoma gene therapy.
abstract: 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.
authors: Department of Ophthalmology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: T
authors: T
authors: Borrás
authors: Department of Ophthalmology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: L K
authors: LK
authors: Buie
authors: Department of Ophthalmology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: M G
authors: MG
authors: Spiga
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005477:Fluprednisolone / Q000008:administration & dosage / Q000031:analogs & derivatives; D015316:Genetic Therapy; D005822:Genetic Vectors; D005901:Glaucoma / Q000235:genetics / Q000628:therapy*; D005938:Glucocorticoids / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000627:therapeutic use; D012756:Sheep; D014129:Trabecular Meshwork / Q000187:drug effects* / Q000473:pathology
chemical_list: D005938:Glucocorticoids; D005477:Fluprednisolone; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; C015808:difluprednate