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

Gene Therapy volume 23, pages 438–449 (2016)Cite this article

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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.

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Acknowledgements

This study was supported by National Institutes of Health Grants EY11906 (TB) and by an unrestricted grant from the Research to Prevent Blindness to the Department of Ophthalmology at the University of North Carolina at Chapel Hill. We thank Dr Donald L. Budenz for suggestions and advise, Dr Scott D. Lawrence for performing the sub-tenon injections; and members of the laboratory Dr Juan Carabana, Dr Brandon Lane and Renekia Elliot, for their help managing the sheep.

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  1. Department of Ophthalmology, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    T Borrás, L K Buie & M G Spiga

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  1. T Borrás
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Correspondence to T Borrás.

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Borrás, T., Buie, L. & Spiga, M. Inducible scAAV2.GRE.MMP1 lowers IOP long-term in a large animal model for steroid-induced glaucoma gene therapy. Gene Ther 23, 438–449 (2016). https://doi.org/10.1038/gt.2016.14

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