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R. Gerometta, M. G. Spiga, O. A. Candia, T. Borras; Treatment of Steroid-induced Ocular Hypertension by Inducible Gene Transfer of MMP1 in Sheep. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5722.
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We recently developed an in vivo ovine model of steroid-induced ocular hypertension (IOVS, E-pub, Sept. 2008) with 100% reliability. Now, we investigated 1) whether intracameral injection of the adenoviral vector AdhGRE.MMP1 would reduce the elevated pressure induced by triamcinolone and/or prednisolone in sheep, and 2) whether the delivery of this vector would produce inflammation.
An adenoviral vector was constructed carrying the coding cDNA (1.4 Kb) of the human metalloproteinase 1 gene (MMP1) under the control of 3 tandem copies of the glucocorticoid response element (GRE) consensus sequence fused to a TATA-like promoter region from the HSV-thymidine kinase gene. A high titer purified viral stock was obtained by double banding in CsCl. The 6 eyes of three sheep were selected for the following protocols: a) in 3 eyes an IOP increase was induced previous to a 30 uL injection of the vector to the anterior chamber (AC); b) in 2 untreated eyes, a same amount of the vector was injected into the AC 24 hrs prior to the starting of the corticosteroid treatment; and c) in one eye prednisolone was applied topically 3 times per day to assure that the lack of response to the corticosteroid in "b" was due to the earlier injection of the viral vector. IOP was measured with a Perkins tonometer. The Perkins readings were converted to mm Hg with a previously obtained calibration curve. Inflammation was monitored by careful visual inspection of the eyes.
In the 3 eyes in which the IOP was already elevated to 24-30, injection of the vector reduced IOP to 15.8 in 24 hrs, and to 10-13 in 48 hrs. This lowering effect remained for the next week that the IOP was monitored. In the 2 eyes with normal IOP, the pre-injection of the virus prevented the increase in IOP normally produced by the corticosteroid (steroid treatment began 24 hrs after the virus injection). IOP remained at a level of about 12 despite the continuous application of the corticosteroid for the 1 week tested. A robust increase in IOP by prednisolone was observed in the eye that only received the steroid. There were no signs of ocular inflammation, or discomfort to the animals.
A single dose of a gene therapy vector carrying an inducible metalloproteinase human gene can both a) prevent the increase in IOP normally produced by corticosteroid instillation in the sheep model, and b) quickly reverse the IOP increase previously elicited by the corticosteroid. These first results open the door for a potential treatment of steroid glaucoma with inducible overexpression of ECM modulator genes.
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