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J.M. Ogilvie, A.K. Hennig, K.K. Ohlemiller, M.S. Sands; AAV–Mediated Intravitreal Gene Therapy Reduces Lysosomal Storage in the Retinal Pigmented Epithelium and Improves Retinal Function in Adult MPS VII Mice . Invest. Ophthalmol. Vis. Sci. 2004;45(13):3697.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: The ß–glucuronidase deficient Mucopolysaccharidosis type VII (MPS VII) mouse accumulates partially degraded glycosaminoglycans in lysosomes. The lysosomal storage in retinal pigmented epithelial (RPE) cells leads to progressive retinal degeneration and reduced retinal function. The purpose of this study was to determine the effect of intraocular gene therapy on lysosomal storage and retinal function. Methods: Recombinant adeno–associated virus containing the human ß–glucuronidase cDNA (AAV–GUSB) was administered to MPS VII mice at 4 weeks of age, when lysosomal storage is evident but functional impairment is minimal. Controls included normal littermates that received intravitreal injections of the same virus, normal mice treated with vehicle (lactated Ringer's solution) without virus, and untreated normal and MPS VII mice. Flash electoretinography was performed twelve weeks after treatment. Tissue samples were then harvested for biochemical and histological examination. Results: AAV–GUSB–treated MPS VII eyes had increased ß–glucuronidase activity levels, preservation of cells in the outer nuclear layer of the retina and decreased lysosomal storage within the RPE. Rod–cone function was also significantly increased compared to untreated and sham–treated MPS VII mice. In contrast, normal mice treated with either culture medium or AAV–GUSB had decreased ERG amplitudes, compared with untreated normal controls. The decrease was, in part, attributable to long–term traumatic effects of the treatment, since decreasing the volume and the dose of virus administered increased amplitudes. Conclusions: Recombinant gene therapy with AAV–GUSB significantly increases preservation of retinal structure and function in MPS VII mice, with the efficacy of treatment dependent on the injection volume and virus dose. These data suggest that intraocular AAV–mediated therapy may be efficacious for the treatment of the retinal disease associated with certain lysosomal storage diseases.
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