AAV-mediated intravitreal gene therapy reduces lysosomal storage in the retinal pigmented epithelium and improves retinal function in adult MPS VII mice.

The beta-glucuronidase-deficient mucopolysaccharidosis type VII (MPS VII) mouse accumulates partially degraded glycosaminoglycans in many cell types, including retinal pigmented epithelial (RPE) cells in the eye. This lysosomal storage in RPE cells leads to progressive retinal degeneration and reduced function as measured by flash electroretinography (ERG). The impact of AAV-mediated intraocular gene therapy on pathology and retinal function was examined in normal and MPS VII mice treated at 4 weeks of age, when lysosomal storage is evident but functional impairment is minimal in affected animals. At 16 weeks, an age at which untreated MPS VII mice have advanced histologic lesions and significantly reduced ERG amplitudes, treated eyes had nearly normal levels of beta-glucuronidase activity, preservation of cells in the outer nuclear layer of the retina, and decreased lysosomal storage within the RPE. The AAV-treated MPS VII mice also had significantly increased dark-adapted ERG amplitudes compared to untreated MPS VII mice. Although retinal function was improved, the efficacy of the treatment depended heavily on parameters related to the injection procedure, such as the injection volume, injection site, and vector dose. These data suggest that intraocular AAV-mediated therapy may be efficacious for treating the retinal disease associated with certain lysosomal storage diseases.