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1From the Vision Science Group, Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, and the 2Department of Ophthalmology, School of Medicine, Mason Eye Institute, University of Missouri-Columbia, Columbia, Missouri; the 3Department of Ophthalmology, Ulleval University Hospital, Oslo, Norway; the 4Department of Pathophysiology of Vision and Neuroophthalmology, University Eye Hospital, Tübingen, Germany; the 5National Eye Institute, National Institutes of Health, Bethesda, Maryland; and the 6Centre for Ophthalmology and Visual Science, University of Western Australia, Nedlands, Australia.
PURPOSE. To assess the efficacy of AAV-mediated gene therapy to restore vision in a large number of RPE65-/- dogs and to determine whether systemic and local side effects are caused by the treatment.
METHODS. Normal RPE65 dog cDNA was subcloned into an rAAV vector under control of a cytomegalovirus promoter, and an AAV.GFP control vector was also produced with the titers 2 x 1012 particles/mL and 2 x 1010 transducing U/mL, respectively. RPE65-/- dogs, aged 4 to 30 months were treated with subretinal injections of the AAV.RPE65 and control vectors, respectively, in each eye, and three 24- to 30-month-old normal control dogs with the latter. Baseline and postoperative systemic and ophthalmic examinations, blood screenings, vision testing, and electroretinography (ERG) were performed. Two RPE65-/- dogs were killed at 3 and 6 months after treatment for morphologic examination of the retinas.
RESULTS. RPE65-/- dogs were practically blind from birth with nonrecordable or low-amplitude ERGs. Construct injections or sham surgeries were performed in 28 eyes; 11 were injected subretinally with the AAV.RPE65 construct. ERGs at 3 months after surgery showed that in the latter eyes, dark-adapted b-wave amplitudes recovered to an average of 28% of normal, and light adapted b-wave amplitudes to 32% of normal. ERG amplitudes were not reduced during a 6- to 9-month follow-up. No systemic side effects were observed, but uveitis developed in nine AAV.RPE65-treated eyes. No uveitis was observed in the eyes treated with the control vector. Immunocytochemistry showed expression of RPE65 in the retinal pigment epithelium (RPE) of AAV.RPE65-treated eyes. Fluorescence microscopy showed expression of green fluorescent protein (GFP) in the RPE and, to a lesser extent, in the neural retinas of AAV.GFP-treated eyes. Ultrastructurally, a reversal of RPE lipid droplet accumulation was observed at the AAV.RPE65 transgene injection site, but not at the site of injection of the control vector.
CONCLUSIONS. In 10 of 11 treated RPE65-/- eyes, gene transfer resulted in development of vision, both subjectively apparent by loss of nystagmus, and objectively recorded by ERG. Structurally, there was reversal of lipid droplet accumulation in the RPE. Uveitis developed in 75% of the transgene-treated eyes, a complication possibly due to an immunopathogenic response to the RPE65 molecule.
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