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Background  RPE65 is an essential molecule in the retinoid-visual cycle, and  RPE65  gene mutations cause the congenital human blindness known as Leber congenital amaurosis (LCA). Somatic gene therapy delivered to the retina of blind dogs with an  RPE65  mutation dramatically restores retinal physiology and has sparked international interest in human treatment trials for this incurable disease. An unanswered question is how the visual cortex responds after prolonged sensory deprivation from retinal dysfunction. We therefore studied the cortex of  RPE65 -mutant dogs before and after retinal gene therapy. Then, we inquired whether there is visual pathway integrity and responsivity in adult humans with LCA due to  RPE65  mutations ( RPE65 -LCA).    Methods and Findings    RPE65 -mutant dogs were studied with fMRI. Prior to therapy, retinal and subcortical responses to light were markedly diminished, and there were minimal cortical responses within the primary visual areas of the lateral gyrus (activation amplitude mean ± standard deviation [SD] = 0.07% ± 0.06% and volume = 1.3 ± 0.6 cm 3 ). Following therapy, retinal and subcortical response restoration was accompanied by increased amplitude (0.18% ± 0.06%) and volume (8.2 ± 0.8 cm 3 ) of activation within the lateral gyrus ( p  < 0.005 for both). Cortical recovery occurred rapidly (within a month of treatment) and was persistent (as long as 2.5 y after treatment). Recovery was present even when treatment was provided as late as 1–4 y of age. Human  RPE65 -LCA patients (ages 18–23 y) were studied with structural magnetic resonance imaging. Optic nerve diameter (3.2 ± 0.5 mm) was within the normal range (3.2 ± 0.3 mm), and occipital cortical white matter density as judged by voxel-based morphometry was slightly but significantly altered (1.3 SD below control average,  p  = 0.005). Functional magnetic resonance imaging in human  RPE65 -LCA patients revealed cortical responses with a markedly diminished activation volume (8.8 ± 1.2 cm 3 ) compared to controls (29.7 ± 8.3 cm 3 ,  p  < 0.001) when stimulated with lower intensity light. Unexpectedly, cortical response volume (41.2 ± 11.1 cm 3 ) was comparable to normal (48.8 ± 3.1 cm 3 ,  p  = 0.2) with higher intensity light stimulation.    Conclusions  Visual cortical responses dramatically improve after retinal gene therapy in the canine model of  RPE65 -LCA. Human  RPE65 -LCA patients have preserved visual pathway anatomy and detectable cortical activation despite limited visual experience. Taken together, the results support the potential for human visual benefit from retinal therapies currently being aimed at restoring vision to the congenitally blind with genetic retinal disease.

Canine and Human Visual Cortex Intact and Responsive Despite Early Retinal Blindness from RPE65 Mutation