Gene Therapy Restores Vision-Dependent Behavior as Well as Retinal Structure and Function in a Mouse Model of RPE65 Leber Congenital Amaurosis

摘要: Retinal pigment epithelium-specific protein 65 kDa (RPE65) is a responsible for isomerization of all-trans-retinaldehyde to its photoactive 11-cis-retinaldehyde and essential the visual cycle. RPE65 mutations can cause severe, early onset retinal diseases such as Leber congenital amaurosis (LCA). A naturally occurring rodent model LCA with recessive nonsense Rpe65 mutation, rd12 mouse, displays profoundly diminished rod electroretinogram (ERG), an absence rhodopsin, overaccumulation retinyl esters in pigmented epithelial (RPE) cells, photoreceptor degeneration. mice were injected subretinally at postnatal day 14 rAAV5-CBA-hRPE65 vector. expression was found over large areas RPE soon after treatment. This led improved rhodopsin levels ERG signals restored near normal. Retinyl ester maintained normal, fundus morphology remained All parameters health stable least 7 months. The Morris water maze behavioral test modified function under very dim light; treated one eye performed similar normally sighted C57BL/6J mice, while untreated poorly, demonstrating that gene therapy restore normal vision-dependent behavior congenitally blind animal.