title: Gene therapy restores vision-dependent behavior as well as retinal structure and function in a mouse model of RPE65 Leber congenital amaurosis.
abstract: Retinal pigment epithelium-specific protein 65 kDa (RPE65) is a protein responsible for isomerization of all-trans-retinaldehyde to its photoactive 11-cis-retinaldehyde and is essential for the visual cycle. RPE65 mutations can cause severe, early onset retinal diseases such as Leber congenital amaurosis (LCA). A naturally occurring rodent model of LCA with a recessive nonsense Rpe65 mutation, the rd12 mouse, displays a profoundly diminished rod electroretinogram (ERG), an absence of 11-cis-retinaldehyde and rhodopsin, an overaccumulation of retinyl esters in retinal pigmented epithelial (RPE) cells, and photoreceptor degeneration. rd12 mice were injected subretinally at postnatal day 14 with rAAV5-CBA-hRPE65 vector. RPE65 expression was found over large areas of RPE soon after treatment. This led to improved rhodopsin levels with ERG signals restored to near normal. Retinyl ester levels were maintained at near normal, and fundus and retinal morphology remained normal. All parameters of restored retinal health remained stable for at least 7 months. The Morris water maze behavioral test was modified to test rod function under very dim light; rd12 mice treated in one eye performed similar to normally sighted C57BL/6J mice, while untreated rd12 mice performed very poorly, demonstrating that gene therapy can restore normal vision-dependent behavior in a congenitally blind animal.
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA. jpang@eye.ufl.edu
authors.forename: Ji-jing
authors.initials: JJ
authors.lastname: Pang
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.forename: Steven
authors.initials: S
authors.lastname: Nusinowitz
authors.forename: Syed M
authors.initials: SM
authors.lastname: Noorwez
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Asha
authors.initials: A
authors.lastname: Rani
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Foster
authors.forename: Vince A
authors.initials: VA
authors.lastname: Chiodo
authors.forename: Thomas
authors.initials: T
authors.lastname: Doyle
authors.forename: Huashi
authors.initials: H
authors.lastname: Li
authors.forename: Ritu
authors.initials: R
authors.lastname: Malhotra
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Teusner
authors.forename: J Hugh
authors.initials: JH
authors.lastname: McDowell
authors.forename: Seok-Hong
authors.initials: SH
authors.lastname: Min
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Li
authors.forename: Shalesh
authors.initials: S
authors.lastname: Kaushal
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics*; D000229:Dependovirus; D004195:Disease Models, Animal; D004952:Esters; D005136:Eye Proteins / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D051379:Mice; D008810:Mice, Inbred C57BL; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D012160:Retina / Q000033:anatomy & histology* / Q000473:pathology / Q000502:physiology*; D012243:Rhodopsin / Q000096:biosynthesis; D014785:Vision, Ocular / Q000235:genetics*; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D004952:Esters; D005136:Eye Proteins; D012243:Rhodopsin; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase