title: Gene Augmentation Therapy Restores Retinal Function and Visual Behavior in a Sheep Model of CNGA3 Achromatopsia.
abstract: Achromatopsia is a hereditary form of day blindness caused by cone photoreceptor dysfunction. Affected patients suffer from congenital color blindness, photosensitivity, and low visual acuity. Mutations in the CNGA3 gene are a major cause of achromatopsia, and a sheep model of this disease was recently characterized by our group. Here, we report that unilateral subretinal delivery of an adeno-associated virus serotype 5 (AAV5) vector carrying either the mouse or the human intact CNGA3 gene under the control of the red/green opsin promoter results in long-term recovery of visual function in CNGA3-mutant sheep. Treated animals demonstrated shorter maze passage times and a reduced number of collisions with obstacles compared with their pretreatment status, with values close to those of unaffected sheep. This effect was abolished when the treated eye was patched. Electroretinography (ERG) showed marked improvement in cone function. Retinal expression of the transfected human and mouse CNGA3 genes at the mRNA level was shown by polymerase chain reaction (PCR), and cone-specific expression of CNGA3 protein was demonstrated by immunohistochemisrty. The rescue effect has so far been maintained for over 3 years in the first-treated animals, with no obvious ocular or systemic side effects. The results support future application of subretinal AAV5-mediated gene-augmentation therapy in CNGA3 achromatopsia patients.
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.affiliation: Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel.
authors.forename: Elisha
authors.initials: E
authors.lastname: Gootwine
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Alexey
authors.initials: A
authors.lastname: Obolensky
authors.affiliation: Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Raaya
authors.initials: R
authors.lastname: Ezra-Elia
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ayala
authors.initials: A
authors.lastname: Ejzenberg
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Lina
authors.initials: L
authors.lastname: Zelinger
authors.affiliation: Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel.
authors.forename: Hen
authors.initials: H
authors.lastname: Honig
authors.affiliation: Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rosov
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Yamin
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
authors.affiliation: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Edward
authors.initials: E
authors.lastname: Averbukh
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, Florida, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.affiliation: Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Ron
authors.initials: R
authors.lastname: Ofri
mesh_terms: D000818:Animals; D003117:Color Vision Defects / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006720:Homozygote; D006801:Humans; D056965:Injections, Intraocular; D008297:Male; D018782:Maze Learning; D051379:Mice; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics; D012160:Retina / Q000378:metabolism*; D012756:Sheep; D014785:Vision, Ocular / Q000235:genetics*
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D012333:RNA, Messenger