title: Restoration of vision in the pde6β-deficient dog, a large animal model of rod-cone dystrophy.
abstract: Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6β (n = 4) or AAV2/8RK.cpde6β (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6β- and AAV2/8RK.cpde6β-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment.
authors: Translational Gene Therapy for Retinal and Neuromuscular Diseases, INSERM UMR 1089, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France.
authors: Lolita
authors: L
authors: Petit
authors: Elsa
authors: E
authors: Lhériteau
authors: Michel
authors: M
authors: Weber
authors: Guylène
authors: G
authors: Le Meur
authors: Jack-Yves
authors: JY
authors: Deschamps
authors: Nathalie
authors: N
authors: Provost
authors: Alexandra
authors: A
authors: Mendes-Madeira
authors: Lyse
authors: L
authors: Libeau
authors: Caroline
authors: C
authors: Guihal
authors: Marie-Anne
authors: MA
authors: Colle
authors: Philippe
authors: P
authors: Moullier
authors: Fabienne
authors: F
authors: Rolling
mesh_terms: D000818:Animals; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000172:deficiency* / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D004596:Electroretinography; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012171:Retinal Vessels / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000503:physiopathology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes; D016896:Treatment Outcome; D014785:Vision, Ocular
chemical_list: D012333:RNA, Messenger; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6