title: AAV-mediated Gene Therapy Halts Retinal Degeneration in PDE6β-deficient Dogs.
abstract: We previously reported that subretinal injection of AAV2/5 RK.cpde6β allowed long-term preservation of photoreceptor function and vision in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency. The present study builds on these earlier findings to provide a detailed assessment of the long-term effects of gene therapy on the spatiotemporal pattern of retinal degeneration in rcd1 dogs treated at 20 days of age. We analyzed the density distribution of the retinal layers and of particular photoreceptor cells in 3.5-year-old treated and untreated rcd1 dogs. Whereas no rods were observed outside the bleb or in untreated eyes, gene transfer halted rod degeneration in all vector-exposed regions. Moreover, while gene therapy resulted in the preservation of cones, glial cells and both the inner nuclear and ganglion cell layers, no cells remained in vector-unexposed retinas, except in the visual streak. Finally, the retinal structure of treated 3.5-year-old rcd1 dogs was identical to that of unaffected 4-month-old rcd1 dogs, indicating near complete preservation. Our findings indicate that gene therapy arrests the degenerative process even if intervention is initiated after the onset of photoreceptor degeneration, and point to significant potential of this therapeutic approach in future clinical trials.
authors: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors: Virginie
authors: V
authors: Pichard
authors: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors: Nathalie
authors: N
authors: Provost
authors: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors: Alexandra
authors: A
authors: Mendes-Madeira
authors: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors: Lyse
authors: L
authors: Libeau
authors: Cellular and Tissular Imaging Core Facility of Nantes University, SFR Santé Francois Bonamy, INSERM UMS016/CNRS UMS3556, Nantes, France.
authors: Philippe
authors: P
authors: Hulin
authors: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors: Kizito-Tshitoko
authors: KT
authors: Tshilenge
authors: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors: Marine
authors: M
authors: Biget
authors: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
authors: Baptiste
authors: B
authors: Ameline
authors: Emergency and Critical Care Unit, ONIRIS, Nantes-Atlantic College of Veterinary Medicine, Food Science and Engineering, Nantes, France.
authors: Jack-Yves
authors: JY
authors: Deschamps
authors: CHU de Nantes, Service d'Ophtalmologie, Nantes, France.
authors: Michel
authors: M
authors: Weber
authors: CHU de Nantes, Service d'Ophtalmologie, Nantes, France.
authors: Guylène
authors: G
authors: Le Meur
authors: UMR 703 PAnTher INRA/ONIRIS, Nantes-Atlantic College of Veterinary Medicine, Food Science and Engineering, Nantes, France.
authors: Marie-Anne
authors: MA
authors: Colle
authors: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.|Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida, USA.
authors: Philippe
authors: P
authors: Moullier
authors: Atlantic Gene Therapies, INSERM UMR 1089, Université de Nantes, CHU de Nantes, Nantes, France.
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; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D012160:Retina / Q000503:physiopathology; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology*
chemical_list: D054707:Cyclic Nucleotide Phosphodiesterases, Type 6