title: Regulation of retinal function but nonrescue of vision in RPE65-deficient dogs treated with doxycycline-regulatable AAV vectors.
abstract: In previous studies, we demonstrated that recombinant adeno-associated virus (rAAV)-mediated gene transfer of the doxycycline (Dox)-regulatable system allows for the regulation of erythropoietin (EPO) expression in the retina of nonhuman primates after intravenous or oral administration of Dox. In addition, it was shown that administrating different amounts of Dox resulted in a dose-response dynamic of transgene expression. Adeno-associated viral gene therapy has raised hope for the treatment of patients with Leber congenital amaurosis, caused by mutations in the retinal pigment epithelium (RPE)-specific gene RPE65. The preliminary results of three clinical trials suggest some improvement in visual function. However, further improvements might be necessary to optimize vision recovery and this means developing vectors able to generate transgene expression at physiological levels. The purpose of this study was to investigate the ability of the Dox-regulatable system to regulate retinal function in RPE65(-/-) Briard dogs. rAAV vectors expressing RPE65 under the control of either the TetOff and TetOn Dox-regulated promoters or the cytomegalovirus (CMV) constitutive promoter were generated and administered subretinally to seven RPE65-deficient dogs. We demonstrate that the induction and deinduction of retinal function, as assessed by electroretinography (ERG), can be achieved using a Dox-regulatable system, but do not lead to any recovery of vision.
authors.affiliation: Laboratoire de Thérapie Génique, INSERM UMR U649, Institut de Recherche Thérapeutique 1, Université de Nantes, Nantes, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Lhériteau
authors.forename: Lyse
authors.initials: L
authors.lastname: Libeau
authors.forename: Alexandra
authors.initials: A
authors.lastname: Mendes-Madeira
authors.forename: Jack-Yves
authors.initials: JY
authors.lastname: Deschamps
authors.forename: Michel
authors.initials: M
authors.lastname: Weber
authors.forename: Guylène
authors.initials: G
authors.lastname: Le Meur
authors.forename: Nathalie
authors.initials: N
authors.lastname: Provost
authors.forename: Caroline
authors.initials: C
authors.lastname: Guihal
authors.forename: Philippe
authors.initials: P
authors.lastname: Moullier
authors.forename: Fabienne
authors.initials: F
authors.lastname: Rolling
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004285:Dogs; D004318:Doxycycline / Q000494:pharmacology*; D005136:Eye Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005822:Genetic Vectors; D012160:Retina / Q000503:physiopathology*; D014786:Vision Disorders / Q000503:physiopathology / Q000628:therapy*
chemical_list: D005136:Eye Proteins; D004318:Doxycycline