title: A long-term efficacy study of gene replacement therapy for RPGR-associated retinal degeneration.
abstract: Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene account for >70% of X-linked retinitis pigmentosa (XLRP) and 15-20% of all inherited retinal degeneration. Gene replacement therapy for RPGR-XLRP was hampered by the relatively slow disease progression in mouse models and by difficulties in cloning the full-length RPGR-ORF15 cDNA that includes a purine-rich 3'-coding region; however, its effectiveness has recently been demonstrated in four dogs with RPGR mutations. To advance the therapy to clinical stage, we generated new stable vectors in AAV8 or AAV9 carrying mouse and human full-length RPGR-ORF15-coding sequence and conducted a comprehensive long-term dose-efficacy study in Rpgr-knockout mice. After validating their ability to produce full-length proteins that localize to photoreceptor connecting cilia, we evaluated various vector doses in mice during a 2-year study. We demonstrate that eyes treated with a single injection of mouse or human RPGR-ORF15 vector at an optimal dose maintained the expression of RPGR-ORF15 throughout the study duration and exhibited higher electroretinogram amplitude, thicker photoreceptor layer and better targeting of opsins to outer segments compared with sham-treated eyes. Furthermore, mice that received treatment at an advanced age also showed remarkable preservation of retinal structure and function. Retinal toxicity was observed at high vector doses, highlighting the importance of careful dose optimization in future clinical experiments. Our long-term dose-efficacy study should facilitate the design of human trials with human RPGR-ORF15 vector as a clinical candidate.
authors: National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA wuzh@mail.nih.gov swaroopa@nei.nih.gov.
authors: Zhijian
authors: Z
authors: Wu
authors: National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Suja
authors: S
authors: Hiriyanna
authors: National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Haohua
authors: H
authors: Qian
authors: National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Suddhasil
authors: S
authors: Mookherjee
authors: National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Maria M
authors: MM
authors: Campos
authors: National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Chun
authors: C
authors: Gao
authors: National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Robert
authors: R
authors: Fariss
authors: National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Paul A
authors: PA
authors: Sieving
authors: National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Tiansen
authors: T
authors: Li
authors: National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Peter
authors: P
authors: Colosi
authors: National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA wuzh@mail.nih.gov swaroopa@nei.nih.gov.
authors: Anand
authors: A
authors: Swaroop
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004596:Electroretinography; D005091:Exons; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D016366:Open Reading Frames; D012160:Retina / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; C099929:RPGR protein, human; C513598:RPGR protein, mouse