title: AAV-mediated lysophosphatidylcholine acyltransferase 1 (Lpcat1) gene replacement therapy rescues retinal degeneration in rd11 mice.
abstract: OBJECTIVE
  The retinal degeneration 11 (rd11) mouse is a newly discovered, naturally occurring animal model with early photoreceptor dysfunction and rapid rod photoreceptor degeneration followed by cone degeneration. The rd11 mice carry a spontaneous mutation in the lysophosphatidylcholine acyltransferase 1 (Lpcat1) gene. Here, we evaluate whether gene replacement therapy using the fast-acting tyrosine-capsid mutant AAV8 (Y733F) can arrest retinal degeneration and restore retinal function in this model.
  
  
  METHODS
  The AAV8 (Y733F)-smCBA-Lpcat1 was delivered subretinally to postnatal day 14 (P14) rd11 mice in one eye only. At 10 weeks after injection, treated rd11 mice were examined by visually-guided behavior, electroretinography (ERG) and spectral domain optical coherence tomography (SD-OCT), and then killed for morphologic and biochemical examination.
  
  
  RESULTS
  Substantial scotopic and photopic ERG signals were maintained in treated rd11 eyes, whereas untreated eyes in the same animals showed extinguished signals. The SD-OCT (in vivo) and light microscopy (in vitro) showed a substantial preservation of the outer nuclear layer in most parts of the treated retina only. Almost wild-type LPCAT1 expression in photoreceptors with strong rod rhodopsin and M/S cone opsin staining, and normal visually-guided water maze behavioral performances were observed in treated rd11 mice.
  
  
  CONCLUSIONS
  The results demonstrate that the tyrosine-capsid mutant AAV8 (Y733F) vector is effective for treating rapidly degenerating models of retinal degeneration and, moreover, is more therapeutically effective than AAV2 (Y444, 500, 730F) vector with the same promoter-cDNA payload. To our knowledge, this is the first demonstration of phenotypic rescue by gene therapy in an animal model of retinal degeneration caused by Lpcat1 mutation.
authors.affiliation: Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xufeng
authors.initials: X
authors.lastname: Dai
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Han
authors.forename: Yan
authors.initials: Y
authors.lastname: Qi
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Lue
authors.initials: L
authors.lastname: Xiang
authors.forename: Jineng
authors.initials: J
authors.lastname: Lv
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Deng
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Ji-jing
authors.initials: JJ
authors.lastname: Pang
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004596:Electroretinography; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology*; D012162:Retinal Degeneration / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D041623:Tomography, Optical Coherence
chemical_list: D004247:DNA; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C526203:Lpcat1 protein, mouse
keywords: AAV; Lpcat1; gene therapy; mice; rd11