title: Allele-Specific Inhibition of Rhodopsin With an Antisense Oligonucleotide Slows Photoreceptor Cell Degeneration.
abstract: OBJECTIVE
  To preserve photoreceptor cell structure and function in a rodent model of retinitis pigmentosa with P23H rhodopsin by selective inhibition of the mutant rhodopsin allele using a second generation antisense oligonucleotide (ASO).
  
  
  METHODS
  Wild-type mice and rats were treated with ASO by intravitreal (IVT) injection and rhodopsin mRNA and protein expression were measured. Transgenic rats expressing the murine P23H rhodopsin gene (P23H transgenic rat Line 1) were administered either a mouse-specific P23H ASO or a control ASO. The contralateral eye was injected with PBS and used as a comparator control. Electroretinography (ERG) measurements and analyses of the retinal outer nuclear layer were conducted and correlated with rhodopsin mRNA levels.
  
  
  RESULTS
  Rhodopsin mRNA and protein expression was reduced after a single ASO injection in wild-type mice with a rhodopsin-specific ASO. Transgenic rat eyes that express a murine P23H rhodopsin gene injected with a murine P23H ASO had a 181 ± 39% better maximum amplitude response (scotopic a-wave) as compared with contralateral PBS-injected eyes; the response in control ASO eyes was not significantly different from comparator contralateral eyes. Morphometric analysis of the outer nuclear layer showed a significantly thicker nuclear layer in eyes injected with murine P23H ASO (18%) versus contralateral PBS-injected eyes.
  
  
  CONCLUSIONS
  Allele-specific ASO-mediated knockdown of mutant P23H rhodopsin expression slowed the rate of photoreceptor degeneration and preserved the function of photoreceptor cells in eyes of the P23H rhodopsin transgenic rat. Our data indicate that ASO treatment is a potentially effective therapy for the treatment of retinitis pigmentosa.
authors.affiliation: Isis Pharmaceuticals Carlsbad, California, United States.
authors.forename: Susan F
authors.initials: SF
authors.lastname: Murray
authors.affiliation: Isis Pharmaceuticals Carlsbad, California, United States.
authors.forename: Ali
authors.initials: A
authors.lastname: Jazayeri
authors.affiliation: University of California at San Francisco School of Medicine, Beckman Vision Center, San Francisco, California, United States.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Matthes
authors.affiliation: University of California at San Francisco School of Medicine, Beckman Vision Center, San Francisco, California, United States.
authors.forename: Douglas
authors.initials: D
authors.lastname: Yasumura
authors.affiliation: University of California at San Francisco School of Medicine, Beckman Vision Center, San Francisco, California, United States.
authors.forename: Haidong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Isis Pharmaceuticals Carlsbad, California, United States.
authors.forename: Raechel
authors.initials: R
authors.lastname: Peralta
authors.affiliation: Isis Pharmaceuticals Carlsbad, California, United States.
authors.forename: Andy
authors.initials: A
authors.lastname: Watt
authors.affiliation: Isis Pharmaceuticals Carlsbad, California, United States.
authors.forename: Sue
authors.initials: S
authors.lastname: Freier
authors.affiliation: Isis Pharmaceuticals Carlsbad, California, United States.
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.affiliation: GlaxoSmithKlein, Brentford, Middlesex, United Kingdom.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Adamson
authors.affiliation: Isis Pharmaceuticals Carlsbad, California, United States.
authors.forename: Shuling
authors.initials: S
authors.lastname: Guo
authors.affiliation: Isis Pharmaceuticals Carlsbad, California, United States.
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.affiliation: University of California at San Francisco School of Medicine, Beckman Vision Center, San Francisco, California, United States.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: LaVail
authors.affiliation: Isis Pharmaceuticals Carlsbad, California, United States.
authors.forename: Michael L
authors.initials: ML
authors.lastname: McCaleb
mesh_terms: D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004596:Electroretinography; D005786:Gene Expression Regulation; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D055647:Rats, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D012243:Rhodopsin / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D012243:Rhodopsin