title: Pharmacological and rAAV gene therapy rescue of visual functions in a blind mouse model of Leber congenital amaurosis.
abstract: BACKGROUND
  Leber congenital amaurosis (LCA), a heterogeneous early-onset retinal dystrophy, accounts for approximately 15% of inherited congenital blindness. One cause of LCA is loss of the enzyme lecithin:retinol acyl transferase (LRAT), which is required for regeneration of the visual photopigment in the retina.
  
  
  RESULTS
  An animal model of LCA, the Lrat-/- mouse, recapitulates clinical features of the human disease. Here, we report that two interventions--intraocular gene therapy and oral pharmacologic treatment with novel retinoid compounds--each restore retinal function to Lrat-/- mice. Gene therapy using intraocular injection of recombinant adeno-associated virus carrying the Lrat gene successfully restored electroretinographic responses to approximately 50% of wild-type levels (p < 0.05 versus wild-type and knockout controls), and pupillary light responses (PLRs) of Lrat-/- mice increased approximately 2.5 log units (p < 0.05). Pharmacological intervention with orally administered pro-drugs 9-cis-retinyl acetate and 9-cis-retinyl succinate (which chemically bypass the LRAT-catalyzed step in chromophore regeneration) also caused long-lasting restoration of retinal function in LRAT-deficient mice and increased ERG response from approximately 5% of wild-type levels in Lrat-/- mice to approximately 50% of wild-type levels in treated Lrat-/- mice (p < 0.05 versus wild-type and knockout controls). The interventions produced markedly increased levels of visual pigment from undetectable levels to 600 pmoles per eye in retinoid treated mice, and approximately 1,000-fold improvements in PLR and electroretinogram sensitivity. The techniques were complementary when combined.
  
  
  CONCLUSIONS
  Intraocular gene therapy and pharmacologic bypass provide highly effective and complementary means for restoring retinal function in this animal model of human hereditary blindness. These complementary methods offer hope of developing treatment to restore vision in humans with certain forms of hereditary congenital blindness.
authors.affiliation: Department of Ophthalmology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Batten
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Imanishi
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Tu
authors.forename: Thuy
authors.initials: T
authors.lastname: Doan
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Jijing
authors.initials: J
authors.lastname: Pang
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Glushakova
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Moise
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
authors.forename: Russell N
authors.initials: RN
authors.lastname: Van Gelder
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Fred
authors.initials: F
authors.lastname: Rieke
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D000217:Acyltransferases / Q000235:genetics*; D000256:Adenoviridae / Q000235:genetics; D000284:Administration, Oral; D000818:Animals; D001766:Blindness / Q000188:drug therapy* / Q000235:genetics*; D004195:Disease Models, Animal; D004224:Diterpenes; D015316:Genetic Therapy; D005822:Genetic Vectors; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D029242:Optic Atrophy, Hereditary, Leber / Q000188:drug therapy* / Q000235:genetics*; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011680:Pupil / Q000502:physiology; D012168:Retinal Pigments / Q000032:analysis; D000084562:Retinyl Esters; D014801:Vitamin A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C510876:9-retinyl succinate; D004224:Diterpenes; D011355:Prodrugs; D012168:Retinal Pigments; D000084562:Retinyl Esters; D014801:Vitamin A; C009166:retinol acetate; D000217:Acyltransferases; C056942:lecithin-retinol acyltransferase