title: Natural history of cone disease in the murine model of Leber congenital amaurosis due to CEP290 mutation: determining the timing and expectation of therapy.
abstract: BACKGROUND
  Mutations in the CEP290 (cilia-centrosomal protein 290 kDa) gene in Leber congenital amaurosis (LCA) cause early onset visual loss but retained cone photoreceptors in the fovea, which is the potential therapeutic target. A cone-only mouse model carrying a Cep290 gene mutation, rd16;Nrl-/-, was engineered to mimic the human disease. In the current study, we determined the natural history of retinal structure and function in this murine model to permit design of pre-clinical proof-of-concept studies and allow progress to be made toward human therapy. Analyses of retinal structure and visual function in CEP290-LCA patients were also performed for comparison with the results in the model.
  
  
  METHODS
  Rd16;Nrl-/- mice were studied in the first 90 days of life with optical coherence tomography (OCT), electroretinography (ERG), retinal histopathology and immunocytochemistry. Structure and function data from a cohort of patients with CEP290-LCA (n = 15; ages 7-48) were compared with those of the model.
  
  
  RESULTS
  CEP290-LCA patients retain a central island of photoreceptors with normal thickness at the fovea (despite severe visual loss); the extent of this island declined slowly with age. The rd16;Nrl-/- model also showed a relatively slow photoreceptor layer decline in thickness with ∼80% remaining at 3 months. The number of pseudorosettes also became reduced. By comparison to single mutant Nrl-/- mice, UV- and M-cone ERGs of rd16;Nrl-/- were at least 1 log unit reduced at 1 month of age and declined further over the 3 months of monitoring. Expression of GNAT2 and S-opsin also decreased with age.
  
  
  CONCLUSIONS
  The natural history of early loss of photoreceptor function with retained cone cell nuclei is common to both CEP290-LCA patients and the rd16;Nrl-/- murine model. Pre-clinical proof-of-concept studies for uniocular therapies would seem most appropriate to begin with intervention at P35-40 and re-study after one month by assaying interocular difference in the UV-cone ERG.
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Boye
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Wei-Chieh
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Roman
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sumaroka
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Renee C
authors.initials: RC
authors.lastname: Ryals
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Melani B
authors.initials: MB
authors.lastname: Olivares
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ruan
authors.affiliation: Stephen A. Wynn Institute for Vision Research, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Budd A
authors.initials: BA
authors.lastname: Tucker
authors.affiliation: Stephen A. Wynn Institute for Vision Research, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America; Howard Hughes Medical Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.affiliation: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.affiliation: Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.affiliation: Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D018797:Cell Cycle Proteins; D002648:Child; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D055537:Light Signal Transduction; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D012160:Retina / Q000473:pathology; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology; D013997:Time Factors; D041623:Tomography, Optical Coherence
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; C513600:Cep290 protein, mouse; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins