Journal article
Natural history of cone disease in the murine model of Leber congenital amaurosis due to CEP290 mutation: determining the timing and expectation of therapy
PloS one, Vol.9(3), pp.e92928-e92928
2014
DOI: 10.1371/journal.pone.0092928
PMCID: PMC3966841
PMID: 24671090
Abstract
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. 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. 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. 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.
Details
- Title: Subtitle
- Natural history of cone disease in the murine model of Leber congenital amaurosis due to CEP290 mutation: determining the timing and expectation of therapy
- Creators
- Shannon E Boye - Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of AmericaWei-Chieh Huang - Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of AmericaAlejandro J Roman - Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of AmericaAlexander Sumaroka - Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of AmericaSanford L Boye - Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of AmericaRenee C Ryals - Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of AmericaMelani B Olivares - Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of AmericaQing Ruan - Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of AmericaBudd A Tucker - Stephen A. Wynn Institute for Vision Research, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of AmericaEdwin M Stone - 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 AmericaAnand Swaroop - Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of AmericaArtur V Cideciyan - Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of AmericaWilliam W Hauswirth - Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of AmericaSamuel G Jacobson - Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.9(3), pp.e92928-e92928
- DOI
- 10.1371/journal.pone.0092928
- PMID
- 24671090
- PMCID
- PMC3966841
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- United States
- Grant note
- Intramural NIH HHS DP2 OD007483 / NIH HHS P30 EY021721 / NEI NIH HHS Howard Hughes Medical Institute
- Language
- English
- Date published
- 2014
- Academic Unit
- Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
- Record Identifier
- 9983980066702771
Metrics
26 Record Views