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Natural history of cone disease in the murine model of Leber congenital amaurosis due to CEP290 mutation: determining the timing and expectation of therapy.

Authors: Boye, SE  Huang, WC  Roman, AJ  Sumaroka, A  Boye, SL  Ryals, RC  Olivares, MB  Ruan, Q  Tucker, BA  Stone, EM  Swaroop, A  Cideciyan, AV  Hauswirth, WW  Jacobson, SG 
Citation: Boye SE, etal., PLoS One. 2014 Mar 26;9(3):e92928. doi: 10.1371/journal.pone.0092928. eCollection 2014.
Pubmed: (View Article at PubMed) PMID:24671090
DOI: Full-text: DOI:10.1371/journal.pone.0092928

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 approximately 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.

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RGD Object Information
RGD ID: 8662304
Created: 2014-06-18
Species: All species
Last Modified: 2014-06-18
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.