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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.
PLoS One 2014; 9(3):e92928Plos

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+Show Affiliations

Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.Stephen A. Wynn Institute for Vision Research, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.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.Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, Florida, United States of America.Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24671090

Citation

Boye, Shannon E., et al. "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, no. 3, 2014, pp. e92928.
Boye SE, Huang WC, Roman AJ, et al. 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. 2014;9(3):e92928.
Boye, S. E., Huang, W. C., Roman, A. J., Sumaroka, A., Boye, S. L., Ryals, R. C., ... Jacobson, S. G. (2014). 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, 9(3), pp. e92928. doi:10.1371/journal.pone.0092928.
Boye SE, et al. 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. 2014;9(3):e92928. PubMed PMID: 24671090.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Natural history of cone disease in the murine model of Leber congenital amaurosis due to CEP290 mutation: determining the timing and expectation of therapy. AU - Boye,Shannon E, AU - Huang,Wei-Chieh, AU - Roman,Alejandro J, AU - Sumaroka,Alexander, AU - Boye,Sanford L, AU - Ryals,Renee C, AU - Olivares,Melani B, AU - Ruan,Qing, AU - Tucker,Budd A, AU - Stone,Edwin M, AU - Swaroop,Anand, AU - Cideciyan,Artur V, AU - Hauswirth,William W, AU - Jacobson,Samuel G, Y1 - 2014/03/26/ PY - 2014/01/26/received PY - 2014/02/26/accepted PY - 2014/3/28/entrez PY - 2014/3/29/pubmed PY - 2015/12/15/medline SP - e92928 EP - e92928 JF - PloS one JO - PLoS ONE VL - 9 IS - 3 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24671090/Natural_history_of_cone_disease_in_the_murine_model_of_Leber_congenital_amaurosis_due_to_CEP290_mutation:_determining_the_timing_and_expectation_of_therapy_ L2 - http://dx.plos.org/10.1371/journal.pone.0092928 DB - PRIME DP - Unbound Medicine ER -