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

Shannon E. Boye; Wei Chieh Huang; Alejandro J. Roman; Alexander Sumaroka; Sanford L. Boye; Renee C. Ryals; Melani B. Olivares; Qing Ruan; Budd A. Tucker; Edwin M. Stone; Anand Swaroop; Artur V. Cideciyan; William W. Hauswirth; Samuel G. Jacobson

doi:10.1371/journal.pone.0092928

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

Shannon E. Boye, Wei Chieh Huang, Alejandro J. Roman, Alexander Sumaroka, Sanford L. Boye, Renee C. Ryals, Melani B. Olivares, Qing Ruan, Budd A. Tucker, Edwin M. Stone, Anand Swaroop, Artur V. Cideciyan, William W. Hauswirth, Samuel G. Jacobson

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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 preclinical 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.

Original language	English (US)
Article number	e92928
Journal	PloS one
Volume	9
Issue number	3
DOIs	https://doi.org/10.1371/journal.pone.0092928
State	Published - Mar 26 2014
Externally published	Yes

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Boye, S. E., Huang, W. C., Roman, A. J., Sumaroka, A., Boye, S. L., Ryals, R. C., Olivares, M. B., Ruan, Q., Tucker, B. A., Stone, E. M., Swaroop, A., Cideciyan, A. V., Hauswirth, W. W., & 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), Article e92928. https://doi.org/10.1371/journal.pone.0092928

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 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, vol. 9, no. 3, e92928. https://doi.org/10.1371/journal.pone.0092928

@article{79396255dde94d2080e278f479d216a1,

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 preclinical 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.",

author = "Boye, {Shannon E.} and Huang, {Wei Chieh} and Roman, {Alejandro J.} and Alexander Sumaroka and Boye, {Sanford L.} and Ryals, {Renee C.} and Olivares, {Melani B.} and Qing Ruan and Tucker, {Budd A.} and Stone, {Edwin M.} and Anand Swaroop and Cideciyan, {Artur V.} and Hauswirth, {William W.} and Jacobson, {Samuel G.}",

year = "2014",

month = mar,

day = "26",

doi = "10.1371/journal.pone.0092928",

language = "English (US)",

volume = "9",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "3",

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TY - JOUR

T1 - Natural history of cone disease in the murine model of Leber congenital amaurosis due to CEP290 mutation

T2 - 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.

PY - 2014/3/26

Y1 - 2014/3/26

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 preclinical 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.

AB - 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 preclinical 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.

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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

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