Recovery of visual functions in a mouse model of leber congenital amaurosis

J. Van Preston Hooser, Yan Liang, Tadao Maeda, Vladimir Kuksa, Geeng Fu Jang, Yu Guang He, Fred Rieke, Henry K W Fong, Peter B. Detwiler, Krzysztof Palczewski

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

The visual process is initiated by the photoisomerization of 11-cis-retinal to all-trans-retinal. For sustained vision the 11-cis-chromophore must be regenerated from all-trans-retinal. This requires RPE65, a dominant retinal pigment epithelium protein. Disruption of the RPE65 gene results in massive accumulation of all-trans-retinyl esters in the retinal pigment epithelium, lack of 11-cis-retinal and therefore rhodopsin, and ultimately blindness. We reported previously (Van Hooser, J. P., Aleman, T. S., He, Y. G., Cideciyan, A. V., Kuksa, V., Pittler, S. J., Stone, E. M., Jacobson, S. G., and Palczewski, K. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 8623-8628) that in Rpe65-/-mice, oral administration of 9-cis-retinal generated isorhodopsin, a rod photopigment, and restored light sensitivity to the electroretinogram. Here, we provide evidence that early intervention by 9-cis-retinal administration significantly attenuated retinal ester accumulation and supported rod retinal function for more than 6 months post-treatment. In single cell recordings rod light sensitivity was shown to be a function of the amount of regenerated isorhodopsin; high doses restored rod responses with normal sensitivity and kinetics. Highly attenuated residual rod function was observed in untreated Rpe65-/-mice. This rod function is likely a consequence of low efficiency production of 11-cis-retinal by photo-conversion of all-trans-retinal in the retina as demonstrated by retinoid analysis. These studies show that pharmacological intervention produces long lasting preservation of visual function in dark-reared Rpe65-/-mice and may be a useful therapeutic strategy in recovering vision in humans diagnosed with Leber congenital amaurosis caused by mutations in the RPE65 gene, an inherited group of early onset blinding and retinal degenerations.

Original languageEnglish (US)
Pages (from-to)19173-19182
Number of pages10
JournalJournal of Biological Chemistry
Volume277
Issue number21
DOIs
StatePublished - May 24 2002

Fingerprint

Leber Congenital Amaurosis
Retinaldehyde
Recovery of Function
Photophobia
Retinal Pigment Epithelium
Recovery
Esters
Photosensitivity
Retinal Pigments
Retinal Rod Photoreceptor Cells
Retinal Degeneration
Rhodopsin
Retinoids
Blindness
Genes
Oral Administration
Retina
Photoisomerization
Pharmacology
Chromophores

ASJC Scopus subject areas

  • Biochemistry

Cite this

Van Preston Hooser, J., Liang, Y., Maeda, T., Kuksa, V., Jang, G. F., He, Y. G., ... Palczewski, K. (2002). Recovery of visual functions in a mouse model of leber congenital amaurosis. Journal of Biological Chemistry, 277(21), 19173-19182. https://doi.org/10.1074/jbc.M112384200

Recovery of visual functions in a mouse model of leber congenital amaurosis. / Van Preston Hooser, J.; Liang, Yan; Maeda, Tadao; Kuksa, Vladimir; Jang, Geeng Fu; He, Yu Guang; Rieke, Fred; Fong, Henry K W; Detwiler, Peter B.; Palczewski, Krzysztof.

In: Journal of Biological Chemistry, Vol. 277, No. 21, 24.05.2002, p. 19173-19182.

Research output: Contribution to journalArticle

Van Preston Hooser, J, Liang, Y, Maeda, T, Kuksa, V, Jang, GF, He, YG, Rieke, F, Fong, HKW, Detwiler, PB & Palczewski, K 2002, 'Recovery of visual functions in a mouse model of leber congenital amaurosis', Journal of Biological Chemistry, vol. 277, no. 21, pp. 19173-19182. https://doi.org/10.1074/jbc.M112384200
Van Preston Hooser J, Liang Y, Maeda T, Kuksa V, Jang GF, He YG et al. Recovery of visual functions in a mouse model of leber congenital amaurosis. Journal of Biological Chemistry. 2002 May 24;277(21):19173-19182. https://doi.org/10.1074/jbc.M112384200
Van Preston Hooser, J. ; Liang, Yan ; Maeda, Tadao ; Kuksa, Vladimir ; Jang, Geeng Fu ; He, Yu Guang ; Rieke, Fred ; Fong, Henry K W ; Detwiler, Peter B. ; Palczewski, Krzysztof. / Recovery of visual functions in a mouse model of leber congenital amaurosis. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 21. pp. 19173-19182.
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