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Originally published In Press as doi:10.1074/jbc.M112384200 on March 15, 2002

J. Biol. Chem., Vol. 277, Issue 21, 19173-19182, May 24, 2002
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Recovery of Visual Functions in a Mouse Model of Leber Congenital Amaurosis*

J. Preston Van HooserDagger , Yan LiangDagger , Tadao MaedaDagger , Vladimir KuksaDagger , Geeng-Fu JangDagger , Yu-Guang HeDagger §, Fred Rieke, Henry K. W. Fong||, Peter B. Detwiler, and Krzysztof PalczewskiDagger **Dagger Dagger §§

From the Departments of Dagger  Ophthalmology, ** Chemistry, Dagger Dagger  Pharmacology, and  Physiology and Biophysics, University of Washington, Seattle, Washington 98195 and the || Departments of Ophthalmology and Microbiology, University of Southern California School of Medicine and Doheny Eye Institute, Los Angeles, California 90033

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.

* This work was supported in part by United States Public Health Service Grants EY01730, EY08061, EY66388, EY02048, and EY11850 from the NEI, National Institutes of Health, an unrestricted grant from Research to Prevent Blindness, Inc. to the Department of Ophthalmology at the University of Washington, a grant from Ruth and Milton Steinbach Fund, and funds from the E. K. Bishop Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by Vision Training Grant EY07031 from the National Research Service. Present address: Dept. of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390.

§§ To whom correspondence should be addressed: University of Washington, Dept. of Ophthalmology, Box 356485, Seattle, WA 98195-6485. Tel.: 206-543-9074; Fax: 206-221-6784; E-mail: palczews@u.washington.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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