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Review
. 2013 Jul 12;5(7):2646-66.
doi: 10.3390/nu5072646.

Vitamin A derivatives as treatment options for retinal degenerative diseases

Lindsay Perusek  1 , Tadao Maeda
Affiliations
Review

Vitamin A derivatives as treatment options for retinal degenerative diseases

Lindsay Perusek et al. Nutrients. .

Abstract

The visual cycle is a sequential enzymatic reaction for vitamin A, all-trans-retinol, occurring in the outer layer of the human retina and is essential for the maintenance of vision. The central source of retinol is derived from dietary intake of both retinol and pro-vitamin A carotenoids. A series of enzymatic reactions, located in both the photoreceptor outer segment and the retinal pigment epithelium, transform retinol into the visual chromophore 11-cis-retinal, regenerating visual pigments. Retina specific proteins carry out the majority of the visual cycle, and any significant interruption in this sequence of reactions is capable of causing varying degrees of blindness. Among these important proteins are Lecithin:retinol acyltransferase (LRAT) and retinal pigment epithelium-specific 65-kDa protein (RPE65) known to be responsible for esterification of retinol to all-trans-retinyl esters and isomerization of these esters to 11-cis-retinal, respectively. Deleterious mutations in these genes are identified in human retinal diseases that cause blindness, such as Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Herein, we discuss the pathology of 11-cis-retinal deficiency caused by these mutations in both animal disease models and human patients. We also review novel therapeutic strategies employing artificial visual chromophore 9-cis-retinoids which have been employed in clinical trials involving LCA patients.

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Figures

Figure 1
Figure 1
The metabolism of carotenoids and retinoids begin in the intestinal lumen, where provitamin A and retinoid molecules are absorbed. Retinyl esters are transported to the liver via the lymphatic system, while retinol is transported through the bloodstream before delivery to target tissues, such as the retina.
Figure 2
Figure 2
Visual cycle. Absorption of light by visual pigments (rhodopsin or cone opsin) causes isomerization of 11-cis-retinal to all-trans-retinal, resulting in phototransduction. Decay of activated rhodopsin yields opsin and all-trans-retinal, which is released and pumped out into the cytosol by a photoreceptor specific ATP-binding transporter (ABCA4) and reduced to all-trans-retinol by all-trans-retinal dehydrogenases (RDH8 and RDH12). All-trans-retinol diffuses into the RPE where it is esterified by lecithin:retinol acyltransferase (LRAT) to all-trans-retinyl esters, which are stored in retinosomes. All-trans-retinyl esters are isomerized to 11-cis-retinol in a reaction involving a 65 kDa RPE-specific protein (RPE65). To complete the visual cycle, 11-cis-retinol is then oxidized by 11-cis–retinal specific RDH (RDH5) to 11-cis-retinal, which then diffuses back into the photoreceptor where it combines with opsin to regenerate visual pigments. IRBP, interphotoreceptor retinoid-binding protein; Stra6, stimulated by retinoic acid gene 6.
Figure 3
Figure 3
(A) Horizontal EM images of RPE in 3 month old Rpe65−/−, Lrat−/− and wild-type mice. Of particular interest are the large retinosomes present around the perimeter of RPE cells in Rpe65−/− mice (black arrows), these formations are indicative of excessive ester accumulation in the retina. (B) Two photon imaging of the RPE in 3 month old Rpe65−/−, Lrat−/− and wild-type mice. Large autofluorescent spots are observed in the RPE of Rpe65−/− mice (white arrows), while such spots are absent in Lrat−/− mice, and are minimally observed in wild type mice. Scale bar 5.0 µm.
Figure 4
Figure 4
Isomers of the opsin chromophore. Both 11-cis-retinal and 9-cis-retinal form a Schiff base with residue K296 of the opsin molecule forming the light sensitive chromophore used in vision.
Figure 5
Figure 5
Normal phase HPLC analysis of retinoids in dark adapted mouse models of retinal degeneration. Concentrations of cis-retinoids and retinyl esters in the retina differ before and after 9-cis-retinoid treatment. Control Rpe65 knockout mice exhibit significantly increased concentrations of retinyl esters and are devoid of 11-cis-retinal. Rpe65−/− mice treated with 9-cis-retinoids show increase 9-cis-retinal bound to rhodopsin. Likewise, untreated Lrat knockout mice lack both 11-cis-retinal and retinyl esters, while treated Lrat knockout mice show an increase 9-cis-retinal bound to rhodopsin. WT mice show normal concentrations of 11-cis-retinal, as well as small amounts of retinyl esters.
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