The specific binding of retinoic acid to RPE65 and approaches to the treatment of macular degeneration

Gollapalli, Deviprasad R.; Rando, Robert R.

doi:10.1073/pnas.0401936101

Cited by 43 publications

(34 citation statements)

References 32 publications

(56 reference statements)

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“…This contradicts previous reports proposing that 13-cis-RA inhibits visual chromophore regeneration by binding to RPE65 (28,65). An alternative explanation is that 13-cis-RA inhibits 11-cis-RDH and all-trans-RDH in RPE and rod outer segments, respectively (27,40).…”

Section: Discussioncontrasting

confidence: 55%

“…Clinical reports showing delayed dark adaptation and night blindness upon 13-cis-RA treatment drew attention to these compounds as potential visual therapeutics (25,26). 13-cis-RA was found to inhibit 11-cisretinol dehydrogenase, which catalyzes the final enzymatic step in the visual cycle (27), and to bind RPE65 (28). Fenretinide slowed the flux of retinoids into the eyes, most probably by reducing levels of vitamin A bound to serum retinol-binding protein (RBP) (17).…”

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confidence: 99%

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Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina

Golczak

Maeda

Bereta

et al. 2008

Journal of Biological Chemistry

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In vertebrate retinal photoreceptors, the absorption of light by rhodopsin leads to photoisomerization of 11-cis-retinal to its all-trans isomer. To sustain vision, a metabolic system evolved that recycles all-trans-retinal back to 11-cis-retinal. The importance of this visual (retinoid) cycle is underscored by the fact that mutations in genes encoding visual cycle components induce a wide spectrum of diseases characterized by abnormal levels of specific retinoid cycle intermediates. In addition, intense illumination can produce retinoid cycle by-products that are toxic to the retina. Thus, inhibition of the retinoid cycle has therapeutic potential in physiological and pathological states. Four classes of inhibitors that include retinoid and nonretinoid compounds have been identified. We investigated the modes of action of these inhibitors by using purified visual cycle components and in vivo systems. We report that retinylamine was the most potent and specific inhibitor of the retinoid cycle among the tested compounds and that it targets the retinoid isomerase, RPE65. Hydrophobic primary amines like farnesylamine also showed inhibitory potency but a short duration of action, probably due to rapid metabolism. These compounds also are reactive nucleophiles with potentially high cellular toxicity. We also evaluated the role of a specific proteinmediated mechanism on retinoid cycle inhibitor uptake by the eye. Our results show that retinylamine is transported to and taken up by the eye by retinol-binding protein-independent and retinoic acid-responsive gene product 6-independent mechanisms. Finally, we provide evidence for a crucial role of lecithin: retinol acyltransferase activity in mediating tissue specific absorption and long lasting therapeutic effects of retinoid-based visual cycle inhibitors.In vertebrate photoreceptor cells, absorbance of light by the visual chromophore, 11-cis-retinal, coupled to rhodopsin leads to its photoisomerization to all-trans-retinal and initiation of the phototransduction signal cascade (reviewed in Ref. 1). To ensure constant vision, 11-cis-retinal is efficiently regenerated by a complex sequence of enzymatic reactions called the visual or retinoid cycle (reviewed in Refs. 2-4). This pathway is located in both retinal pigment epithelium (RPE) 3 and photoreceptor cells. The key enzymatic step of visual chromophore regeneration is the isomerization of all-trans-retinyl palmitate and other esters to 11-cis-retinol in a reaction catalyzed by RPE65 (5-7).The importance of the retinoid cycle for maintaining vision is documented by the number and variety of diseases caused by mutations in genes encoding proteins involved in this process (2). Three main strategies have been developed to treat these diseases. The first uses virally mediated transfer gene technology to replace the defective gene. This approach has successfully rescued vision in mouse and dog models of Leber congenital amaurosis and retinitis pigmentosa (8 -13). The second approach involving pharmacological supplementation...

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Section: Discussioncontrasting

confidence: 55%

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confidence: 99%

Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina

Golczak

Maeda

Bereta

et al. 2008

Journal of Biological Chemistry

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“…This effect is due to its inhibitory effect on 11-cis-RDH in RPE cells (197,198) (Figure 5). Isotretinoin also binds to Rpe65 (199) and therefore might also inhibit the isomerase. Treatment of WT albino rats with isotretinoin prevented light-induced retinal damage, prompting the suggestion that this visual-cycle inhibitor may be useful for treating retinal or macular degenerations in humans (211).…”

Section: Retinoid Inhibitors Of A2e Formationmentioning

confidence: 99%

Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents

Travis

Golczak

Moise

et al. 2007

Annu. Rev. Pharmacol. Toxicol.

368

452

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Absorption of a photon by an opsin pigment causes isomerization of the chromophore from 11-cisretinaldehyde to all-trans-retinaldehyde. Regeneration of visual chromophore following light exposure is dependent on an enzyme pathway called the retinoid or visual cycle. Our understanding of this pathway has been greatly facilitated by the identification of disease-causing mutations in the genes coding for visual cycle enzymes. Defects in nearly every step of this pathway are responsible for human-inherited retinal dystrophies. These retinal dystrophies can be divided into two etiologic groups. One involves the impaired synthesis of visual chromophore. The second involves accumulation of cytotoxic products derived from all-trans-retinaldehyde. Gene therapy has been successfully used in animal models of these diseases to rescue the function of enzymes involved in chromophore regeneration, restoring vision. Dystrophies resulting from impaired chromophore synthesis can also be treated by supplementation with a chromophore analog. Dystrophies resulting from the accumulation of toxic pigments can be treated pharmacologically by inhibiting the visual cycle, or limiting the supply of vitamin A to the eyes. Recent progress in both areas provides hope that multiple inherited retinal diseases will soon be treated by pharmaceutical intervention.

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“…RPE65 encodes a 65-kDa protein located in the retinal pigment epithelium (RPE) and essential for vertebrate vision. RPE65 mutations prevent the normal cycling of retinoids, leading to photoreceptors without light-sensitive visual pigment and eyes with blindness (1)(2)(3)(4)(5)(6)(7)(8). Proof-of-concept studies using viral vector-mediated RPE65 gene delivery to the eye have shown dramatic restoration of vision in a naturally occurring canine model (9,10) and a murine knockout (11).…”

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confidence: 99%

Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success

Jacobson

Alemán

Cideciyan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

249

279

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Mutations in RPE65, a gene essential to normal operation of the visual (retinoid) cycle, cause the childhood blindness known as Leber congenital amaurosis (LCA). Retinal gene therapy restores vision to blind canine and murine models of LCA. Gene therapy in blind humans with LCA from RPE65 mutations may also have potential for success but only if the retinal photoreceptor layer is intact, as in the early-disease stage-treated animals. Here, we use high-resolution in vivo microscopy to quantify photoreceptor layer thickness in the human disease to define the relationship of retinal structure to vision and determine the potential for gene therapy success. The normally cone photoreceptor-rich central retina and rod-rich regions were studied. Despite severely reduced cone vision, many RPE65-mutant retinas had near-normal central microstructure. Absent rod vision was associated with a detectable but thinned photoreceptor layer. We asked whether abnormally thinned RPE65-mutant retina with photoreceptor loss would respond to treatment. Gene therapy in Rpe65 ؊/؊ mice at advanceddisease stages, a more faithful mimic of the humans we studied, showed success but only in animals with better-preserved photoreceptor structure. The results indicate that identifying and then targeting retinal locations with retained photoreceptors will be a prerequisite for successful gene therapy in humans with RPE65 mutations and in other retinal degenerative disorders now moving from proof-of-concept studies toward clinical trials.visual cycle ͉ Leber congenital amaurosis ͉ rod ͉ cone ͉ retinal imaging

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The specific binding of retinoic acid to RPE65 and approaches to the treatment of macular degeneration

Abstract: visual cycle ͉ rate-limiting step ͉ retinylester binding

Cited by 43 publications

References 32 publications

Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina

Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina

Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents

Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success

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