Open Access
Review  |   March 2016
Potential Therapeutic Agents Against Retinal Diseases Caused by Aberrant Metabolism of Retinoids
Author Affiliations & Notes
  • Xin Liu
    Eye Center of the Second Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
  • Jingmeng Chen
    School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang Province, China
  • Zhe Liu
    Department of Ophthalmology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang Province, China
  • Jie Li
    Taizhou First People's Hospital, Taizhou, Zhejiang Province, China
  • Ke Yao
    Eye Center of the Second Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
  • Yalin Wu
    Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian Province, China
  • Correspondence: Yalin Wu, Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiang'an South Road, Xiamen 361102, Fujian Province, China; yalinw@xmu.edu.cn
  • Ke Yao, Eye Center of the Second Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China; xlren@zju.edu.cn
Investigative Ophthalmology & Visual Science March 2016, Vol.57, 1017-1030. doi:10.1167/iovs.15-18429
  • Views
  • PDF
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Xin Liu, Jingmeng Chen, Zhe Liu, Jie Li, Ke Yao, Yalin Wu; Potential Therapeutic Agents Against Retinal Diseases Caused by Aberrant Metabolism of Retinoids. Invest. Ophthalmol. Vis. Sci. 2016;57(3):1017-1030. doi: 10.1167/iovs.15-18429.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

The retinoid (visual) cycle is a complex enzymatic pathway that operates in the retina for the regeneration of 11-cis-retinal (11-cis-Ral), the inherent visual chromophore indispensable for vision. Deficiencies in the retinoid metabolism are involved in pathologic mechanisms of several forms of retinal diseases including age-related macular degeneration, Stargardt's disease, and Leber's congenital amaurosis, for which no effective cures presently exist. Nevertheless, the interference of abnormal retinoid metabolism with chemicals has been considered to be a promising strategy aimed at alleviating these retinal dysfunctions. Moreover, since gene therapy is gaining increasing importance in clinical practice, the modulation of key enzymes implicated with the retinoid cycle at a genetic level will hold great promise for the treatment of patients with degenerative diseases of the retina.

Perception of light is extremely important in visual function or vision. Photoisomerization of opsin-bound visual chromophore 11-cis-retinal (11-cis-Ral) to all-trans-retinal (ATRal) in vertebrate rod photoreceptors triggers visual phototransduction events. The 11-cis-Ral regeneration, a fundamental step in restoring bleached visual pigment rhodopsin (Rh) to its dark-adapted state, is a critical process called the retinoid (visual) cycle leading to vision. The retinoid cycle takes place in the rod outer segments (ROS) and the retinal pigment epithelium (RPE). All-trans-retinol (ATRol), also known as vitamin A, serves as a key metabolite of the retinoid metabolism. It forms from the reduction of ATRal with retinol dehydrogenases (RDHs) in the cytoplasm of the ROS, and is then transferred to the RPE where it is ultimately converted back to 11-cis-Ral.1 Furthermore, food intake is an additional source of vitamin A in the visual cycle. 
Disruption of the retinoid metabolism is correlated with the etiology and pathogenesis of several forms of retinal diseases, including age-related macular degeneration (AMD), Stargardt's disease (STGD), Leber's congenital amaurosis (LCA), retinitis pigmentosa (RP), congenital stationary night blindness, fundus albipunctatus, cone–rod dystrophy (CRD), and retinitis punctata albescens.24 The retinoid cycle arrest will lead to an insufficient supply of visual chromophores for phototransduction, or an excess buildup of toxic retinoid-derived by-products in the RPE.3,4 Hence, it may be feasible to treat retinal disorders by mediating the visual cycle with the purpose of sustaining the retinoid metabolism balance. 
Replacement therapy is one of the strategies for preventing the degeneration of the retina. Indeed, supplementation of vitamin A and its derivatives has proved effective in animal models59 and human patients10,11 with retinal degenerative diseases. In addition, chemical5,1216 and genetic1719 methods have been developed to treat retinal degeneration by affecting functional enzymes in the retinoid cycle, some of which have been under the inspection of clinical trials.2025 However, these pharmaceutical approaches still need to be assessed in terms of pharmacokinetics and pharmacodynamics before clinical significance is confirmed. Here we provide a review of retinal diseases related to aberrant metabolism of retinoids and summarize recent advances in the development of their therapeutic agents. 
The Metabolism of Retinoids in the Retina
The metabolism of retinoids in the retina is essential for vision. The retinoid (visual) cycle is a complex enzymatic pathway for retinoids to metabolize and function continuously within the retina. Light is converted into electrical signals in the ROS, whereas the regeneration of 11-cis-Ral, an inherent chromophore of visual pigment, is accomplished in the RPE.26 Since chromophore supplementation from choroid blood vessels in the form of ATRol is very limited, the chromophore needed for continuous phototransduction mostly comes from the regeneration through the retinoid cycle.27 In addition to cone outer segments and RPE, it is suggested that Müller cells are also active participants in the cone-specific visual cycle,28 thereby making alternative pathways of the visual chromophore regeneration possible for cone photoreceptors.3 
The sensitivity and adaptation to environmental light is achieved by structural transformation and restoration of 11-cis-Ral, the inherent Rh chromophore that is most sensitive to the visible light region in the wavelength range from approximately 360 to 620 nm.4 In the visual cycle (Fig. 1), 11-cis-Ral binds with opsin, a seven-helix transmembrane protein, to form Rh embedded in the ROS disk lumen.2931 Vision begins when a photon of light is absorbed by Rh, and 11-cis-Ral chromophore isomerizes into its all-trans configuration. Rh will undergo transformation into batho-, lumi-, meta-I, and meta-II Rh intermediates, after which ATRal and opsin are separated.2,32 Yet, excess accumulation of free ATRal in the retina could cause cytotoxicity to photoreceptors and RPE.3335 
Figure 1
 
The visual cycle between RPE and ROS. When a photon of light reaches ROS, Rh, which consists of the 11-cis-Ral chromophore and opsin, will be bleached to form an intermediate called meta II. ATRal, generated from the 11-cis-Ral photoisomerization, will be reduced to ATRol in rod cytoplasm by RDH8, RDH11, and RDH12. ATRol can be regenerated back to 11-cis-Ral in the RPE where the most important isomerase is the retinal pigment epithelium–specific 65-kDa protein RPE65. Like RDH5, both RDH10 and RDH11 likely have similar effects in transforming 11-cis-Rol into 11-cis-Ral. In the RPE, ATRal combines with CRBP, whereas 11-cis-Rol and 11-cis-Ral bind with CRALBP. 11-cis-Rol and ATRol can also be stored in the RPE retinosomes in the form of 11-cis-retinyl esters and all-trans-retinyl esters, respectively; LRAT and retinyl ester hydrolase catalyze these esterification reactions. Free 11-cis-Ral and ATRol could form complexes with IRBP in the IPM. On the other hand, a portion of free ATRal that evades reduction will react with NR-PE present in the ROS disk lumen, enabling the release of extra ATRal condensation products, which can be phagocytosed daily by the RPE through the MERTK-mediated signaling pathway. “Rim protein,” called ABCA4 on the ROS disk membrane, plays an important role in clearing NR-PE from the ROS disk lumen, thus decreasing excess accumulation of ATRal in the ROS. However, the role of ABCA4 in the transportation of 11-cis-Ral and ATRal remains unclear. ATRol, also called vitamin A, is a fat soluble compound that is transported in the blood and stored in the liver by mostly combining RBP. Vitamin A from peripheral tissues such as choroid blood vessels can be taken up by the RPE and thus involved in the visual cycle.
Figure 1
 
The visual cycle between RPE and ROS. When a photon of light reaches ROS, Rh, which consists of the 11-cis-Ral chromophore and opsin, will be bleached to form an intermediate called meta II. ATRal, generated from the 11-cis-Ral photoisomerization, will be reduced to ATRol in rod cytoplasm by RDH8, RDH11, and RDH12. ATRol can be regenerated back to 11-cis-Ral in the RPE where the most important isomerase is the retinal pigment epithelium–specific 65-kDa protein RPE65. Like RDH5, both RDH10 and RDH11 likely have similar effects in transforming 11-cis-Rol into 11-cis-Ral. In the RPE, ATRal combines with CRBP, whereas 11-cis-Rol and 11-cis-Ral bind with CRALBP. 11-cis-Rol and ATRol can also be stored in the RPE retinosomes in the form of 11-cis-retinyl esters and all-trans-retinyl esters, respectively; LRAT and retinyl ester hydrolase catalyze these esterification reactions. Free 11-cis-Ral and ATRol could form complexes with IRBP in the IPM. On the other hand, a portion of free ATRal that evades reduction will react with NR-PE present in the ROS disk lumen, enabling the release of extra ATRal condensation products, which can be phagocytosed daily by the RPE through the MERTK-mediated signaling pathway. “Rim protein,” called ABCA4 on the ROS disk membrane, plays an important role in clearing NR-PE from the ROS disk lumen, thus decreasing excess accumulation of ATRal in the ROS. However, the role of ABCA4 in the transportation of 11-cis-Ral and ATRal remains unclear. ATRol, also called vitamin A, is a fat soluble compound that is transported in the blood and stored in the liver by mostly combining RBP. Vitamin A from peripheral tissues such as choroid blood vessels can be taken up by the RPE and thus involved in the visual cycle.
To regenerate 11-cis-Ral, ATRal in the ROS disk lumen is transported out into the photoreceptor cytoplasm, probably by diffusion or with the assistance of ATP-binding cassette transporter 4 (ABCA4).3,31,36 In the cytoplasmic space, ATRal is reduced mostly via retinol dehydrogenase 8 (RDH8) to generate ATRol in a nicotinamide adenine dinucleotide phosphate (NADP)–dependent manner. The newly formed ATRol moves to the interphotoreceptor matrix (IPM), which is an essential process facilitated and protected by interphotoreceptor retinoid-binding protein (IRBP).3,26,37,38 With the help of cellular retinol-binding protein (CRBP), RPE cells take up ATRol via endocytosis or phagocytosis before it is esterified by lecithin:retinol acyltransferase (LRAT) to form all-trans-retinyl esters. Owing to the propensity of fatty acid retinyl esters to cluster,2,3941 these constituents are retained as a stable storage form of retinoids in lipid droplets of the RPE and are thereby termed “retinosomes.”3 Retinosomes can be metabolically active in response to the demand for chromophore regeneration42 and accordingly, all-trans-retinyl esters can undergo isomerization into 11-cis-retinol (11-cis-Rol) by an extremely critical isomerase, the RPE-specific 65-kDa protein RPE65. Cellular retinal-binding protein (CRALBP) in the RPE can bind 11-cis-Rol to speed up the isomerization by regulating the reaction equilibrium.3,28,43 11-cis-Rol, after binding to CRALBP, is oxidized by retinol dehydrogenase 5 (RDH5) to form 11-cis-Ral.28 The latter can be then transported through IPM with the aid of IRBP, and move back into the ROS disk lumen where a fresh dark-adapted Rh forms, followed by initiation of a new retinoid cycle. In addition to its fate in converting into 11-cis-Ral, 11-cis-Rol can also be esterified by LRAT to form 11-cis retinyl esters, which can be stably stored and are convenient for use when chromophore supplementation is needed.28,44,45 
Alternatively, a portion of free ATRal that evades reduction will react with phosphatidylethanolamine (PE) in the ROS disk lumen, thus resulting in the formation of all-trans N-retinylidene-phosphatidylethanolamine (all-trans NR-PE).32,46,47 It should be mentioned here that this is a readily reversible reaction in vivo, producing an equilibrium mixture of all-trans NR-PE and free ATRal in the ROS disk lumen.29 The acidic pH of the ROS disk lumen can trap the protonated form of all-trans NR-PE in the lumen leaflet of the disc membranes48,49 and thus, all-trans NR-PE cannot cross the membrane by itself.36 ABCA4 transporter is important to decrease the amassment of all-trans NR-PE in the ROS disk lumen by flipping all-trans NR-PE from the disk membrane to the photoreceptor cytoplasmic side.48,49 With the assistance of this “inward” flippase all-trans NR-PE is capable of being dissociated into ATRal and PE in the cytoplasm where ATRal will be further reduced to ATRol by RDH8, and thus the retinoid cycle can continue without excess buildup of all-trans NR-PE.32,49,50 
Loss or decrease in ABCA4 activity results in the formation of a series of retinal-derived lipofuscin adducts (Fig. 2). The latter compounds form in the ROS and accumulate in the RPE with time via phagocytosis, thereby causing damage to both photoreceptors and RPE.28,36 In all of these pigments, A2E and its isomers, all-trans-retinal dimer, A2-DHP-PE, A2-GPE, and pdA2E and its isomer, have been isolated and identified structurally.32,46,5158 Because of their relatively high physiological significance, the in vitro cytotoxicity and phototoxicity of A2E have been extensively investigated.5964 It is of note that retinal-derived lipofuscin fluorophores accumulate to a less extent in eyes of wild-type mice than Abca4 gene knockout mice.53,59 Although ATRal is thought to play a leading role in the formation of RPE lipofuscin,34 Boyer et al.65 demonstrate that, in the absence of light exposure, the primary source of lipofuscin deposits is 11-cis-Ral rather than ATRal. 11-cis-Ral, like ATRal, is highly toxic owing to its highly reactive aldehyde moiety, and it will positively undergo detoxification by either reduction to retinol or sequestration within retinal-binding proteins in vivo. In addition to all-trans NR-PE, ABCA4 is also responsible for the translocation of 11-cis NR-PE, the Schiff-base conjugate of 11-cis-Ral and PE, from the lumen to the cytoplasmic leaflet of disk membranes. The transport function of ABCA4—together with chemical isomerization of 11-cis-Ral to ATRal, which is followed by reduction to ATRol via RDHs—can prevent the buildup of excess 11-cis-Ral and 11-cis NR-PE as well as the formation of toxic retinal-derived products as found in ABCA4-deficient mice and individuals with STGD.66 
Figure 2
 
Retinal-derived lipofuscin compounds associated with AMD and STGD.
Figure 2
 
Retinal-derived lipofuscin compounds associated with AMD and STGD.
Previous reports3,18,29,43,67,68 indicate that the onset and progression of some ocular diseases are definitely related to aberrant metabolism of retinoids in the retina (Table 1). Strategies that can directly fix the dysfunction of retinoid metabolism include retinoid replacement, retinoid cycle regulation, and genetic interference. Yet, it should be borne in mind that heterogeneity is strikingly common in retinal diseases, and the final ocular status is likely attributed to more than one abnormal participant in the retinoid cycle.18 
Table 1
 
Human Retinal Diseases Related to Aberrant Metabolism of Retinoids
Table 1
 
Human Retinal Diseases Related to Aberrant Metabolism of Retinoids
Potential Therapeutic Agents for Treating Aberrant Metabolism of Retinoids
Retinoid Replacement Therapy
11-cis-Ral chromophore is an indispensable participant for phototransduction (Fig. 1) and accordingly, a continuously adequate supply of 11-cis-Ral is required to produce visual pigments, maintain vision, and preserve photoreceptor function.69,70 Lack of 11-cis-Ral can ultimately lead to complete loss of vision.11 The abnormality in either biosynthesis or regeneration of the retinoids can cause a deficiency of 11-cis-Ral in the retina. Since the function of LRAT and RPE65 in the visual cycle is of utmost concern to replenish 11-cis-Ral, it is not surprising that mutations of LRAT and RPE65 are detected among hereditary retinal dystrophies such as LCA and RP. 
Although only approximately 10% of LCA patients10,18,71 and less than 5% of RP patients18 have mutations in LRAT or RPE65, replacement therapy with the retinoids (Table 2) is still beneficial for these specific patients. Direct supplementation of 11-cis-Ral in Rpe65 gene knockout (Rpe65−/−) mice has shown improved photoreceptor function.72 Nevertheless, 11-cis-Ral is vulnerable, which has led researchers to discover 9-cis-Ral as a more effective candidate.73,74 Indeed, 9-cis-Ral can be readily synthesized and has the ability to bind with opsin to form 9-cis Rh, which will trigger the phototransduction signaling cascade as well when activated by light.7375 However, the photoreceptor sensitivity of 9-cis Rh will be 3-fold lower than that of control Rh containing 11-cis-Ral chromophore because of the 3-fold lower quantum efficiency of 9-cis Rh than of 11-cis Rh76 and the unavoidable consequence even after full regeneration of the pigment with 9-cis-Ral. Despite that, Gearhart and coworkers77 have demonstrated that 9-cis-Ral can improve visual performance in Rpe65−/− dogs. Moreover, a series of 9-cis-retinoids, including 9-cis-retinyl acetate, 9-cis-retinal succinate, 9-cis-retinal palmitate, and 9-cis-retinol, are also studied for their therapeutic effects in several animal models characterized by retinoid deficiency. The data indicate that 9-cis-retinyl acetate exhibits better stability and lower reactivity, making it suitable for oral administration.3,5 QLT091001, a synthetic 9-cis-retinyl acetate that can be converted into 9-cis-retinal in the vertebrate body, is the most anticipated candidate for replacement therapy and is undergoing clinical trials for retinoid deficiency–caused retinal disorders, such as LCA with LRAT or RPE65 mutations.10 Furthermore, 9-cis-β-carotene, a precursor of 9-cis-retinoids, is an additional promising replacement agent. Oral 9-cis-β-carotene has been proved quite effective in patients with fundus albipunctatus78 and RP,79 and it exhibits no adverse effects in humans owing to its long history as an over-the-counter medication. However, patient heterogeneity may impede uniform efficacy by oral 9-cis-β-carotene, and the long duration (2–3 months) of drug administration also poses a practical problem for its wider use. Accordingly, future treatments will focus on 9-cis-β-carotene–based restoration in combination with other approaches that can enhance the survival of impaired photoreceptors. Although the teratogenicity of retinoid replacement therapy has been proposed because of its possible effect on nuclear retinoic acid receptor (RAR)/retinoid x receptor (RXR), no similar adverse effects are present in mouse models3 or clinical trials.10 Considering that the subjects of clinical trials are mostly young and early-onset LCA patients, follow-up observation and safety evaluation should be further evaluated. 
Table 2
 
Replacement Therapy in Humans and Laboratory Animals With Retinal Dystrophies Characterized by the Retinoid Deficiency
Table 2
 
Replacement Therapy in Humans and Laboratory Animals With Retinal Dystrophies Characterized by the Retinoid Deficiency
Chemically Synthesized Regulators of the Retinoid Metabolism
The foregoing description has indicated that the etiology of some retinal diseases is associated with the retinoid deficiency. Conversely, excess accumulation of retinoids or their metabolites as RPE lipofuscin can also be toxic to normal vision function. Increased levels of deleterious lipofuscin due to the disruption of retinoid clearance are pathologic in retinal degenerative diseases such as STGD, RP, AMD, Best vitelliform macular dystrophy, and a subset of CRDs.3,46,47 A2E, the most studied retinal-derived component of RPE lipofuscin, has been shown to induce pathologic changes in RPE cells, including oxidative stress,80 mitochondrial apoptosis,81,82 membrane damage,59,61 increased photosensitivity,63,64,82 reduced mitochondrial membrane potential,83 diminished function of lysosomal enzymes60 and phagocytosis,83 increased level of interleukin-1β62 and VEGF,84 accumulated advanced glycation endproducts,85 and RPE65 isomerase inhibition.86 It is well-known that damage to RPE results in direct degeneration of photoreceptors.80 Controversy is mounting as to whether a major factor contributing to the death of RPE cells, particularly in the macula, is A2E accumulation. Ablonczy et al.87,88 and Grey et al.89 have shown a lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human RPE. A possible explanation for the study disputing the significance of A2E in humans is that the lipofuscin autofluorescence, which was formerly believed to be associated with retinopathy progression,90,91 is probably a relevant but not causal indicator.9294 By comparison with free ATRal, A2E is less cytotoxic and phototoxic to human RPE cells, suggesting that the production of A2E may decrease ATRal toxicity and serves as a protective mechanism to prevent ATRal-caused retinal damage.95 While it is clear that there are levels of A2E that are tolerated by RPE cells, intracellular concentrations can be reached above which A2E is certainly damaging to the cells. 
Ten regulating agents with different structures (Fig. 3) and therapeutic effects (Table 3) have been experimentally reported to treat retinal diseases characterized by abnormal retinoid metabolism.13 Although all of these agents manifest inhibitory effects on lipofuscin buildup, a resultant lack of chromophores that comes with slowing of the retinoid cycle could induce ocular problems including insensitive daylight vision, delayed dark adaptation, and night blindness.3,13 13-cis-retinoic acid, also known as isotretinoin or accutane, is a common drug used for the treatment of acne.96 However, some patients under isotretinoin treatment develop impaired nocturnal visual sensitivity and diurnal glare sensitivity,97,98 suggesting that isotretinoin may affect the retinoid cycle to some extent. Studies on the amelioration of retinal dysfunction in laboratory animals reveal that isotretinoin impairs rod function rather than inducing rod death, and causes a slowdown of chromophore recovery after photobleaching,7 indicative of the inhibitory effect of isotretinoin on the retinoid cycle. Since STGD is a typical hereditary retinal disease characterized by the inability of retinoids to be cleared from photoreceptors and RPE cells, isotretinoin displays a significant inhibitory effect on lipofuscin accumulation in the STGD mouse model.6 The mechanism underlying isotretinoin-mediated decrease in the levels of RPE lipofuscin may be its ability to inhibit RDH5.99,100 Besides, evidence from in vivo experiments indicates that isotretinoin likely has a role in inhibiting specific isomerization of all-trans-retinyl esters to 11-cis-Rol by interfering with RPE65 activity6,101 or all-trans-RDHs such as RDH8.13 Clinical trials such as NCT01445028 and NCT02149615 have investigated the effect of isotretinoin on nerve fiber layer102,103 and proliferative vitreoretinopathy (PVR),104 suggestive of the ability of isotretinoin to compromise retinal nerve fiber layer thickness, thereby potentially improving the rate of retinal reattachment in PVR patients. A clinical study of 11 patients has shown that oral isotretinoin treatment can cause ocular side effects and does not improve vision, although it may slow visual acuity loss in AMD patients, characterized by occult subfoveal choroidal neovascularization.105 
Figure 3
 
Structures of 10 regulators of abnormal retinoid metabolism.
Figure 3
 
Structures of 10 regulators of abnormal retinoid metabolism.
Table 3
 
Mechanism and Clinical Trials of Synthesized Regulators Against Aberrant Retinoid Metabolism
Table 3
 
Mechanism and Clinical Trials of Synthesized Regulators Against Aberrant Retinoid Metabolism
N-(4-hydroxyphenyl)retinamide, also known as fenretinide or 4-HPR, has been used as a chemotherapeutic agent to treat cancer.3 It has also been discovered that fenretinide can affect the serum vitamin A level.106,107 Physiologically, vitamin A from the diet will bind to retinoid-binding protein (RBP) in the liver and stay in blood after the complex is bound to transthyretin (TTR), because the latter complex will be large enough to avoid glomerular filtration.108,109 Treatment with fenretinide in laboratory animals, however, will displace vitamin A from RBP, and the newly formed complex will not bind to TTR, thus reducing the levels of retinols and RBP in serum by rapid elimination of the RBP–fenretinide complex in urine, and inhibiting the chromophore biosynthesis within the retina.110 In the STGD animal model, fenretinide effectively decreases lipofuscin accumulation by reducing vitamin A in serum.110 The actual mechanism of fenretinide-mediated decrease of lipofuscin levels has been questioned. Some researchers point out that the retina, with strong ability to store retinoids, is highly resistant to peripheral vitamin A deprivation,4 whereas others claim that RBP−/− mice display a significant ocular phenotype.111 Since Rh regeneration is still preserved in IRBP gene knockout mice,112,113 RBP is also likely to be present in the IPM area,3 thereby revealing its function under certain pathologic circumstances. Furthermore, Golczak and coworkers13 argue against the role of RBP binding in the regulatory effect of fenretinide. On the other hand, the mechanism of action for chemopreventive activity of fenretinide is unrelated to its function as a RBP4 ligand but seems to be associated with its ability to generate reactive oxygen species and induce apoptosis in malignant cells.114 Despite the ambiguous mechanism of fenretinide in the retina, a phase II clinical trial with a 2-year observation shows decelerated lesion growth and later onset of choroidal neovascularization in AMD patients.115 In addition, as a traditional drug for systemic use, fenretinide is thought to have less teratogenicity than isotretinoin3,110 and exhibits no clinical signs of systematic vitamin A loss except for a delayed dark adaptability.116,117 
Retinylamine, also known as Ret-NH2, is a positively charged primary amine–containing retinoid. It has the ability to inhibit chromophore regeneration and rod function recovery,12 probably by suppression of the RPE65-mediated isomerization process or blockage of retinal-derived by-product accumulation by directly binding excess free ATRal.13 Retinylamine can acquire exact structures as 11-cis-Ret-NH2, 9-cis-Ret-NH2, 13-cis-Ret-NH2 and all-trans-Ret-NH2, among which 11-cis-Ret-NH2 exerts the strongest inhibition on the RPE65-induced isomerization process.12 Compared to isotretinoin and fenretinide, Ret-NH2 displays greater and more prolonged inhibitory effect on chromophore biosynthesis, as well as less influence on RAR/RXR activation13,118 and cone function.12 Being a substrate also for LRAT, Ret-NH2 undergoes N-amidation to be stored in the liver or RPE retinosomes for further release,4,12 but the resulting amidated metabolites exhibit a weaker effect on the retinoid cycle.12 Interestingly, Ret-NH2 can be oxidized into retinol and later be esterified into retinyl esters by LRAT, and then stored in retinosomes in vivo.119 As for the free ATRal–binding mechanism, a therapeutic study using more than 20 Food and Drug Administration-approved drugs with primary amine groups indicates that primary amines could protect against retinal degeneration without any evidence of inhibition of the retinoid cycle enzymes.120 Rather, the formation of a reversible Schiff base from ATRal and primary amines decelerates the accumulation of retinal-derived lipofuscin while slowly releasing ATRal into the retinoid cycle to alleviate adverse effects such as delayed dark adaptation.13,120 Although no clinical trials with Ret-NH2 have been performed, advances have been made to synthesize and evaluate Ret-NH2 analogues with a strong RPE65 inhibition activity, a high ATRal-binding ability, and a superior LRAT affinity.14 Chemical modifications of Ret-NH2 have been carried out for future drug development. Zhang et al.14 demonstrate that the conformation of the β-ionone ring is a critical structural feature for LRAT substrate recognition. Indeed, replacements within the β-ionone ring, together with elongation of the double-bond conjugations and a variety of substitutions of the C9 methyl, do not abolish the LRAT-mediated acylation, thereby revealing broad substrate specificity for LRAT. As for the inhibition of RPE65 enzymatic activity, an altered β-ionone ring structure, characterized by the absence of methyl groups and the presence of one bulky group at the C9 position, will weaken its inhibition effect on RPE65. Polyethylene glycol121 and polylactic acid nanoparticle technologies122 are also being explored to enhance the pharmacokinetic properties of Ret-NH2. Then, Ret-NH2 could be a more promising candidate for clinical use in retinal degenerative diseases, with higher solubility in water, lower level of accumulative toxicity in liver, prolonged duration of retina protection, and a convenient way of drug administration, without strong RAR/RXR activation or severe ocular adverse effects. In addition to STGD and AMD, the application of Ret-NH2 has also been expanded to treat early diabetic retinopathy (DR) in mice because photoreceptors have been identified as major contributors to the vascular damage in DR.123 
Two farnesyl-containing isoprenoids, TDT and TDH, exert inhibitory effects on the biosynthesis of visual chromophores to approximately the same extent as isoretinoin, but these two chemicals exhibit more persistent inhibitory effects on the chromophore biosynthesis and a remarkable specificity to block RPE65 activity.124 Evidence has indicated the role of the farnesyl moiety as a posttranslational modification device in the phototransduction cascade.125127 A1120 has previously been designed to treat diabetes mellitus. As a nonretinoid RBP antagonist, A1120 shares similar effect and mechanism with fenretinide, but it demonstrates more potent activity and less RAR/RXR activation.128,129 Although A1120 effectively diminishes lipofuscin buildup, this adduct, unlike other retinoid metabolism regulators, does not lead to a significant delay of rod function after photobleaching.128 Such a phenomenon indicates that A1120 may possess the ability to ameliorate ocular adverse effects such as night blindness and delayed dark adaptation. To enhance the RBP4-binding affinity and metabolic stability, chemical modifications of A1120 have drawn much attention.130132 Using A1120 as a template, bicyclic-octahydrocyclopenta[c]-pyrrolo analogues have been synthesized that display more favorable RBP-binding potency and inhibition effects on lipofuscin formation.131,132 α-Phenyl-N-tert-butylnitrone (PBN), a free radical spin trap, may have the capacity to inhibit RPE65 activity, and to protect photoreceptor cells by means of free radical scavenging and c-fos suppression.15 Although a delayed recovery of rod response function is observed in laboratory animals treated with PBN, the cone visual cycle is not significantly affected, such that the extent of night blindness after PBN treatment is supposed to be slight.15 
ACU-4429, often in the form of emixustat hydrochloride tablet, is also a small-molecule nonretinoid modulator of the visual cycle that was initially found to serve as an inhibitor of RPE65.16 (R)-isomer of ACU-4429 shows higher affinity toward RPE65 than its (S)-isomer.133 Compared to Ret-NH2, ACU-4429 possesses stronger inhibitory activity of 11-cis-Rol production and could lead to prolonged blockage of the visual pigment regeneration in vivo. Similar to Ret-NH2, ACU-4429 is able to sequester ATRal, and the tendency of ACU-4429 to form a Schiff base with ATRal seems to be stronger than that of Ret-NH2. Efficient amidation upon incubation of ACU-4429 with bovine RPE microsomes indicates that tissue uptake of the drug can be facilitated by LRAT enzymatic activity, whereas component analysis of an incubation mixture of eye extracts from mice in the presence of ACU-4429 gives rise to a predominantly free form of ACU-4429. Moreover, antiangiogenic properties of ACU-4429 have also been observed in animal models of retinal neovascularization.134 In clinical trials, safety, tolerability, and effect of oral ACU-4429 on healthy subjects (phase I) have been followed up since 2008. Single-dose (2–75 mg) or multidose (5–40 mg, 14 days) applications manifest a dose-dependent effect of ACU-4429 in rod function inhibition.16 Ocular side effects such as dyschromatopsia or nyctalopia occur in more than 50% of healthy subjects but are mostly resolved after 2 weeks. And yet, a long-time observation should not be underestimated.135 Phase II/III clinical trials of ACU-4429 are still under way. In this regard, the latest report shows that oral administration of emixustat hydrochloride tablet (2–10 mg) for 90 days may benefit AMD patients with geographic atrophy lesions.136 C20-D3-vitamin A, a form of deuterated vitamin A, can retard the retinoid cycle without impairing rod function and dark adaptation. Since the rate-determining step in vitamin A dimerization is the cleavage of a C20 carbon–hydrogen bond of the NR-PE Schiff base,137 replacement of three C20-H bonds with C20-D bonds will result in a primary kinetic isotope effect slowing the formation of A2E and all-trans-retinal dimer.137 Studies carried out in wild-type mice137 and STGD1 mice138,139 demonstrate that, when C20-D3-vitamin A acts as the sole source of vitamin A intake, there is a greater than 50% decrease in the formation of cytotoxic bisretinoids and a significant reduction of fundus autofluorescence. 
Gene Therapy
Table 1 gives reason to consider gene therapy as a direct modification method for the expression of key enzymes and other functional proteins in the retinoid cycle. Since several retinal diseases, such as hereditary macular degeneration or AMD, are associated with or caused by certain genetic mutations, the repair of responsible genes is a promising approach to strike a normal balance back in retinal environments. Replacement of defective genes and suppression of abnormal mutants are possible ways to cure retinal diseases genetically. It is noted that 95% of STGD, 30% of CRD, and 8% of autosomal recessive RP patients have ABCA4 mutations,140 and 6% of LCA patients have RPE65 mutation.141 The genetic heterogeneity in the whole population makes gene therapy costly for clinical trials and use. Nevertheless, the same genetic mutations will not all develop into clinical syndromes, which makes it challenging for the application of gene therapy as a preventive measure in progressive eye diseases. Despite the complicated pathologic situation, studies of gene therapy in retinal diseases have been advancing owing to preliminary success of gene augmentation therapy in LCA caused by the RPE65 mutation. 
Early onset of visual impairment occurs in LCA patients. Gene-based ocular therapy has found application in the treatment of RPE65-related LCA, commonly categorized as LCA2. The genetic augmentation therapy has been tested for its safety and effect in dogs,142148 mice,73,148152 and primates153 before starting clinical trials in humans. The protective effect of Rpe65 gene augmentation has even lasted for 3 years in a canine model.144 Clinical trials on LCA patients with RPE65 mutation have been advancing to phase III (Table 4). Importantly, the short-time (less than 12 months) observation shows no local or systemic adverse effects after subretinal injection,20 and visual function appears to be improved21, 22 by Rpe65 gene augmentation. It is also suggested that earlier use of gene therapy results in better visual improvement,23 probably because a significant decrease of plasticity in the connection between retina and central nervous system is detected in children older than 3 years.18 Although visual function can be ameliorated, retinal degeneration cannot be retarded by Rpe65 gene therapy.154 In addition, prolonged observations of up to 3 years still achieve visual improvement after single-dose treatment with Rpe65 gene augmentation,24,25,155157 but recent studies that observe treated patients for up to 6 years show that improvements in retinal sensitivity are only evident for the first 3 years, peaking at 6 to 12 months after treatment, and then decline.158,159 Therefore, re-administration of Rpe65 gene should be considered for persistent therapeutic effects on LCA patients.160 
Table 4
 
Gene Therapies That Repair Aberrant Metabolism of Retinoids for Retinal Dysfunctions
Table 4
 
Gene Therapies That Repair Aberrant Metabolism of Retinoids for Retinal Dysfunctions
Stargardt's disease is another retinal disease with no presently effective treatment. Most of the STGD cases are characterized by juvenile onset and autosomal recessive heredity.18,161 The autosomal recessive STGD, namely STGD1, is thought to be the most common hereditary macular dystrophy.162 It was identified by Allikmets et al.163 who claim that STGD1 is caused by ABCA4 mutation and is considered to be a monogenic retinal disease. The retinoid metabolism indicates that ABCA4 is responsible for clearing NR-PE in photoreceptor outer segments, thus blocking lipofuscin formation in the RPE and photoreceptor. Since ABCA4 is present in rod and cone photoreceptors,162 different phenotypes of STGD1 can be detected in clinic and in animal models.140 Abca4 gene knockout (Abca4−/−) mice, an animal model of STGD1, have shown phenotype corrections after Abca4 gene augmentation by lentivirus164 or nanoparticle165 vectors. Phase I/II clinical trials for gene-based treatment of STGD1 have initiated140 but reports are not available yet. Retinitis pigmentosa is a retinal disease that predominantly influences rod function18 and is associated with more than 60 gene mutations, such as MERTK gene mutation. MERTK (c-mer protooncogene receptor tyrosine kinase) is required for the phagocytosis of photoreceptor outer segments by the RPE, and gene transfer of MERTK by a virus vector is effective in Royal College of Surgeons (RCS) rats with MERTK deficiency by repairing retinal functions and structures.166169 Some promising gene therapies that repair aberrant retinoid metabolism in retinal diseases are shown in Table 4, but many preclinical studies must still be performed to discover more potential gene targets. Rh gene–related RP has long been studied in the preclinical phase for the feasibility of gene therapy. Despite this common method to replace deficient genes by augmentation,170 several lines of investigations in Rh-related RP have opted to suppress mutant genes by gene-silencing technology.171180 
Conclusions
In this review, we have mainly focused on aberrant metabolism of retinoids within the retina and potential agents used for its interference. Today, replacement therapy with vitamin A derivatives is still a developing field with ongoing clinical trials. 9-cis-retinyl acetate, also known by its drug name QLT091001, is likely to be a future candidate for LCA treatment. Replacement therapy is merely recommended to be used for retinoid deficiency diseases, and conversely, for retinal diseases caused by abnormal retinoid accumulation, inhibitors of retinoid biosynthesis should be considered. Regulating agents of aberrant retinoid metabolism, which were not discovered and well studied until 2000, are classified into retinoid and nonretinoid compounds. Retinoid compounds include isotretinoin, fenretinide, retinylamine, and C20-D3-vitamin A; the retinoid structure allows them to mimick physiological retinoids in the visual cycle without triggering real functions, thus inhibiting the normal retinoid metabolism. But similar to vitamin A derivatives used for replacement therapy, these retinoid-resembling drugs have the potential ability to activate nuclear receptor RAR/RXR, which will affect cell proliferation and cellular functions. Among all these retinoid metabolism modulators, retinylamine and C20-D3-vitamin A may be thought of as the most promising agents owing to more effective inhibition activity and less adverse effects. Development of deuterated vitamin A likely solves a long-term problem regarding how to balance the contradiction between inhibiting formation of bisretinoids and retarding the function of photoreceptors. On the other hand, it is proposed that nonretinoid regulating agents would prevent the occurrence of systemic adverse effects by RAR/RXR activation. Although the efficiency of nonretinoid regulating agents has yet to be confirmed, modifications in chemical structure may broaden their biological significance. 
Yet, both retinoid or nonretinoid regulating agents will cause relative deficiency of chromophores in the visual cycle except perhaps for deuterated vitamin A, because their targets are not specific to certain pathologic mechanisms. To tackle the phenomenon, gene therapy is envisioned and is considered to be a promising strategy to alleviate nonspecific and systemic adverse effects induced by the foregoing two categories of therapeutic agents. The challenge with using gene therapy agents remains the presence of genetic and phenotype heterogeneity in retinal diseases, which will hinder the universal use of gene therapy for one type of ocular disease. Moreover, gene repair requires direct contact with targeted structures, and therefore intraocular methods should be applied to treat retinal diseases genetically; it is quite clear that this is far more complicated and risky than taking drugs orally. However, with the advancement in both gene screening technology and exploration of more suitable strategies, we believe that existing obstacles will be removed, and gene/drug therapies will gain greater practical significance. 
Acknowledgments
Supported in part by China National Natural Science Foundation Grants 81570857 (YW) and 81271018 (YW); the Fundamental Research Funds for the Central Universities grant (YW); and Zhejiang Key Laboratory Funds of China Grant 2011E10006 (KY). 
Disclosure: X. Liu, None; J. Chen, None; Z. Liu, None; J. Li, None; K. Yao, None; Y. Wu, None 
References
Kiser PD, Golczack M, Palczewski K. Chemistry of the retinoid (visual) cycle. Chem Rev. 2014; 114: 194–232.
Kiser PD, Golczak M, Maeda A, Palczewski K. Key enzymes of the retinoid (visual) cycle in vertebrate retina. Biochim Biophys Acta. 2012; 1821: 137–151.
Travis GH, Golczak M, Moise AR, Palczewski K. Diseases caused by defects in the visual cycle: retinoids as potential therapeutic agents. Annu Rev Pharmacol Toxicol. 2007; 47: 469–512.
Palczewski K. Retinoids for treatment of retinal diseases. Trends Pharmacol Sci. 2010; 31: 284–295.
Maeda T, Maeda A, Casadesus G, Palczewski K, Margaron P. Evaluation of 9-cis-retinyl acetate therapy in Rpe65−/− mice. Invest Ophthalmol Vis Sci. 2009; 50: 4368–4378.
Radu RA, Mata NL, Nusinowitz S, Liu X, Sieving PA, Travis GH. Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. Proc Natl Acad Sci U S A. 2003; 100: 4742–4747.
Sieving PA, Chaudhry P, Kondo M, et al. Inhibition of the visual cycle in vivo by 13-cis-retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc Natl Acad Sci U S A. 2001; 98: 1835–1840.
Berkowitz BA, Bissig D, Patel P, Bhatia A, Roberts R. Acute systemic 11-cis-retinal intervention improves abnormal outer retinal ion channel closure in diabetic mice. Mol Vis. 2012; 18: 372–376.
Perusek L, Maeda A, Maeda T. Supplementation with vitamin A derivatives to rescue vision in animal models of degenerative retinal diseases. Methods Mol Biol. 2015; 1271: 345–362.
Koenekoop RK, Sui R, Sallum J, et al. Oral 9-cis retinoid for childhood blindness due to Leber congenital amaurosis caused by RPE65 or LRAT mutations: an open-label phase 1b trial. Lancet. 2014; 384: 1513–1520.
Perusek L, Maeda T. Vitamin A derivatives as treatment options for retinal degenerative diseases. Nutrients. 2013; 5: 2646–2666.
Golczak M, Kuksa V, Maeda T, Moise AR, Palczewski K. Positively charged retinoids are potent and selective inhibitors of the trans-cis isomerization in the retinoid (visual) cycle. Proc Natl Acad Sci U S A. 2005; 102: 8162–8167.
Golczak M, Maeda A, Bereta G, et al. Metabolic basis of visual cycle inhibition by retinoid and nonretinoid compounds in the vertebrate retina. J Biol Chem. 2008; 283: 9543–9554.
Zhang J, Dong Z, Mundla SR, et al. Expansion of the first-in-class drug candidates that sequester toxic all-trans-retinal and prevent light-induced retinal degeneration. Mol Pharmacol. 2015; 87: 477–491.
Mandal MN, Moiseyev GP, Elliott MH, et al. Alpha-phenyl-N-tert-butylnitrone (PBN) prevents light-induced degeneration of the retina by inhibiting RPE65 protein isomerohydrolase activity. J Biol Chem. 2011; 286: 32491–32501.
Kubota R, Boman NL, David R, Mallikaarjun S, Patil S, Safety Birch D. and effect on rod function of ACU-4429 a novel small-molecule visual cycle modulator. Retina. 2012; 32: 183–188.
Colella P, Cotugno G, Auricchio A. Ocular gene therapy: current progress and future prospects. Trends Mol Med. 2008; 15: 23–31.
den Hollander A, Black A, Bennett J, Cremers FP. Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies. J Clin Invest. 2010; 120: 3042–3053.
Cideciyan AV. Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy. Prog Retin Eye Res. 2010; 29: 398–427.
Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008; 358: 2240–2248.
Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008; 358: 2231–2239.
Cideciyan AV, Aleman TS, Boye SL, et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A. 2008; 105: 15112–15117.
Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009; 374: 1597–1605.
Cideciyan AV, Hauswirth WW, Aleman TS, et al. Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther. 2009; 20: 999–1004.
Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in fifteen children and adults followed up to three years. Arch Ophthalmol. 2012; 130: 9–24.
Tang PH, Kono M, Koutalos Y, Ablonczy Z, Crouch RK. New insights into retinoid metabolism and cycling within the retina. Prog Retin Eye Res. 2013; 32: 48–63.
Carotenoids Wald G. and the visual cycle. J Gen Physiol. 1935; 19: 351–371.
Wang JS, Kefalov VJ. The cone-specific visual cycle. Prog Retin Eye Res. 2011; 30: 115–128.
Molday RS. ATP-binding cassette transporter ABCA4: molecular properties and role in vision and macular degeneration. J Bioenerg Biomembr. 2007; 39: 507–517.
Molday RS, Zhong M, Quazi F. The role of the photoreceptor ABC transporter ABCA4 in lipid transport and Stargardt macular degeneration. Biochim Biophys Acta. 2009; 1791: 573–583.
Biswas-Fiss EE, Affet S, Ha M, Biswas SB. Retinoid binding properties of nucleotide binding domain 1 of the Stargardt disease-associated ATP binding cassette (ABC) transporter, ABCA4. J Biol Chem. 2012; 287: 44097–44107.
Sparrow JR, Wu Y, Kim CY, Zhou J. Phospholipid meets all-trans-retinal: the making of RPE bisretinoids. J Lipid Res. 2010; 51: 247–261.
Maeda A, Maeda T, Golczak M, et al. Involvement of all-trans-retinal in acute light-induced retinopathy of mice. J Biol Chem. 2009; 284: 15173–15183.
Maeda A, Maeda T, Golczak M, Palczewski K. Retinopathy in mice induced by disrupted all-trans-retinal clearance. J Biol Chem. 2008; 283: 26684–26693.
Li J, Cai X, Xia Q, et al. Involvement of endoplasmic reticulum stress in all-trans-retinal-induced retinal pigment epithelium degeneration. Toxicol Sci. 2015; 143: 196–208.
Tsybovsky Y, Molday RS, Palczewski K. The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease. Adv Exp Med Biol. 2010; 703: 105–125.
Crouch RK, Hazard ES, Lind T, Wiggert B, Chader G, Corson DW. Interphotoreceptor retinoid-binding protein and alpha-tocopherol preserve the isomeric and oxidation state of retinol. Photochem Photobiol. 1992; 56: 251–255.
Pepperberg DR, Okajima TL, Wiggert B, Ripps H, Crouch RK, Chader GJ. Interphotoreceptor retinoid-binding protein (IRBP): molecular biology and physiological role in the visual cycle of rhodopsin. Mol Neurobiol. 1993; 7: 61–85.
Imanishi Y, Batten ML, Piston DW, Baehr W, Palczewski K. Noninvasive two-photon imaging reveals retinyl ester storage structures in the eye. J Cell Biol. 2004; 164: 373–383.
Imanishi Y, Gerke V, Palczewski K. Retinosomes: new insights into intracellular managing of hydrophobic substances in lipid bodies. J Cell Biol. 2004; 166: 447–453.
Orban T, Palczewska G, Palczewski K. Retinyl ester storage particles (retinosomes) from the retinal pigmented epithelium resemble lipid droplets in other tissues. J Biol Chem. 2011; 286: 17248–17258.
Golczak M, Bereta G, Maeda A, Palczewski K. Molecular biology and analytical chemistry methods used to probe the retinoid cycle. Methods Mol Biol. 2010; 652: 229–245.
Thompson DA, Gal A. Vitamin A metabolism in the retinal pigment epithelium: genes, mutations, and diseases. Prog Retin Eye Res. 2003; 22: 683–703.
Mata JR, Mata NL, Tsin AT. Substrate specificity of retinyl ester hydrolase activity in retinal pigment epithelium. J Lipid Res. 1998; 39: 604–612.
Saari JC, Bredberg DL, Farrell DF. Retinol esterification in bovine retinal pigment epithelium: reversibility of lecithin:retinol acyltransferase. Biochem J. 1993; 291: 697–700.
Wu Y, Fishkin NE, Pande A, Pande J, Sparrow JR. Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease. J Biol Chem. 2009; 284: 20155–20166.
Wu Y, Yanase E, Feng X, Siegel M, Sparrow J. Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration. Proc Natl Acad Sci U S A. 2010; 107: 7275–7280.
Chen C, Jiang Y, Koutalos Y. Dynamic behavior of rod photoreceptor disks. Biophys J. 2002; 83: 1403–1412.
Sullivan JM. Focus on molecules: ABCA4 (ABCR)-an import-directed photoreceptor retinoid flipase. Exp Eye Res. 2009; 89: 602–603.
Sun H, Nathans J. Mechanistic studies of ABCR, the ABC transporter in photoreceptor outer segments responsible for autosomal recessive Stargardt disease. J Bioenerg Biomembr. 2001; 33: 523–530.
Li J, Yao K, Yu X, et al. Identification of a novel lipofuscin pigment (iisoA2E) in retina and its effects in the retinal pigment epithelial cells. J Biol Chem. 2013; 288: 35671–35682.
Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH. Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice. Cell. 1999; 98: 13–23.
Mata NL, Weng J, Travis GH. Biosynthesis of a major lipofuscin fluorophorein mice and humans with ABCR-mediated retinal and macular degeneration. Proc Natl Acad Sci U S A. 2000; 97: 7154–7159.
Fishkin NE, Sparrow JR, Allikmets R, Nakanishi K. Isolation and characterization of a retinal pigment epithelial cell fluorophore: an all-trans-retinal dimer conjugate. Proc Natl Acad Sci U S A. 2005; 102: 7091–7096.
Kim S, Jang Y, Jockusch S, Fishkin NE, Turro NJ, Sparrow JR. The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model. Proc Natl Acad Sci U S A. 2007; 104: 19273–19278.
Wu Y, Jin Q, Yao K, et al. Retinal metabolism in humans induces the formation of an unprecedented lipofuscin fluorophore ‘pdA2E'. Biochem J. 2014; 460: 343–352.
Zhao J, Yao K, Jin Q, et al. Preparative and biosynthetic insights into pdA2E and isopdA2E, retinal-derived fluorophores of retinal pigment epithelial lipofuscin. Invest Ophthalmol Vis Sci. 2014; 55: 8241–8250.
Yamamoto K, Yoon KD, Ueda K, Hashimoto M, Sparrow JR. A novel bisretinoid of retina is an adduct on glycerophosphoethanolamine. Invest Ophthalmol Vis Sci. 2011; 52: 9084–9090.
Eldred GE, Lasky MR. Retinal age pigments generated by self-assembling lysosomotrophic detergents. Nature. 1993; 361: 724–726.
Holz FG, Schütt F, Kopitz J, et al. Inhibition of lysosomal degradative functions in RPE cells by a retinoid component of lipofuscin. Invest Ophthalmol Vis Sci. 1999; 40: 737–743.
Sparrow JR, Parish CA, Hashimoto M, Nakanishi K. A2E a lipofuscin fluorophore, in human retinal pigmented epithelial cells in culture. Invest Ophthalmol Vis Sci. 1999; 40: 2988–2995.
Anderson OA, Finkelstein A, Shima DT. A2E induces IL-1β production in retinal pigment epithelial cells via the NLRP3 inflammasome. PLoS One. 2013; 8: e67263.
Radu RA, Mata NL, Bagla A, Travis GH. Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt's macular degeneration. Proc Natl Acad Sci U S A. 2004; 101: 5928–5933.
Jang YP, Matsuda H, Itagaki Y, Nakanishi K, Sparrow JR. Characterization of peroxy-A2E and furan-A2E photooxidation products and detection in human and mouse retinal pigment epithelial cell lipofuscin. J Biol Chem. 2005; 280: 39732–39739.
Boyer NP, Higbee D, Currin MB, et al. Lipfuscin and N-retinylidene-N-retinylethanolamine (A2E) accumulate in retinal pigment epithelium in absence of light exposure: their origin is 11-cis-retinal. J Biol Chem. 2012; 287: 22276–22286.
Quazi F, Molday RS. ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11-cis-retinal. Proc Natl Acad Sci U S A. 2014; 111: 5024–5029.
Klevering BJ, Deutman AF, Maugeri A, Cremers FP, Hoyng CB. The spectrum of retinal phenotypes caused by mutations in the ABCA4 gene. Graefes Arch Clin Exp Ophthalmol. 2005; 243: 90–100.
Noble KG, Carr RE. Stargardt's disease and fundus flavimaculatus. Arch Ophthalmol. 1979; 97: 1281–1285.
Gao SQ, Maeda T, Okano K, Palczewski K. A microparticle/hydrogel combination drug-delivery system for sustained release of retinoids. Invest Ophthalmol Vis Sci. 2012; 53: 6314–6323.
Palczewski K. Blind dogs that can see: pharmacological treatment of Leber congenital amaurosis caused by a defective visual cycle. Arch Ophthalmol. 2010; 128: 1483–1485.
Chacon-Camacho OF, Zenteno JC. Review and update on the molecular basis of Leber congenital amaurosis. World J Clin Cases. 2015; 3: 112–124.
Ablonczy Z, Crouch RK, Goletz PW, et al. 11-cis-retinal reduces constitutive opsin phosphorylation and improves quantum catch in retinoid-deficient mouse rod photoreceptors. J Biol Chem. 2002; 277: 40491–40498.
Van Hooser JP, Aleman TS, He YG, et al. Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness. Proc Natl Acad Sci U S A. 2000; 97: 8623–8628.
Van Hooser JP, Liang Y, Maeda T, et al. Recovery of visual functions in a mouse model of Leber congenital amaurosis. J Biol Chem. 2002; 277: 19173–19182.
Fan J, Rohrer B, Moiseyev G, Ma JX, Crouch RK. Isorhodopsin rather than rhodopsin mediates rod function in RPE65 knockout mice. Proc Natl Acad Sci U S A. 2003; 100: 13662–13667.
Hubbard R, Kropf A. The action of light on rhodopsin. Proc Natl Acad Sci U S A. 1958; 44: 130–139.
Gearhart PM, Gearhart C, Thompson DA, Petersen-Jones SM. Improvement of visual performance with intravitreal administration of 9-cis-retinal in Rpe65-mutant dogs. Arch Ophthalmol. 2010; 128: 1442–1448.
Rotenstreich Y, Harats D, Shaish A, Pras E, Belkin M. Treatment of a retinal dystrophy fundus albipunctatus, with oral 9-cis-β-carotene. Br J Ophthalmol. 2010; 94: 616–621.
Rotenstreich Y, Belkin M, Sadetzki S, et al. Treatment with 9-cis β-carotene-rich powder in patients with retinitis pigmentosa: a randomized crossover trial. JAMA Ophthalmol. 2013; 131: 985–992.
Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol. 2004; 122: 598–614.
Suter M, Remé C, Grimm C, et al. Age-related macular degeneration: the lipofusion component N-retinyl-N-retinylidene ethanolamine detaches proapoptotic proteins from mitochondria and induces apoptosis in mammalian retinal pigment epithelial cells. J Biol Chem. 2000; 275: 39625–39630.
Sparrow JR, Cai B. Blue light-induced apoptosis of A2E-containing RPE: involvement of caspase-3 and protection by Bcl2. Invest Ophthalmol Vis Sci. 2001; 42: 1356–1362.
Vives-Bauza C, Anand M, Shiraz AK, et al. The age lipid A2E and mitochondrial dysfunction synergistically impair phagocytosis by retinal pigment epithelial cells. J Biol Chem. 2008; 283: 24770–24780.
Zhou J, Cai B, Jang YP, Pachydaki S, Schmidt AM, Sparrow JR. Mechanisms for the induction of HNE- MDA- and AGE-adducts RAGE and VEGF in retinal pigment epithelial cells. Exp Eye Res. 2005; 80: 567–580.
Yoon KD, Yamamoto K, Ueda K, Zhou J, Sparrow JR. A novel source of methylglyoxal and glyoxal in retina: implications for age-related macular degeneration. PLoS One. 2012; 7: e41309.
Moiseyev G, Nikolaeva O, Chen Y, Farjo K, Takahashi Y, Ma JX. Inhibition of the visual cycle by A2E through direct interaction with RPE65 and implications in Stargardt disease. Proc Natl Acad Sci U S A. 2010; 107: 17551–17556.
Ablonczy Z, Higbee D, Anderson DM, et al. Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2013; 54: 5535–5542.
Ablonczy Z, Higbee D, Grey AC, Koutalos Y, Schey KL, Crouch RK. Similar molecules spatially correlate with lipofuscin and N-retinylidene-N-retinylethanolamine in the mouse but not in the human retinal pigment epithelium. Arch Biochem Biophys. 2013; 539: 196–202.
Grey AC, Crouch RK, Koutalos Y, Schey KL, Ablonczy Z. Spatial localization of A2E in the retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2011; 52: 3926–3933.
Holz FG, Bellman C, Staudt S, Schütt F, Völcker HE. Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2001; 42: 1051–1056.
Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HP, Schmitz-Valckenberg S. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol. 2007; 143: 463–472.
Rudolf M, Vogt SD, Curcio CA, et al. Histologic basis of variations in retinal pigment epithelium autofluorescence in eyes with geographic atrophy. Ophthalmology. 2013; 120: 821–828.
Biarnés M, Arias L, Alonso J, et al. Increased fundus autofluorescence and progression of geographic atrophy secondary to age-related macular degeneration: the GAIN study. Am J Ophthalmol. 2015; 160: 345–353.
Hwang JC, Chan JW, Chang S, Smith RT. Predictive value of fundus autofluorescence for development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2006; 47: 2655–2661.
Wielgus AR, Chignell CF, Ceger P, Roberts JE. Comparison of A2E cytotoxicity and phototoxicity with all-trans-retinal in human retinal pigment epithelial cells. Photochem Photobiol. 2010; 86: 781–791.
Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med. 1979; 300: 329–333.
Fraunfelder FT, LaBraico JM, Meyer SM. Adverse ocular reactions possibly associated with isotretinoin. Am J Ophthalmol. 1985; 100: 534–537.
Weleber RG, Denman ST, Hanifin JM, Cunningham WJ. Abnormal retinal function associated with isotretinoin therapy for acne. Arch Ophthalmol. 1986; 104: 831–837.
Law WC, Rando RR. The molecular basis of retinoic acid induced night blindness. Biochem Biophys Res Commun. 1989; 161: 825–829.
Gamble MV, Mata NL, Tsin AT, Mertz JR, Blaner WS. Substrate specificities and 13-cis-retinoic acid inhibition of human mouse and bovine cis-retinol dehydrogenases. Biochim Biophys Acta. 2000; 1476: 3–8.
Gollapalli DR, Rando RR. The specific binding of retinoic acid to Rpe65 and approaches to the treatment of macular degeneration. Proc Natl Acad Sci U S A. 2004; 101: 10030–10035.
Sekeryapan B, Dılek N, Oner V, Turkyılmaz K, Aslan MG. Retinal nerve fiber layer and ganglion cell layer thickness in patients receiving systemic isotretinoin therapy. Int Ophthalmol. 2013; 33: 481–484.
Ucak H, Aykut V, Ozturk S, Cicek D, Erden I, Demir B. Effect of oral isotretinoin treatment on retinal nerve fiber layer thickness. J Cutan Med Surg. 2014; 18: 236–242.
Khan MA, Brady CJ, Kaiser RS. Clinical management of proliferative vitreoretinopathy: an update. Retina. 2015; 35: 165–175.
Lim JI, Walonker AF, Levin L, et al. One-year results of a pilot study using oral 13-cis retinoic acid as a treatment for subfoveal predominantly occult choroidal neovascularization in patients with age-related macular degeneration. Retina. 2006; 26: 314–321.
Noy N, Xu ZJ. Interactions of retinol with binding proteins: implications for the mechanism of uptake by cells. Biochemistry. 1990; 29: 3878–3883.
Berni R, Formelli F. In vitro interaction of fenretinide with plasma retinol-binding protein and its functional consequences. FEBS Lett. 1992; 308: 43–45.
Schaffer EM, Ritter SJ, Smith JE. N-(4-hydroxyphenyl)retinamide (fenretinide) induces retinol-binding protein secretion from liver and accumulation in the kidneys in rats. J Nutr. 1993; 123: 1497–1503.
Adams WR, Smith JE, Green MH. Effects of N-(4-hydroxyphenyl)retinamide on vitamin A metabolism in rats. Proc Soc Exp Biol Med. 1995; 208: 178–185.
Radu RA, Han Y, Bui TV, et al. Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases. Invest Ophthalmol Vis Sci. 2005; 46: 4393–4401.
Vogel S, Piantedosi R, O'Byrne SM, et al. Retinol-binding protein-deficient mice: biochemical basis for impaired vision. Biochemistry. 2002; 41: 15360–15368.
Palczewski K, Van Hooser JP, Garwin GG, Chen J, Liou GI, Saari JC. Kinetics of visual pigment regeneration in excised mouse eyes and in mice with a targeted disruption of the gene encoding interphotoreceptor retinoid-binding protein or arrestin. Biochemistry. 1999; 38: 12012–12019.
Ripps H, Peachey NS, Xu X, Nozell SE, Smith SB, Liou GI. The rhodopsin cycle is preserved in IRBP “knockout” mice despite abnormalities in retinal structure and function. Vis Neurosci. 2000; 17: 97–105.
Petrukhin K. Pharmacological inhibition of lipofuscin accumulation in the retina as a therapeutic strategy for dry AMD treatment. Drug Discov Today Ther Strateg. 2013; 10: e11–e20.
Mata NL, Lichter JB, Vogel R, Han Y, Bui TV, Singerman LJ. Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration. Retina. 2013; 33: 498–507.
Decensi A, Fontana V, Fioretto M, et al. Long-term effects of fenretinide on retinal function. Eur J Cancer. 1997; 33: 80–84.
Wolf G. A case of human vitamin A deficiency caused by an inherited defect in retinol-binding protein without clinical symptoms except night blindness. Nutr Rev. 1999; 57: 258–260.
Maeda A, Maeda T, Golczak M, et al. Effects of potent inhibitors of the retinoid cycle on visual function and photoreceptor protection from light damage in mice. Mol Pharmacol. 2006; 70: 1220–1229.
Golczak M, Imanishi Y, Kuksa V, Maeda T, Kubota R, Palczewski K. Lecithin:retinol acyltransferase is responsible for amidation of retinylamine a potent inhibitor of the retinoid cycle. J Biol Chem. 2005; 280: 42263–42273.
Maeda A, Golczak M, Chen Y, et al. Primary amines protect against retinal degeneration in mouse models of retinopathies. Nat Chem Biol. 2011; 8: 170–178.
Yu G, Wu X, Ayat N, et al. Multifunctional PEG retinylamine conjugate provides prolonged protection against retinal degeneration in mice. Biomacromolecules. 2014; 15: 4570–4578.
Puntel A, Maeda A, Golczak M, et al. Prolonged prevention of retinal degeneration with retinylamine loaded nanoparticles. Biomaterials. 2015; 44: 103–110.
Liu H, Tang J, Du Y, et al. Retinylamine benefits early diabetic retinopathy in mice. J Biol Chem. 2015; 290: 21568–21579.
Maiti P, Kong J, Kim SR, Sparrow JR, Allikmets R, Rando RR. Small molecule RPE65 antagonists limit the visual cycle and prevent lipofuscin formation. Biochemistry. 2006; 45: 852–860.
Tanaka H, Kuo CH, Matsuda T, et al. MEKA/phosducin attenuates hydrophobicity of transducin beta gamma subunits without binding to farnesyl moiety. Biochem Biophys Res Commun. 1996; 223: 587–591.
McCarthy NE, Akhtar M. Function of the farnesyl moiety in visual signaling. Biochem J. 2000; 347: 163–171.
Roosing S, Collin RW, den Hollander AI, Cremers FP, Siemiatkowska AM. Prenylation defects in inherited retinal diseases. J Med Genet. 2014; 51: 143–151.
Motani A, Wang Z, Conn M, et al. Identification and characterization of a non-retinoid ligand for retinol-binding protein 4 which lowers serum retinol-binding protein 4 levels in vivo. J Biol Chem. 2009; 284: 7673–7680.
Dobri N, Qin Q, Kong J, et al. A1120, a nonretinoid RBP4 antagonist, inhibits formation of cytotoxic bisretinoids in the animal model of enhanced retinal lipofuscinogenesis. Invest Ophthalmol Vis Sci. 2013; 54: 85–95.
Wang Y, Connors R, Fan P, et al. Structure-assisted discovery of the first non-retinoid ligands for retinol-binding protein 4. Bioorg Med Chem Lett. 2014; 24: 2885–2891.
Cioffi CL, Dobri N, Freeman EE, et al. Design, synthesis, and evaluation of nonretinoid retinol binding protein 4 antagonists for the potential treatment of atrophic age-related macular degeneration and Stargardt disease. J Med Chem. 2014; 57: 7731–7757.
Cioffi CL, Racz B, Freeman EE, et al. Bicyclic [3.3.0]-octahydrocyclopenta[c]pyrrolo antagonists of retinol binding protein 4: potential treatment of atrophic age-related macular degeneration and Stargardt disease. J Med Chem. 2015; 58: 5863–5888.
Zhang J, Kiser PD, Badiee M, et al. Molecular pharmacodynamics of emixustat in protection against retinal degeneration. J Clin Invest. 2015; 125: 2781–2794.
Bavik C, Henry SH, Zhang Y, et al. Visual cycle modulation as an approach toward preservation of retinal integrity. PLoS One. 2015; 10: e0124940.
Jack LS, Sadiq MA, Do DV, Nguyen QD. Emixustat and lampalizumab: potential therapeutic options for geographic atrophy. Dev Ophthalmol. 2016; 55: 302–309.
Dugel PU, Novack RL, Csaky KG, Richmond PP, Birch DG, Kubota R. Phase II, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration. Retina. 2015; 35: 1173–1183.
Kaufman Y, Ma L, Washington I. Deuterium enrichment of vitamin A at the C20 position slows the formation of detrimental vitamin A dimers in wild-type rodents. J Biol Chem. 2011; 286: 7958–7965.
Ma L, Kaufman Y, Zhang J, Washington I. C20-D3-vitamin A slows lipofuscin accumulation and electrophysiological retinal degeneration in a mouse model of Stargardt disease. J Biol Chem. 2011; 286: 7966–7974.
Charbel Issa P, Barnard AR, Herrmann P, Washington I, MacLaren RE. Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization. Proc Natl Acad Sci U S A. 2015; 112: 8415–8420.
Sheffield VC, Stone EM. Genomics and the eye. N Engl J Med. 2011; 364: 1932–1942.
den Hollander AI, Roepman R, Koenekoop RK, Cremers FP. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res. 2008; 27: 391–419.
Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet. 2001; 28: 92–95.
Narfström K, Katz ML, Bragadottir R, et al. Functional and structural recovery of the retina after gene therapy in the RPE65 null mutation dog. Invest Ophthalmol Vis Sci. 2003; 44: 1663–1672.
Acland GM, Aguirre GD, Bennett J, et al. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther. 2005; 12: 1072–1082.
Narfström K, Vaegan, Katz M, Bragadottir R, Rakoczy EP, Seeliger M. Assessment of structure and function over a 3-year period after gene transfer in RPE65−/− dogs. Doc Ophthalmol. 2005; 111: 39–48.
Le Meur G, Stieger K, Smith AJ, et al. Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Gene Ther. 2007; 14: 292–303.
Narfström K, Seeliger M, Lai CM, et al. Morphological aspects related to long-term functional improvement of the retina in the 4 years following rAAV-mediated gene transfer in the RPE65 null mutation dog. Adv Exp Med Biol. 2008; 613: 139–146.
Bennicelli J, Wright JF, Komaromy A, et al. Reversal of blindness in animal models of Leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol Ther. 2008; 16: 458–465.
Batten ML, Imanishi Y, Tu DC, et al. Pharmacological and rAAV gene therapy rescue of visual functions in a blind mouse model of Leber congenital amaurosis. PLoS Med. 2005; 2: e333.
Jacobson SG, Aleman TS, Cideciyan AV, et al. Identifying photoreceptors in blind eyes caused by RPE65 mutations: prerequisite for human gene therapy success. Proc Natl Acad Sci U S A. 2005; 102: 6177–6182.
Pang JJ, Chang B, Kumar A, et al. Gene therapy restores vision-dependent behavior as well as retinal structure and function in a mouse model of RPE65Leber congenital amaurosis. Mol Ther. 2006; 13: 565–572.
Bemelmans AP, Kostic C, Crippa SV, et al. Lentiviral gene transfer of RPE65 rescues survival and function of cones in a mouse model of Leber congenital amaurosis. PLoS Med. 2006; 3: e347.
Jacobson SG, Boye SL, Aleman TS, et al. Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis. Hum Gene Ther. 2006; 17: 845–858.
Cideciyan AV, Jacobson SG, Beltran WA, et al. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U S A. 2013; 110: E517–E525.
Cideciyan AV, Hauswirth WW, Aleman TS, et al. Vision 1 year after gene therapy for Leber's congenital amaurosis. N Engl J Med. 2009; 361: 725–727.
Banin E, Bandah-Rozenfeld D, Obolensky A, et al. Molecular anthropology meets genetic medicine to treat blindness in the North African Jewish population: human gene therapy initiated in Israel. Hum Gene Ther. 2010; 21: 1749–1757.
Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber's congenital amaurosisis is safe and effective through 1.5 years after vector administration. Mol Ther. 2010; 18: 643–650.
Bainbridge JW, Mehat MS, Sundaram V, et al. Long-term effect of gene therapy on Leber's congenital amaurosis. N Engl J Med. 2015; 372: 1887–1897.
Jacobson SG, Cideciyan AV, Roman AJ, et al. Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med. 2015; 372: 1920–1926.
Bennett J, Ashtari M, Wellman J, et al. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med. 2012; 4:120ra115.
Boye SE, Boye SL, Lewin AS, Hauswirth WW. A comprehensive review of retinal gene therapy. Mol Ther. 2013; 21: 509–519.
Molday LL, Rabin AR, Molday RS. ABCR expression in foveal cone photoreceptors and its role in Stargardt macular dystrophy. Am J Ophthalmol. 2000; 130: 689.
Allikmets R, Singh N, Sun H, et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997; 15: 236–246.
Kong J, Kim SR, Binley K, et al. Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy. Gene Ther. 2008; 15: 1311–1320.
Han Z, Conley SM, Makkia RS, Cooper MJ, Naash MI. DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice. J Clin Invest. 2012; 122: 3221–3226.
Vollrath D, Feng W, Duncan JL, et al. Correction of the retinal dystrophy phenotype of the RCS rat by viral gene transfer of Mertk. Proc Natl Acad Sci U S A. 2001; 98: 12584–12589.
Smith AJ, Schlichtenbrede FC, Tschernutter M, Bainbridge JW, Thrasher AJ, Ali RR. AAV-mediated gene transfer slows photoreceptor loss in the RCS rat model of retinitis pigmentosa. Mol Ther. 2003; 8: 188–195.
Tschernutter M, Schlichtenbrede FC, Howe S, et al. Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy. Gene Ther. 2005; 12: 694–701.
Deng W, Dinculescu A, Li Q, et al. Tyrosine mutant AAV8 delivery of human MERTK provides long-term retinal preservation in RCS rats. Invest Ophthalmol Vis Sci. 2012; 53: 1895–1904.
Mao H, James T, Schwein A, et al. AAV delivery of wild-type rhodopsin preserves retinal function in a mouse model of autosomal dominant retinitis pigmentosa. Hum Gene Ther. 2011; 22: 567–575.
Lewin AS, Drenser KA, Hauswirth WW, et al. Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant retinitis pigmentosa. Nat Med. 1998; 4: 967–971.
LaVail MM, Yasumura D, Matthes MT, et al. Ribozyme rescue of photoreceptor cells in P23H transgenic rats: long-term survival and late-stage therapy. Proc Natl Acad Sci U S A. 2000; 97: 11488–11493.
Gorbatyuk MS, Pang JJ, Thomas J, Hauswirth WW, Lewin AS. Knockdown of wild-type mouse rhodopsin using an AAV vectored ribozyme as part of an RNA replacement approach. Mol Vis. 2005; 11: 648–656.
O'Reilly M, Palfi A, Chadderton N, et al. RNA interference-mediated suppression and replacement of human rhodopsin in vivo. Am J Hum Genet. 2007; 81: 127–135.
Gorbatyuk M, Justilien V, Liu J, Hauswirth WW, Lewin AS. Preservation of photoreceptor morphology and function in P23H rats using an allele independent ribozyme. Exp Eye Res. 2007; 84: 44–52.
Chadderton N, Millington-Ward S, Palfi A, et al. Improved retinal function in a mouse model of dominant retinitis pigmentosa following AAV-delivered gene therapy. Mol Ther. 2009; 17: 593–599.
Palfi A, Millington-Ward S, Chadderton N, et al. Adeno-associated virus-mediated rhodopsin replacement provides therapeutic benefit in mice with a targeted disruption of the rhodopsin gene. Hum Gene Ther. 2010; 21: 311–323.
Cai X, Conley SM, Nash Z, Fliesler SJ, Cooper MJ, Naash MI. Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa. FASEB J. 2010; 24: 1178–1191.
Millington-Ward S, Chadderton N, O'Reilly M, et al. Suppression and replacement gene therapy for autosomal dominant disease in a murine model of dominant retinitis pigmentosa. Mol Ther. 2011; 19: 642–649.
Mao H, Gorbatyuk MS, Rossmiller B, Hauswirth WW, Lewin AS. Long-term rescue of retinal structure and function by rhodopsin RNA replacement with a single adeno-associated viral vector in P23H RHO transgenic mice. Hum Gene Ther. 2012; 23: 356–366.
Maeda T, Dong Z, Jin H, et al. QLT091001, a 9-cis-retinal analog, is well-tolerated by retinas of mice with impaired visual cycles. Invest Ophthalmol Vis Sci. 2013; 54: 455–466.
Gamel JW, Barr CC. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993; 111: 1462–1463.
Maeda T, Perusek L, Amengual J, Babino D, Palczewski K, von Lintig J. Dietary 9-cis-β,β-carotene fails to rescue vision in mouse models of leber congenital amaurosis. Mol Pharmacol. 2011; 80: 943–952.
Figure 1
 
The visual cycle between RPE and ROS. When a photon of light reaches ROS, Rh, which consists of the 11-cis-Ral chromophore and opsin, will be bleached to form an intermediate called meta II. ATRal, generated from the 11-cis-Ral photoisomerization, will be reduced to ATRol in rod cytoplasm by RDH8, RDH11, and RDH12. ATRol can be regenerated back to 11-cis-Ral in the RPE where the most important isomerase is the retinal pigment epithelium–specific 65-kDa protein RPE65. Like RDH5, both RDH10 and RDH11 likely have similar effects in transforming 11-cis-Rol into 11-cis-Ral. In the RPE, ATRal combines with CRBP, whereas 11-cis-Rol and 11-cis-Ral bind with CRALBP. 11-cis-Rol and ATRol can also be stored in the RPE retinosomes in the form of 11-cis-retinyl esters and all-trans-retinyl esters, respectively; LRAT and retinyl ester hydrolase catalyze these esterification reactions. Free 11-cis-Ral and ATRol could form complexes with IRBP in the IPM. On the other hand, a portion of free ATRal that evades reduction will react with NR-PE present in the ROS disk lumen, enabling the release of extra ATRal condensation products, which can be phagocytosed daily by the RPE through the MERTK-mediated signaling pathway. “Rim protein,” called ABCA4 on the ROS disk membrane, plays an important role in clearing NR-PE from the ROS disk lumen, thus decreasing excess accumulation of ATRal in the ROS. However, the role of ABCA4 in the transportation of 11-cis-Ral and ATRal remains unclear. ATRol, also called vitamin A, is a fat soluble compound that is transported in the blood and stored in the liver by mostly combining RBP. Vitamin A from peripheral tissues such as choroid blood vessels can be taken up by the RPE and thus involved in the visual cycle.
Figure 1
 
The visual cycle between RPE and ROS. When a photon of light reaches ROS, Rh, which consists of the 11-cis-Ral chromophore and opsin, will be bleached to form an intermediate called meta II. ATRal, generated from the 11-cis-Ral photoisomerization, will be reduced to ATRol in rod cytoplasm by RDH8, RDH11, and RDH12. ATRol can be regenerated back to 11-cis-Ral in the RPE where the most important isomerase is the retinal pigment epithelium–specific 65-kDa protein RPE65. Like RDH5, both RDH10 and RDH11 likely have similar effects in transforming 11-cis-Rol into 11-cis-Ral. In the RPE, ATRal combines with CRBP, whereas 11-cis-Rol and 11-cis-Ral bind with CRALBP. 11-cis-Rol and ATRol can also be stored in the RPE retinosomes in the form of 11-cis-retinyl esters and all-trans-retinyl esters, respectively; LRAT and retinyl ester hydrolase catalyze these esterification reactions. Free 11-cis-Ral and ATRol could form complexes with IRBP in the IPM. On the other hand, a portion of free ATRal that evades reduction will react with NR-PE present in the ROS disk lumen, enabling the release of extra ATRal condensation products, which can be phagocytosed daily by the RPE through the MERTK-mediated signaling pathway. “Rim protein,” called ABCA4 on the ROS disk membrane, plays an important role in clearing NR-PE from the ROS disk lumen, thus decreasing excess accumulation of ATRal in the ROS. However, the role of ABCA4 in the transportation of 11-cis-Ral and ATRal remains unclear. ATRol, also called vitamin A, is a fat soluble compound that is transported in the blood and stored in the liver by mostly combining RBP. Vitamin A from peripheral tissues such as choroid blood vessels can be taken up by the RPE and thus involved in the visual cycle.
Figure 2
 
Retinal-derived lipofuscin compounds associated with AMD and STGD.
Figure 2
 
Retinal-derived lipofuscin compounds associated with AMD and STGD.
Figure 3
 
Structures of 10 regulators of abnormal retinoid metabolism.
Figure 3
 
Structures of 10 regulators of abnormal retinoid metabolism.
Table 1
 
Human Retinal Diseases Related to Aberrant Metabolism of Retinoids
Table 1
 
Human Retinal Diseases Related to Aberrant Metabolism of Retinoids
Table 2
 
Replacement Therapy in Humans and Laboratory Animals With Retinal Dystrophies Characterized by the Retinoid Deficiency
Table 2
 
Replacement Therapy in Humans and Laboratory Animals With Retinal Dystrophies Characterized by the Retinoid Deficiency
Table 3
 
Mechanism and Clinical Trials of Synthesized Regulators Against Aberrant Retinoid Metabolism
Table 3
 
Mechanism and Clinical Trials of Synthesized Regulators Against Aberrant Retinoid Metabolism
Table 4
 
Gene Therapies That Repair Aberrant Metabolism of Retinoids for Retinal Dysfunctions
Table 4
 
Gene Therapies That Repair Aberrant Metabolism of Retinoids for Retinal Dysfunctions
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×