Abstract
We discuss how an imperfect visual cycle results in the formation of vitamin A dimers, thought to be involved in the pathogenesis of various retinal diseases, and summarize how slowing vitamin A dimerization has been a therapeutic target of interest to prevent blindness. To elucidate the molecular mechanism of vitamin A dimerization, an alternative form of vitamin A, one that forms dimers more slowly yet maneuvers effortlessly through the visual cycle, was developed. Such a vitamin A, reinforced with deuterium (C20-D3-vitamin A), can be used as a non-disruptive tool to understand the contribution of vitamin A dimers to vision loss. Eventually, C20-D3-vitamin A could become a disease-modifying therapy to slow or stop vision loss associated with dry age-related macular degeneration (AMD), Stargardt disease and retinal diseases marked by such vitamin A dimers. Human clinical trials of C20-D3-vitamin A (ALK-001) are underway.
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Alberts D, Ranger-Moore J, Einspahr J et al (2004) Safety and efficacy of dose-intensive oral vitamin A in subjects with sun-damaged skin. Clin Cancer Res 10:1875–1880
Allen LH, Haskell M (2002) Estimating the potential for vitamin A toxicity in women and young children. J Nutr 132:2907S–2919S
Charbel Issa P, Barnard A, Herrmann P et al (2015) Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization. Proc Natl Acad Sci doi: 10.1073/pnas.1506960112
Dugel PU, Novack RL, Csaky KG et al (2015) Phase II, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration. Retina 35:1173–83
Golczak M, Maeda A, Bereta G et al (2008) Metabolic basis of visual cycle inhibition by retinoid and nonretinoid compounds in the vertebrate retina. J Biol Chem 283:9543–9554
Infante M, Pastorino U, Chiesa G et al (1991) Laboratory evaluation during high-dose vitamin A administration: a randomized study on lung cancer patients after surgical resection. J Cancer Res Clin Oncol 117:156–162
Kahun (~ 1825 B.C) Kahun Gynecological Papyrus
Kaufman Y, Ma L, Washington I (2011) Deuterium enrichment of vitamin A at the C20 position slows the formation of detrimental vitamin A dimers in wild-type rodents. J Biol Chem 286:7958–7965
Ma L, Kaufman Y, Zhang J et al (2011) C20-D3-vitamin A slows lipofuscin accumulation and electrophysiological retinal degeneration in a mouse model of stargardt disease. J Biol Chem 286:7966–7974
Maeda A, Golczak M, Chen Y et al (2012) Primary amines protect against retinal degeneration in mouse models of retinopathies. Nature Chem Biol 8:170–178
Maiti P, Kong J, Kim SR et al (2006) Small molecule RPE65 antagonists limit the visual cycle and prevent lipofuscin formation. Biochemistry 45:852–860
Mata NL, Lichter JB, Vogel R et al (2013) Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration. Retina 33:498–507
Mihai DM, Jiang H, Blaner WS et al (2013) The retina rapidly incorporates ingested C20-D(3)-vitamin A in a swine model. Mol Vis 19:1677–1683
Myhre AM, Carlsen MH, Bohn SK et al (2003) Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations. Am J Clin Nutri 78:1152–1159
NCI (1996) Clinical development plan: vitamin A. J Cell Biochem Suppl 26:269–307
Radu RA, Mata NL, Nusinowitz S et al (2003) Treatment with isotretinion inhibits lipuscin accumulationin a mouse model of recessive stargardt macular degeneration. Proc Natl Acad Sci U S A 100:4742–4747
Radu RA, Han Y, Bui TV et al (2005) 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 46:4393–4401
Reinersdorff DV, Bush E, Liberato DJ (1996) Plasma kinetics of vitamin A in humans after a single oral dose of [8,9,19-13C]retinyl palmitate. J Lipid Res 37:1875–1885
Vollmer-Snarr HR, Pew MR, Alvarez ML et al (2006) Amino-retinoid compounds in the human retinal pigment epithelium. Adv Exp Med Biol 572:69–74
Acknowledgements
We thank the U.S. National Institutes of Health (1R01EY021207 and 5P30EY019007) and Research to Prevent Blindness (RPB) Inc., New York.
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Saad, L., Washington, I. (2016). Can Vitamin A be Improved to Prevent Blindness due to Age-Related Macular Degeneration, Stargardt Disease and Other Retinal Dystrophies?. In: Bowes Rickman, C., LaVail, M., Anderson, R., Grimm, C., Hollyfield, J., Ash, J. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 854. Springer, Cham. https://doi.org/10.1007/978-3-319-17121-0_47
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DOI: https://doi.org/10.1007/978-3-319-17121-0_47
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