Can Vitamin A be Improved to Prevent Blindness due to Age-Related Macular Degeneration, Stargardt Disease and Other Retinal Dystrophies?

Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 854)

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.

Keywords

Stargardt Age-related macular degeneration AMD Retinal dystrophies ABCA4 Vitamin A Retinaldehyde ALK-001 C20-D3-vitamin A Bisretinoids Vitamin A dimer A2E Lipofuscin Visual cycle 

References

  1. 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 10:1875–1880CrossRefPubMedGoogle Scholar
  2. Allen LH, Haskell M (2002) Estimating the potential for vitamin A toxicity in women and young children. J Nutr 132:2907S–2919SPubMedGoogle Scholar
  3. 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.1506960112PubMedGoogle Scholar
  4. 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 35:1173–83PubMedGoogle Scholar
  5. 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 283:9543–9554CrossRefPubMedPubMedCentralGoogle Scholar
  6. 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 117:156–162CrossRefPubMedGoogle Scholar
  7. Kahun (~ 1825 B.C) Kahun Gynecological PapyrusGoogle Scholar
  8. 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 286:7958–7965CrossRefPubMedPubMedCentralGoogle Scholar
  9. 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 286:7966–7974CrossRefPubMedPubMedCentralGoogle Scholar
  10. Maeda A, Golczak M, Chen Y et al (2012) Primary amines protect against retinal degeneration in mouse models of retinopathies. Nature Chem Biol 8:170–178CrossRefGoogle Scholar
  11. Maiti P, Kong J, Kim SR et al (2006) Small molecule RPE65 antagonists limit the visual cycle and prevent lipofuscin formation. Biochemistry 45:852–860CrossRefPubMedGoogle Scholar
  12. Mata NL, Lichter JB, Vogel R et al (2013) Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration. Retina 33:498–507CrossRefPubMedGoogle Scholar
  13. 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 19:1677–1683PubMedPubMedCentralGoogle Scholar
  14. 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 78:1152–1159Google Scholar
  15. NCI (1996) Clinical development plan: vitamin A. J Cell Biochem Suppl 26:269–307Google Scholar
  16. 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 100:4742–4747CrossRefPubMedPubMedCentralGoogle Scholar
  17. 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 46:4393–4401CrossRefPubMedGoogle Scholar
  18. 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 37:1875–1885PubMedGoogle Scholar
  19. Vollmer-Snarr HR, Pew MR, Alvarez ML et al (2006) Amino-retinoid compounds in the human retinal pigment epithelium. Adv Exp Med Biol 572:69–74CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Alkeus Pharmaceuticals, Inc.BostonUSA
  2. 2.Department of OphthalmologyColumbia University Medical Center, Eye ResearchNew YorkUSA

Personalised recommendations