Substrate Reduction Therapy

  • Frances M. Platt
  • Terry D. Butters

The glycosphingolipidoses are a family of storage diseases that arise due to incomplete catabolism of glycosphingolipids (GSLs) in the lysosome (Wraith, 2002). The majority are autosomal recessive disorders and result from mutations in the genes that encode the catabolic enzymes of the lysosome (Winchester, 2004). Clinically they are highly variable (Beck, 2001) but typically have a neurodegenerative course and commonly present in infancy or early childhood (Wraith, 2004). Adult-onset variants also occur (Rapola, 1994; Wraith, 2004). The age of onset is influenced by the residual enzyme activity present, that in turn reflects the impact a specific mutation has on the properties of the enzyme (Rapola, 1994; Winchester, 2004). Little or no activity leads to rapid storage and early onset of symptoms whereas higher levels of residual activity lead to a slower rate of storage and a longer presymptomatic period. In this chapter, we focus on a drug-based therapy that is relevant to all lysosomal diseases involving the storage of glucosylceramidederived GSLs, including Gaucher, Fabry, Tay-Sachs, Sandhoff, and GM1 gangliosidosis. In addition, storage diseases involving the secondary storage of GSLs


Enzyme Replacement Therapy Fabry Disease Gauche Disease Bovine Viral Diarrhea Virus Lysosomal Storage Disorder 
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  1. Aerts, J. M., & Hollak, C. E. (1997). Plasma and metabolic abnormalities in Gaucher’s disease. Baillieres Clin Haematol, 10(4), 691-709.CrossRefPubMedGoogle Scholar
  2. Andersson, U., Butters, T. D., Dwek, R. A., & Platt, F. M. (2000). N-butyldeoxygalac-tonojirimycin: a more selective inhibitor of glycosphingolipid biosynthesis than N-butyldeoxynojirimycin, in vitro and in vivo. Biochem Pharmacol, 59(7), 821-829.CrossRefPubMedGoogle Scholar
  3. Andersson, U., Reinkensmeier, G., Butters, T. D., Dwek, R. A., & Platt, F. M. (2004). Inhibition of glycogen breakdown by imino sugars in vitro and in vivo. Biochem Pharmacol, 67(4), 697-705.CrossRefPubMedGoogle Scholar
  4. Andersson, U., Smith, D., Jeyakumar, M., Butters, T. D., Borja, M. C., Dwek, R. A., et al. (2004). Improved outcome of N-butyldeoxygalactonojirimycin-mediated substrate reduction therapy in a mouse model of Sandhoff disease. Neurobiol Dis, 16(3), 506-515.CrossRefPubMedGoogle Scholar
  5. Beck, M. (2001). Variable clinical presentation in lysosomal storage disorders. J Inherit Metab Dis, 24 Suppl 2, 47-51; discussion 45-46.CrossRefPubMedGoogle Scholar
  6. Beutler, E., & Grabowski, G. (2001). Gaucher disease. In C. R. Scriver, A. L. Beadet, D. Valle & W. S. Sly (Eds.), The metabolic and molecular bases of inherited diseases (8 ed., Vol. 3, pp. 3636-3668). New York: McGraw Hill.Google Scholar
  7. Block, T. M., Lu, X. Y., Mehta, A. S., Blumberg, B. S., Tennant, B., Ebling, M., et al. (1998). Treatment of chronic hepadnavirus infection in a woodchuck animal model with an inhibitor of protein folding and trafficking. Nature Med, 4(5), 610-614.CrossRefPubMedGoogle Scholar
  8. Brady, R. O. (2003). Gaucher and Fabry diseases: from understanding pathophysiology to rational therapies. Acta Paediatr Suppl, 92(443), 19-24.PubMedGoogle Scholar
  9. Butters, T. D., Dwek, R. A., & Platt, F. M. (2000). Inhibition of Glycosphingolipid Bio-synthesis: Application to Lysosomal Storage Disorders. Chem Rev, 100, 4683-4696.CrossRefPubMedGoogle Scholar
  10. Butters, T. D., Dwek, R. A., & Platt, F. M. (2003). Therapeutic applications of imino sugars in lysosomal storage disorders. Curr Top Med Chem, 3(5), 561-574.CrossRefPubMedGoogle Scholar
  11. Butters, T. D., Mellor, H. R., Narita, K., Dwek, R. A., & Platt, F. M. (2003). Small-molecule therapeutics for the treatment of glycolipid lysosomal storage disorders. Philos Trans R Soc Lond B Biol Sci, 358(1433), 927-945.CrossRefPubMedGoogle Scholar
  12. Butters, T. D., van den Broek, L. A. G. M., Fleet, G. W. J., Krulle, T. M., Wormald, M. R., Dwek, R. A., et al. (2000). Molecular requirements of imino sugars for the selective  control of N-linked glycosylation and glycospingolipid biosynthesis. Tetrahedron Assymetry, 11, 113-124.CrossRefGoogle Scholar
  13. Cabrera-Salazar, M. A., Novelli, E., & Barranger, J. A. (2002). Gene therapy for the lysosomal storage disorders. Curr Opin Mol Ther, 4(4), 349-358.PubMedGoogle Scholar
  14. Carstea, E. D., Morris, J. A., Coleman, K. G., Loftus, S. K., Zhang, D., Cummings, C., et al. (1997). Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeo-stasis. Science, 277(5323), 228-231.CrossRefPubMedGoogle Scholar
  15. Cox, T., Lachmann, R., Hollak, C., Aerts, J., van Weely, S., Hrebicek, M., et al. (2000). Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet, 355(9214), 1481-1485.CrossRefPubMedGoogle Scholar
  16. Cox, T. M., Aerts, J. M., Andria, G., Beck, M., Belmatoug, N., Bembi, B., et al. (2003). The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement. J Inherit Metab Dis, 26(6), 513-526.CrossRefPubMedGoogle Scholar
  17. Dobrenis, K. (2004). Cell-mediated delivery systems. In F. M. Platt & S. U. Walkley (Eds.), Lysosomal Disorders of the Brain (pp. 339-380). Oxford: Oxford University Press.CrossRefGoogle Scholar
  18. Durantel, D., Branza-Nichita, N., Carrouee-Durantel, S., Butters, T. D., Dwek, R. A., & Zitzmann, N. (2001). Study of the Mechanism of Antiviral Action of Iminosugar Derivatives against Bovine Viral Diarrhea Virus. J Virol, 75(19), 8987-8998.CrossRefPubMedGoogle Scholar
  19. Dwek, R. A., Butters, T. D., Platt, F. M., & Zitzmann, N. (2002). Targetting glycosyla-tion as a therapeutic approach. Nature drug discovery, 1(1), 65-75.CrossRefGoogle Scholar
  20. Elstein, D., Hollak, C., Aerts, J. M., Van Weely, S., Maas, M., Cox, T. M., et al. (2004). Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT-918) in type 1 Gaucher disease. J Inherit Metab Dis, In Press.Google Scholar
  21. Fischer, P. B., Collin, M., Karlsson, G. B., James, W., Butters, T. D., Davis, S. J., et al. (1995). The alpha-glucosidase inhibitor N-butyldeoxynojirimycin inhibits human immunodeficiency virus entry at the level of post-CD4 binding. J Virol, 69(9), 5791-5797.PubMedGoogle Scholar
  22. Ginzburg, L., Kacher, Y., & Futerman, A. H. (2004). The pathogenesis of glycosphingo-lipid storage disorders. Semin Cell Dev Biol, 15(4), 417-431.CrossRefPubMedGoogle Scholar
  23. Heitner, R., Elstein, D., Aerts, J., Weely, S., & Zimran, A. (2002). Low-dose N-butyldeoxynojirimycin (OGT 918) for type I Gaucher disease. Blood Cells Mol Dis, 28(2), 127-133.CrossRefPubMedGoogle Scholar
  24. Hopwood, J. J., Crawley, A. C., & Taylor, R. M. (2004). Spontaneous and engineered mammalian storage disease models. In F. M. Platt & S. U. Walkley (Eds.), Lysosomal disorders of the brain (Vol. 1, pp. 257-289). Oxford: Oxford University Press.CrossRefGoogle Scholar
  25. Ikonen, E., & Holtta-Vuori, M. (2004). Cellular pathology of Niemann-Pick type C disease. Semin Cell Dev Biol, 15(4), 445-454.CrossRefPubMedGoogle Scholar
  26. Jeyakumar, M., Butters, T. D., Cortina-Borja, M., Hunnam, V., Proia, R. L., Perry, V. H., et al. (1999). Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin. Proc Natl Acad Sci U S A, 96(11), 6388-6393.CrossRefPubMedGoogle Scholar
  27. Jeyakumar, M., Smith, D. A., Williams, I. M., Borja, M. C., Neville, D. C., Butters, T. D., et al. (2004). NSAIDs increase survival in the Sandhoff disease mouse: Synergy with N-butyldeoxynojirimycin. Ann Neurol, 56(5), 642-649.CrossRefPubMedGoogle Scholar
  28. Jeyakumar, M., Thomas, R., Elliot-Smith, E., Smith, D. A., van der Spoel, A. C., d’Azzo, A., et al. (2003). Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain, 126(Pt 4), 974-987.CrossRefPubMedGoogle Scholar
  29. Ko, D. C., Binkley, J., Sidow, A., & Scott, M. P. (2003). The integrity of a cholesterol-binding pocket in Niemann-Pick C2 protein is necessary to control lysosome cholesterol levels. Proc Natl Acad Sci U S A, 100(5), 2518-2525.CrossRefPubMedGoogle Scholar
  30. Krivit, W. (2002). Stem cell bone marrow transplantation in patients with metabolic storage diseases. Adv Pediatr, 49, 359-378.PubMedGoogle Scholar
  31. Krivit, W., Sung, J. H., Shapiro, E. G., & Lockman, L. A. (1995). Microglia: the effector cell for reconstitution of the central nervous system following bone marrow transplantation for lysosomal and peroxisomal storage diseases. Cell-Transplant, 4 (4), 385-392.CrossRefPubMedGoogle Scholar
  32. Lachmann, R. H. (2003). Miglustat. Oxford GlycoSciences/Actelion. Curr Opin Investig Drugs, 4(4), 472-479.PubMedGoogle Scholar
  33. Lachmann, R. H., & Platt, F. M. (2001). Substrate reduction therapy for glycos-phingolipid storage disorders. Exp. Opin. Invest. Drugs, 10, 455-466.CrossRefGoogle Scholar
  34. Lachmann, R. H., te Vruchte, D., Lloyd-Evans, E., Reinkensmeier, G., Sillence, D. J., Fernandez-Guillen, L., et al. (2004). Treatment with miglustat reverses the lipid-trafficking defect in Niemann-Pick disease type C. Neurobiol Dis, 16(3), 654-658.CrossRefPubMedGoogle Scholar
  35. Liscum, L. (2000). Niemann-Pick type C mutations cause lipid traffic jam. Traffic, 1(3), 218-225.CrossRefPubMedGoogle Scholar
  36. Mayran, N., Parton, R. G., & Gruenberg, J. (2003). Annexin II regulates multivesicular endosome biogenesis in the degradation pathway of animal cells. Embo J, 22(13), 3242-3253.CrossRefPubMedGoogle Scholar
  37. Mellor, H. R., Neville, D. C., Harvey, D. J., Platt, F. M., Dwek, R. A., & Butters, T. D. (2004). Cellular effects of deoxynojirimycin analogues: uptake, retention and inhibition of glycosphingolipid biosynthesis. Biochem J, 381(Pt 3), 861-866.PubMedGoogle Scholar
  38. Mellor, H. R., Nolan, J., Pickering, L., Wormald, M. R., Platt, F. M., Dwek, R. A., et al. (2002). Preparation, biochemical characterization and biological properties of radio-labelled N-alkylated deoxynojirimycins. Biochem J, 366(Pt 1), 225-233.PubMedGoogle Scholar
  39. Mellor, H. R., Platt, F. M., Dwek, R. A., & Butters, T. D. (2003). Membrane disruption and cytotoxicity of hydrophobic N-alkylated imino sugars is independent of the inhibition of protein and lipid glycosylation. Biochem J, 374(Pt 2), 307-314.CrossRefPubMedGoogle Scholar
  40. Moyses, C. (2003). Substrate reduction therapy: clinical evaluation in type 1 Gaucher disease. Philos Trans R Soc Lond B Biol Sci, 358(1433), 955-960.CrossRefPubMedGoogle Scholar
  41. Neufeld, E. F. (2004). Enzyme replacement therapy. In F. M. Platt & S. U. Walkley (Eds.), Lysosomal disorders of the brain (pp. 327-338). Oxford: Oxford University Press.CrossRefGoogle Scholar
  42. Ohgami, N., Ko, D. C., Thomas, M., Scott, M. P., Chang, C. C., & Chang, T. Y. (2004). Binding between the Niemann-Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain. Proc Natl Acad Sci U S A, 101 (34), 12473-12478.CrossRefPubMedGoogle Scholar
  43. Pastores, G. M., Barnett, N. L., Bathan, P., & Kolodny, E. H. (2003). A neurological symptom survey of patients with type I Gaucher disease. J Inherit Metab Dis, 26(7), 641-645.CrossRefPubMedGoogle Scholar
  44. Patterson, M. C., Vecchio, D., Prady, H., Abel, L., Ait-Alissa, N., & Wraith, J. E. (2006). Oral miglustat in Niemann-Pick type C (NPC) disease. Rev Neurol (separata) 43, 8.Google Scholar
  45. Platt, F. M., & Butters, T. D. (2004). Inhibition of substrate synthesis: a pharmacological approach for glycosphingolipid storage disease therapy. In F. M. Platt & S. U. Walkley (Eds.), Lysosomal Disorders of the Brain (pp. 381-408). Oxford: Oxford University Press.CrossRefGoogle Scholar
  46. Platt, F. M., Jeyakumar, M., Andersson, U., Heare, T., Dwek, R. A., & Butters, T. D. (2003). Substrate reduction therapy in mouse models of the glycosphingolipidoses. Phil. Trans. R. Soc. Lond. B, 358, 947-954.CrossRefGoogle Scholar
  47. Platt, F. M., Neises, G. R., Dwek, R. A., & Butters, T. D. (1994). N-butyldeoxy-nojirimycin is a novel inhibitor of glycolipid biosynthesis. J Biol Chem, 269(11), 8362-8365.PubMedGoogle Scholar
  48. Platt, F. M., Neises, G. R., Karlsson, G. B., Dwek, R. A., & Butters, T. D. (1994a). N-butyldeoxygalactonojirimycin inhibits glycolipid biosynthesis but does not affect N-linked oligosaccharide processing. J Biol Chem, 269(43), 27108-27114.Google Scholar
  49. Platt, F. M., Neises, G. R., Reinkensmeier, G., Townsend, M. J., Perry, V. H., Proia, R. L., et al. (1997). Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin. Science, 276(5311), 428-431.CrossRefPubMedGoogle Scholar
  50. Puri, V., Watanabe, R., Dominguez, M., Sun, X., Wheatley, C. L., Marks, D. L., et al. (1999). Cholesterol modulates membrane traffic along the endocytic pathway in sphingolipid-storage diseases. Nat Cell Biol, 1(6), 386-388.CrossRefPubMedGoogle Scholar
  51. Radin, N. S. (1996). Treatment of Gaucher disease with an enzyme inhibitor. Glycoconj J, 13(2), 153-157.CrossRefPubMedGoogle Scholar
  52. Rapola, J. (1994). Lysosomal storage diseases in adults. Pathol Res Pract, 190(8), 759-766.PubMedGoogle Scholar
  53. Ringden, O., Groth, C. G., Erikson, A., Granqvist, S., Mansson, J. E., & Sparrelid, E. (1995). Ten years' experience of bone marrow transplantation for Gaucher disease. Transplantation, 59(6), 864-870.PubMedGoogle Scholar
  54. Sands, M. S. (2004). Gene therapy. In F. M. Platt & S. U. Walkley (Eds.), Lysosomal Disorders of the Brain (pp. 409-430). Oxford: Oxford University Press.CrossRefGoogle Scholar
  55. Sango, K., Yamanaka, S., Hoffmann, A., Okuda, Y., Grinberg, A., Westphal, H., et al. (1995). Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic pheno-type and ganglioside metabolism. Nat Genet, 11(2), 170-176.CrossRefPubMedGoogle Scholar
  56. Sleat, D. E., Wiseman, J. A., El-Banna, M., Price, S. M., Verot, L., Shen, M. M., et al. (2004). Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport. Proc Natl Acad Sci U S A, 101(16), 5886-5891.CrossRefPubMedGoogle Scholar
  57. Snyder, E. Y., Daley, G. Q., & Goodell, M. (2004). Taking stock and planning for the next decade: realistic prospects for stem cell therapies for the nervous system. J Neurosci Res, 76(2), 157-168.CrossRefPubMedGoogle Scholar
  58. te Vruchte, D., Lloyd-Evans, E., Veldman, R. J., Neville, D. C., Dwek, R. A., Platt, F. M., et al. (2004). Accumulation of glycosphingolipids in Niemann-Pick C disease disrupts endosomal transport. J Biol Chem, 279(25), 26167-26175.CrossRefPubMedGoogle Scholar
  59. van der Spoel, A. C., Jeyakumar, M., Butters, T. D., Charleton, H. M., Moore, H. D., Dwek, R. A., et al. (2002). Reversible infertility in male mice following oral admini-stration of alkylated imino sugars: a non-hormonal approach to male contraception. Proc. Natl. Acad. Sci. U.S.A., In Press.Google Scholar
  60. Vanier, M. T., & Millat, G. (2003). Niemann-Pick disease type C. Clin Genet, 64(4), 269-281.CrossRefPubMedGoogle Scholar
  61. Vunnam, R. R., & Radin, N. S. (1980). Analogs of ceramide that inhibit glucocerebroside synthetase in mouse brain. Chem-Phys-Lipids, 26(3), 265-278 issn: 0009-3084.CrossRefPubMedGoogle Scholar
  62. Wada, R., Tifft, C. J., & Proia, R. L. (2000). Microglial activation precedes acute neurodegeneration in Sandhoff disease and is supressed by bone marrow transplant-tation. Proc Natl Acad Sci USA, 97(20), 10954-10959.CrossRefPubMedGoogle Scholar
  63. Walkley, S. U. (2004). Secondary accumulation of gangliosides in lysosomal storage disorders. Semin Cell Dev Biol, 15(4), 433-444.CrossRefPubMedGoogle Scholar
  64. Winchester, B. (2004). Primary defects in lysosomal enzymes. In F. M. Platt & S. U. Walkley (Eds.), Lysosomal Disorders of the Brain (pp. 81-130). Oxford: Oxford University Press.CrossRefGoogle Scholar
  65. Wraith, J. E. (2002). Lysosomal disorders. Semin Neonatol, 7(1), 75-83.CrossRefPubMedGoogle Scholar
  66. Wraith, J. E. (2004). Clinical aspects and diagnosis. In F. M. Platt & S. U. Walkley (Eds.), Lysosomal disorders of the brain (pp. 50-77). Oxford: Oxford University Press.CrossRefGoogle Scholar
  67. Wu, Y. P., & Proia, R. L. (2004). Deletion of macrophage-inflammatory protein 1 alpha retards neurodegeneration in Sandhoff disease mice. Proc Natl Acad Sci U S A, 101 (22), 8425-8430.CrossRefPubMedGoogle Scholar
  68. Yamanaka, S., Johnson, M. D., Grinberg, A., Westphal, H., Crawley, J. N., Taniike, M., et al. (1994). Targeted disruption of the Hexa gene results in mice with biochemical and pathologic features of Tay-Sachs disease. Proc Natl Acad Sci USA, 91(21), 9975-9979.CrossRefPubMedGoogle Scholar
  69. Zervas, M., Somers, K. L., Thrall, M. A., & Walkley, S. U. (2001). Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr Biol, 11(16), 1283-1287.CrossRefPubMedGoogle Scholar
  70. Zimran, A., & Elstein, D. (2003). Gaucher disease and the clinical experience with substrate reduction therapy. Philos Trans R Soc Lond B Biol Sci, 358(1433), 961-966.CrossRefPubMedGoogle Scholar
  71. Zitzmann, N., Mehta, A. S., Carrouee, S., Butters, T. D., Platt, F. M., McCauley, J., et al. (1999). Imino sugars inhibit the formation and secretion of bovine viral diarrhea virus, a pestivirus model of hepatitis C virus: implications for the development of broad spectrum anti-hepatitis virus agents. Proc Natl Acad Sci U S A, 96(21), 11878-11882.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Frances M. Platt
    • 1
  • Terry D. Butters
    • 1
  1. 1.Department of Biochemistry, Glycobiology InstituteUniversity of OxfordUK

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