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Alternative Treatment Options: Enzyme Replacement and Small Molecule Therapies

  • Simon Jones
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Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

The spectacular clinical and financial success of Cerezyme® (Imiglucerase, Genzyme) for the treatment of Gaucher disease has led to the development of similar therapies for other lysosomal storage disorders (LSDs). Fabry disease, mucopolysaccharidoses I, II, VI and Pompe disease all have licensed enzyme replacement therapies (ERT) and many more enzymes are various stages of clinical development. Like all medical treatments this approach has some limitations. Not all patients are suitable for treatment, some organs or tissues are more amenable to correction and there are problems gauging efficacy in this group of highly variable disorders. The burden of weekly or fortnightly infusions, the development of antibodies to the recombinant proteins and the relative impermeability of the central nervous system to intravenous ERT has stimulated the development of alternative therapies using oral small molecules acting as either inhibitors of substrate accumulation or as chaperones to misfolded proteins. With this approach it is hoped that CNS disease can be corrected or prevented and at the same time the burden of therapy reduced. So far the only small molecule product that has gained marketing approval is Zavesca® (Miglustat, Actelion) which is approved in the USA and EU for the treatment of Gaucher disease in those patients unsuitable for ERT and is also approved in the EU for the treatment of progressive neurological abnormalities in adults and children with Niemann–Pick disease type C.

Keywords

Enzyme Replacement Therapy Fabry Disease Gauche Disease Pompe Disease Agalsidase Beta 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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References

  1. 1.
    Aviezer, D., Almon-Brill, E., Shaaltiel, Y., et al.: Novel enzyme replacement therapy for Gaucher disease: phase III pivotal clinical trial with plant cell expressed recombinant glucocerebrosidase (prGCD)—taliglucerase alpha. Mol. Genet. Metab. 99, S9–S10 (2010)CrossRefGoogle Scholar
  2. 2.
    Banikazemi, M., Bultas, J., Waldek, S., et al.: Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann. Intern. Med. 146, 77–86 (2007)PubMedCrossRefGoogle Scholar
  3. 3.
    Barton, N.W., Furbish, F.S., Murray, G.J., et al.: Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc. Natl. Acad. Sci. U.S.A. 87, 1913–1916 (1990)PubMedCrossRefGoogle Scholar
  4. 4.
    Brady, R.O., Barton, N.W.: Enzyme replacement therapy for type 1 Gaucher disease. In: Desnick, R.J. (ed.) Treatment of Genetic Diseases. Churchill Livingstone, New York (1991)Google Scholar
  5. 5.
    Brooks, D.A., Muller, V.J., Hopwood, J.J.: Stop-codon read-through for patients affected by a lysosomal storage disorder. Trends Mol. Med. 12, 367–373 (2006)PubMedCrossRefGoogle Scholar
  6. 6.
    Brown, J., Brown, J.R., Carroll, R., et al.: Small molecule inhibitors of glycosaminoglycan biosynthesis as substrate optimization therapy for mucopolysaccharidoses. Mol. Genet. Metab. 99, S12 (2010)Google Scholar
  7. 7.
    Brumshtein, B., Salinas, P., Peterson, B., et al.: Characterization of gene-activated human acid-beta-glucosidase: crystal structure, glycan composition, and internalization into macrophages. Glycobiology 20, 24–32 (2010)PubMedCrossRefGoogle Scholar
  8. 8.
    Clarke, J.T.R.: Narrative review: Fabry disease. Ann. Intern. Med. 146, 425–433 (2007)PubMedCrossRefGoogle Scholar
  9. 9.
    Clarke, J., Kolodny, E., Mahuran, D., et al.: Open=label Phase I/II clinical trial of pyrimethamine for the treatment of chronic GM2 gangliosidosis. Mol. Genet. Metab. 99, S14 (2010)CrossRefGoogle Scholar
  10. 10.
    Cox, T.M.: Biomarkers in lysosomal storage diseases: a review. Acta Paediatr. 94, 39–42 (2005)CrossRefGoogle Scholar
  11. 11.
    Desnick, R.J. (ed.): Enzyme Therapy in Genetic Diseases. Alan R Liss, New York (1980)Google Scholar
  12. 12.
    Futerman, A.H., Sussman, J.L., Horowitz, M., et al.: New directions in the treatment of Gaucher disease. Trends Pharmacol. Sci. 25, 147–151 (2004)PubMedCrossRefGoogle Scholar
  13. 13.
    Gabrielli, O., Clarke, L.A., Brunt, S., et al.: Enzyme replacement therapy in a 5-month-old boy with attenuated presymptomatic MPS I: 5-year follow up. Pediatrics 125, e183–e187 (2010)PubMedCrossRefGoogle Scholar
  14. 14.
    Galanaud, D., Tourbah, A., Lehéricy, S., et al.: 24 month-treatment with miglustat of three patients with Niemann-Pick disease type C: follow up using brain spectroscopy. Mol. Genet. Metab. 96, 55–58 (2009)PubMedCrossRefGoogle Scholar
  15. 15.
    Giannini, E.H., Mehta, A.B., Hilz, M.J., et al.: A validated disease severity scoring system for Fabry disease. Mol. Genet. Metab. 99(3), 283–290 (2010)PubMedCrossRefGoogle Scholar
  16. 16.
    Grabowski, G.A., Barton, N.W., Pastores, G., et al.: Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose terminated glucocerebrosidase from natural and recombinant sources. Ann. Intern. Med. 122, 33–39 (1995)PubMedCrossRefGoogle Scholar
  17. 17.
    Grabowski, G.A.: Recent clinical progress in Gaucher disease. Curr. Opin. Pediatr. 17, 519–524 (2005)PubMedCrossRefGoogle Scholar
  18. 18.
    Harmatz, P., Giugliani, R., Schwartz, I., et al.: Enzyme replacement therapy for mucopolysaccharidosis VI: A phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension study. J. Pediatr. 148, 533–553 (2006)PubMedCrossRefGoogle Scholar
  19. 19.
    Hemsley, K.M., Norman, E.J., Crawley, A.C., et al.: Effect of cisternal sulfamidase delivery in MPS IIIA Huntaway dogs–a proof of principle study. Mol. Genet. Metab. 98, 383–392 (2009)PubMedCrossRefGoogle Scholar
  20. 20.
    Hollak, C.E., de Fost, M., van Dussen, L., et al.: Enzyme therapy for the treatment of type 1 Gaucher disease: clinical outcomes and dose–response relationships. Curr. Opin. Pharmacother. 10, 2641–2652 (2009)CrossRefGoogle Scholar
  21. 21.
    Hollak, C.E., Hughes, D., van Shaik, I.N.: Miglustat (Zavesca) in type 1 Gaucher disease: 5-year results of a post-authorisation safety surveillance programme. Pharmacoepidemiol. Drug Saf. 18, 770–777 (2009)PubMedCrossRefGoogle Scholar
  22. 22.
    Hollak, C.E., Vom Dahl, S., Aerts, J.M., et al.: Force Majeure: therapeutic measures in response to restricted supply of imiglucerase (Cerezyme) for patients with Gaucher disease. Blood Cells Mol. Dis. 44, 41–47 (2010)PubMedCrossRefGoogle Scholar
  23. 23.
    Imrie, J., Dasgupta, S., Besley, G.T.N., et al.: The natural history of Niemann–Pick disease type C in the UK. J. Inherit. Metab. Dis. 30, 51–59 (2007)PubMedCrossRefGoogle Scholar
  24. 24.
    Kakkis, E.D., McEntee, M.F., Schmidtchen, A., et al.: Long-term and high-dose trials of enzyme replacement therapy in the canine model of mucopolysaccharidosis I. Biochem. Mol. Med. 58, 156–167 (1996)PubMedCrossRefGoogle Scholar
  25. 25.
    Kaplan, A., Achord, D.T., Sly, W.S.: Phosphohexosyl components of a lysosomal enzyme are recognized by pinocytosis receptors on human fibroblasts. Proc. Natl. Acad. Sci. U.S.A. 74, 1016–1030 (1977)CrossRefGoogle Scholar
  26. 26.
    Kim, K.H., Decker, C., Burton, B.K.: Successful management of difficult infusion-associated reactions in a young patient with mucopolysaccharidosis type VI receiving recombinant human arylsulfatase B (galsulfase [Naglazyme]). Pediatrics 121, e714–e717 (2008)PubMedCrossRefGoogle Scholar
  27. 27.
    Kishnani, P.S., Hwu, W.L., Mandel, H., et al.: A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J. Pediatr. 148, 671–676 (2006)PubMedCrossRefGoogle Scholar
  28. 28.
    Kishnani, P.S., Corzo, D., Leslie, N.D., et al.: Early treatment with alglucosidase alpha prolongs long term survival of infants with Pompe disease. Pediatr. Res. 66, 329–335 (2009)PubMedCrossRefGoogle Scholar
  29. 29.
    Kishnani, P.S., Goldenberg, P.C., DeArmey, S.L., et al.: Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. Mol. Genet. Metab. 99, 26–33 (2010)PubMedCrossRefGoogle Scholar
  30. 30.
    Maegawa, G.H., Banwell, B.L., Blaser, S., et al.: Substrate reduction therapy in juvenile GM2 gangliosidosis. Mol. Genet. Metab. 98, 215–224 (2009)PubMedCrossRefGoogle Scholar
  31. 31.
    McDermot, K.D., Holmes, A., Miners, A.H.: Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J. Med. Genet. 38, 750–760 (2001)CrossRefGoogle Scholar
  32. 32.
    Mendelsohn, N.J., Messenger, Y.H., Rosenberg, A.S., et al.: Elimination of antibodies to recombinant enzyme in Pompe’s disease. N. Eng. J. Med. 360, 194–195 (2009)CrossRefGoogle Scholar
  33. 33.
    Messinger, Y.H., Mendelsohn, N.J., Rhead, W., et al.: Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease. Genet. Med. 14, 135–142 (2012)PubMedCrossRefGoogle Scholar
  34. 34.
    Miebach, E.: Management of infusion-related reactions to enzyme replacement therapy in a cohort of patients with mucopolysaccharidosis disorders. Int. J. Clin. Pharmacol. Ther. 47(Suppl 1), S100–S106 (2009)PubMedGoogle Scholar
  35. 35.
    Muenzer, J., Wraith, J.E., Beck, M., et al.: A phase II/III clinical study of enzyme replacement therapy with Idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet. Med. 8, 465–473 (2006)PubMedCrossRefGoogle Scholar
  36. 36.
    Munoz-Rojas, M.V., Vieira, T., Costa, R., et al.: Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am. J. Med. Genet. A 146A, 2538–2544 (2008)PubMedCrossRefGoogle Scholar
  37. 37.
    Pastores, G.M., Weinreb, N.J., Aerts, H., et al.: Therapeutic goals in the treatment of Gaucher disease. Semin. Hematol. 41(Suppl 5), 4–14 (2004)PubMedCrossRefGoogle Scholar
  38. 38.
    Pastores, G.M., Giraldo, P., Cherin, P., et al.: Goal-oriented therapy with miglustat in Gaucher disease. Curr. Med. Res. Opin. 25, 23–37 (2009)PubMedCrossRefGoogle Scholar
  39. 39.
    Patterson, M.C., Vecchio, D., Prady, H., et al.: Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol. 9, 765–772 (2007)CrossRefGoogle Scholar
  40. 40.
    Peterschmitt, J., Lukina, E., Watman, N., et al.: Genz-112638, an investigational oral treatment for Gaucher disease type 1: preliminary phase 2 clinical trial results. Mol. Genet. Metab. 96, S34 (2009)CrossRefGoogle Scholar
  41. 41.
    Pineda, M., Perez-Poyato, M.S., O’Callaghan, M., et al.: Clinical experience with miglustat therapy in pediatric patients with Niemann-Pick disease type C: a case series. Mol. Genet. Metab. 99(4), 358–366 (2009)PubMedCrossRefGoogle Scholar
  42. 42.
    Piotrowska, E., Jakobkiewicz-Banecka, J., Baranska, S., et al.: Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses. Eur. J. Hum. Genet. 14, 846–852 (2006)PubMedCrossRefGoogle Scholar
  43. 43.
    Platt, F.M., Jayakumar, M.: Substrate reduction therapy. Acta Paediatr. Suppl. 97, 88–93 (2008)PubMedCrossRefGoogle Scholar
  44. 44.
    Raben, N., Fukuda, T., Gilbert, A.L., et al.: Replacing acid α-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers. Mol. Ther. 11, 48–56 (2006)CrossRefGoogle Scholar
  45. 45.
    Saif, M.A., Bigger, B.W., Brookes, K.E., et al.: Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler’s syndrome after pharmacological enzyme replacement therapy. Haematologica 97(9), 1320–1328 (2012). doi: 10.3324/haematol.2011.058644. Epub 2012 Feb 27
  46. 46.
    Schaefer, R., Roland, M., Tylki-Szymanska, A., et al.: Enzyme replacement therapy for Fabry disease: a systematic review of available evidence. Drugs 69, 2179–2205 (2009)PubMedCrossRefGoogle Scholar
  47. 47.
    Schiffmann, R., Fitzgibbon, E.J., Harris, C., et al.: Randomized, controlled trial of miglustat in Gaucher’s disease type 3. Ann. Neurol. 64, 514–522 (2008)PubMedCrossRefGoogle Scholar
  48. 48.
    Shapiro, B.E., Pastores, G.M., Gianutsos, J., et al.: Miglustat in late-onset Tay-Sachs disease: a 12-month, randomized, controlled clinical study with 24 months of extended treatment. Genet. Med. 11, 425–433 (2009)PubMedCrossRefGoogle Scholar
  49. 49.
    Spada, M., Pagliardini, S., Yasuda, M., et al.: High incidence of later-onset Fabry disease revealed by newborn screening. Am. J. Hum. Genet. 79, 31–40 (2006)PubMedCrossRefGoogle Scholar
  50. 50.
    Starzyk, K., Richards, S., Yee, J., et al.: The long term international safety experience of imiglucerase therapy for Gaucher disease. Mol. Genet. Metab. 90, 157–163 (2007)PubMedCrossRefGoogle Scholar
  51. 51.
    Strothotte, S., Strigl-Pill, N., Grunert, B., et al.: Enzyme replacement therapy with alglucosidase alfa in 44 patients with late onset glycogen storage disease type 2: 12 month results of an observational clinical trial. J. Neurol. 257, 91–97 (2010)PubMedCrossRefGoogle Scholar
  52. 52.
    Tsai, T.H.: Concurrent measurement of unbound genistein in the blood, brain and bile of anesthetized rats using microdialysis and its pharmacokinetic application. J. Chromatogr. A 1073, 317–322 (2005)PubMedCrossRefGoogle Scholar
  53. 53.
    van der Ploeg, A.T., Reuser, A.J.J.: Pompe disease. Lancet 372, 1342–1353 (2008)PubMedCrossRefGoogle Scholar
  54. 54.
    Walkley, S.U.: Pathogenic cascades in lysosomal disease—Why so complex? J. Inherit. Metab. Dis. 32, 181–189 (2009)PubMedCrossRefGoogle Scholar
  55. 55.
    Wang, J., Lozier, J., Johnson, G., et al.: Neutralizing antibodies to therapeutic enzymes: considerations for testing, prevention and treatment. Nat. Biotechnol. 26, 901–908 (2008)PubMedCrossRefGoogle Scholar
  56. 56.
    Wang, R.Y., Lelis, A., Mirocha, J., et al.: Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet. Med. 9, 34–45 (2007)PubMedCrossRefGoogle Scholar
  57. 57.
    Weinreb, N.J., Barranger, J.A., Charrow, J., et al.: Guidance on the use of miglustat for treating patients with type 1 Gaucher disease. Am. J. Hematol. 80, 223–229 (2005)PubMedCrossRefGoogle Scholar
  58. 58.
    Weinreb, N.J., Cappellini, M.D., Cox, T.M., et al.: A validated disease severity scoring system for adults with type 1 Gaucher disease. Genet. Med. 12, 44–51 (2010)PubMedCrossRefGoogle Scholar
  59. 59.
    Wokke, J.H., Escolar, D.M., Pestronk, A., et al.: Clinical features of late-onset Pompe disease: a prospective cohort study. Muscle Nerve 38, 1236–1245 (2008)PubMedCrossRefGoogle Scholar
  60. 60.
    Wraith, J.E., Clarke, L.A., Beck, M., et al.: Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J. Pediatr. 144, 581–588 (2004)PubMedCrossRefGoogle Scholar
  61. 61.
    Wraith, J.E.: Limitations of enzyme replacement therapy: current and future. J. Inherit. Metab. Dis. 29, 442–447 (2006)PubMedCrossRefGoogle Scholar
  62. 62.
    Zimran, A., Gelbart, T., Westwood, B., et al.: High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews. Am. J. Hum. Genet. 49, 855–859 (1991)PubMedGoogle Scholar
  63. 63.
    Zimran, A., Gonzalez, D., Lukina, E.A., et al.: Enzyme replacement therapy with velaglucerase alfa significantly improves key clinical parameters in type 1 Gaucher disease: positive results from a randomised, double-blind, global, phase III study. Mol. Genet. Metab. 99, S41 (2010)CrossRefGoogle Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Simon Jones
    • 1
  1. 1.Department of Genetic MedicineSt. Mary’s HospitalManchesterUK

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