Journal of Inherited Metabolic Disease

, Volume 29, Issue 2–3, pp 471–476 | Cite as

β-Galactosidase deficiency: An approach to chaperone therapy

SSIEM SYMPOSIUM 2005

Summary

We propose a new molecular therapeutic approach to lysosomal diseases with severe neurological manifestations. Some low-molecular-weight compounds, acting as competitive inhibitors of a lysosomal enzyme in vitro, were found to stabilize and restore catalytic activities of the enzyme molecule as a molecular chaperone. We started this trial first in Fabry disease (generalized vasculopathy) using galactose and 1-deoxygalactonojirimycin, and then in β-galactosidase deficiency disorders (β-galactosidosis) with generalized neurosomatic and/or systemic skeletal manifestations (GM1-gangliosidosis and Morquio B disease), using a newly developed chemical compound N-octyl-4-epi-β-valienamine (NOEV). Administration of this chaperone compound resulted in elevation of intracellular enzyme activity in cultured fibroblasts from patients and genetically engineered model mice. In addition, substrate storage was improved after NOEV had been transported into the brain tissue via the blood–brain barrier. We hope this new approach (chemical chaperone therapy) will be useful for certain patients with β-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Durand P, Fabrega S, Henrissat B, Mornon J-P, Lehn P (2000) Structural features of normal and mutant human lysosomal glycoside hydrolases deduced from bioinformatics analysis. Hum Mol Genet 9: 967–977.PubMedCrossRefGoogle Scholar
  2. Fabrega S, Durand P, Codogno P, et al (2000) Human glucocerebrosidase: heterologous expression of active site mutants in murine null cells. Glycobiology 10: 1217–1224.PubMedCrossRefGoogle Scholar
  3. Fan JQ, Ishii S, Asano N, Suzuki Y (1999) Accelerating transport and maturation of lysosomal α-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nature Medicine 5: 112–115.PubMedCrossRefGoogle Scholar
  4. Frustaci A, Chimenti C, Ricci R, et al (2001) Improvement in cardiac function in the cardiac variant of Fabry's disease with galactose-infusion therapy. N Engl J Med 345: 25–32.PubMedCrossRefGoogle Scholar
  5. Ishii S, Kase R, Okumiya T, Sakuraba H, Suzuki Y (1996) Aggregation of the inactive form of human,α-galactosidase in the endoplasmic reticulum. Biochem Biophys Res Commun 220: 812–815.PubMedCrossRefGoogle Scholar
  6. Itoh M, Matsuda J, Suzuki O, et al (2001) Development of lysosomal storage in mice with targeted disruption of the β-galactosidase gene: a model of human GM1-gangliosidosis. Brain Dev 23: 379–384.PubMedCrossRefGoogle Scholar
  7. Kasperzyuk JL, El-Abbadi MM, Hauser EC, d'Azzo A, Platt FM, Seyfried TN (2004) N-Butyldeoxygalactonojirimycin reduces neonatal brain ganglioside content in a mouse model of GM1-gangliosidosis. J Neurochem 89: 645–653.CrossRefGoogle Scholar
  8. Kasperzyk JL, d'Azzo A, Platt FM, Alroy J, Seyfried TN (2005) Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1gangliosidosis mice. J Lipid Res 46: 744–751.PubMedCrossRefGoogle Scholar
  9. Lin H, Sugimoto Y, Ohsaki Y, et al (2004) N-Octyl-β-valienamine up-regulates activity of F213I mutant β-glucosidase in cultured cells: a potential chemical chaperone therapy for Gaucher disease. Biochim Biophys Acta 1689: 219–228.PubMedGoogle Scholar
  10. Matsuda J, Suzuki O, Oshima A, et al (1997) β-Galactosidase-deficient mouse as an animal model for GM1-gangliosidosis. Glycoconjugate J 14: 729–736.CrossRefGoogle Scholar
  11. Matsuda J, Suzuki O, Oshima A, et al (2003) Chemical chaperone therapy for brain pathology in GM1-gangliosidosis. Proc Natl Acad Sci USA 26: 15912–15917.CrossRefGoogle Scholar
  12. O'Brien JS, Storb R, Raff RF, et al (1990) Bone marrow transplantation in canine GM1 gangliosidosis. Clin Genet 38: 274–280.PubMedCrossRefGoogle Scholar
  13. Ogawa S, Tsunoda H, Inokuchi J-i (1994) Synthesis of glucosylceramide analogues: imino-linked 5a-carbaglycosylceramides, potent and specific glucocerebrosidase inhibitors. J Chem Soc Chem Commun 1317–1318.Google Scholar
  14. Ogawa S, Ashiura M, Uchida C, et al (1996) Synthesis of potent β- d-glucocerebrosidase inhibitors: N-alkyl-β-valienamines. Bioorg Med Chem Lett 6: 929–932.CrossRefGoogle Scholar
  15. Ogawa S, Kobayashi Y, Kabayama K, Jimbo M, Inokuchi J-i (1998) Chemical modification of β-glucocerebrosidase inhibitor N-octyl-β-valienamine: synthesis and biological evaluation of N-alkanoyl and N-alkyl derivatives. Bioorg Med Chem 6: 1955–1962.PubMedCrossRefGoogle Scholar
  16. Ogawa S, Kobayashi Matsunaga Y, Suzuki Y., (2002) Chemical modification of the β-glucocerebrosidase N-octyl-β-valienamine: synthesis and biological evaluation of 4-epimeric and 4-O-(β- d-galactopyranosyl) derivatives. Bioorg Med Chem 10: 1967–1972.PubMedCrossRefGoogle Scholar
  17. Ogawa S, Sakata Y, Ito N, et al (2004) Convenient synthesis and evaluation of glycosidase inhibitory activity of α- and β-galactose-type valienamines, and some N-alkyl derivatives. Bioorg Med Chem 12: 995–1002.PubMedCrossRefGoogle Scholar
  18. Okumiya T, Ishii S, Kase R, Kamei S, Sakuraba H, Suzuki Y (1995a) α-Galactosidase gene mutations in Fabry disease: heterogeneous expressions of mutant enzyme proteins. Hum Genet 95: 557–561.CrossRefGoogle Scholar
  19. Okumiya T, Ishii S, Takenaka T, et al (1995b) Galactose stabilizes various missense mutants of α-galactosidase in Fabry disease. Biochem Biophys Res Commun 214: 1219–1224.CrossRefGoogle Scholar
  20. Suzuki Y, Oshima A, Nanba E (2001) β-Galactosidase deficiency (β-galactosidosis): GM1-gangliosidosis and Morquio B disease. In: Scriver CR, Beaud et al Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 3775–3809.Google Scholar
  21. Tominaga L, Ogawa Y, Taniguchi M, et al (2001) Galactonojirimycin derivatives restore mutant human β-galactosidase activities expressed in fibroblasts from enzyme-deficient knockout mouse. Brain Dev 23: 284–287.PubMedCrossRefGoogle Scholar
  22. Tsunoda H, Inokuchi J-i, Yamagishi K, Ogawa S (1995) Synthesis of glycosylceramide analogs composed of imino-linked unsaturated 5a-carbaglycosyl residues: potent and specific gluco- and galactocerebrosidase inhibitors. Liebigs Ann 279–284.Google Scholar
  23. Tylki Szymanska A, Maciejko D, Kidawa M, Jablonska Buda JU, Czartoryska B (1985) Amniotic tissue transplantation as a trial of treatment in some lysosomal storage diseases. J Inherit Metab Dis 8: 101–104.PubMedCrossRefGoogle Scholar
  24. Zhang S, Bagshaw R, Hilson W, et al (2000) Characterization of β-galactosidase mutations Asp332→Asn and Arg148→Ser, and a polymorphism, Ser532→Gly, in a case of GM1 gangliosidosis. Biochem J 348(Pt 3): 621–632.PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2006

Authors and Affiliations

  1. 1.Clinical Research CenterInternational University of Health and WelfareOtawaraJapan

Personalised recommendations