Skip to main content
Erschienen in: Journal of Inherited Metabolic Disease 3/2009

01.06.2009 | Original Article

The pharmacological chaperone 1-deoxygalactonojirimycin increases α-galactosidase A levels in Fabry patient cell lines

verfasst von: E. R. Benjamin, J. J. Flanagan, A. Schilling, H. H. Chang, L. Agarwal, E. Katz, X. Wu, C. Pine, B. Wustman, R. J. Desnick, D. J. Lockhart, K. J. Valenzano

Erschienen in: Journal of Inherited Metabolic Disease | Ausgabe 3/2009

Einloggen, um Zugang zu erhalten

Summary

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A (α-Gal A), with consequent accumulation of its major glycosphingolipid substrate, globotriaosylceramide (GL-3). Over 500 Fabry mutations have been reported; approximately 60% are missense. The iminosugar 1-deoxygalactonojirimycin (DGJ, migalastat hydrochloride, AT1001) is a pharmacological chaperone that selectively binds α-Gal A, increasing physical stability, lysosomal trafficking, and cellular activity. To identify DGJ-responsive mutant forms of α-Gal A, the effect of DGJ incubation on α-Gal A levels was assessed in cultured lymphoblasts from males with Fabry disease representing 75 different missense mutations, one insertion, and one splice-site mutation. Baseline α-Gal A levels ranged from 0 to 52% of normal. Increases in α-Gal A levels (1.5- to 28-fold) after continuous DGJ incubation for 5 days were seen for 49 different missense mutant forms with varying EC50 values (820 nmol/L to >1 mmol/L). Amino acid substitutions in responsive forms were located throughout both structural domains of the enzyme. Half of the missense mutant forms associated with classic (early-onset) Fabry disease and a majority (90%) associated with later-onset Fabry disease were responsive. In cultured fibroblasts from males with Fabry disease, the responses to DGJ were comparable to those of lymphoblasts with the same mutation. Importantly, elevated GL-3 levels in responsive Fabry fibroblasts were reduced after DGJ incubation, indicating that increased mutant α-Gal A levels can reduce accumulated substrate. These data indicate that DGJ merits further evaluation as a treatment for patients with Fabry disease with various missense mutations.
Literatur
Zurück zum Zitat Bekri S, Enica A, Ghafari T, et al (2005) Fabry disease in patients with end-stage renal failure: the potential benefits of screening. Nephron Clin Pract 101: c33–38. doi:10.1159/000085709.CrossRef Bekri S, Enica A, Ghafari T, et al (2005) Fabry disease in patients with end-stage renal failure: the potential benefits of screening. Nephron Clin Pract 101: c33–38. doi:10.​1159/​000085709.CrossRef
Zurück zum Zitat Bishop D, Grabowski G, Desnick R (1981) Fabry disease: An asymptomatic hemizygote with significant residual alpha-galactosidase A activity. Am J Hum Genet 33: 71A. Bishop D, Grabowski G, Desnick R (1981) Fabry disease: An asymptomatic hemizygote with significant residual alpha-galactosidase A activity. Am J Hum Genet 33: 71A.
Zurück zum Zitat Brady RO, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L (1967) Enzymatic defect in Fabry’s disease: ceramidetrihexosidase deficiency. N Engl J Med 276: 1163–1167.PubMed Brady RO, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L (1967) Enzymatic defect in Fabry’s disease: ceramidetrihexosidase deficiency. N Engl J Med 276: 1163–1167.PubMed
Zurück zum Zitat Desnick R, Ioannou Y, Eng C (2001) alpha-Galactosidase A deficiency; Fabry disease. In: Scriver CR, Beaudet 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, 3507–3534. Desnick R, Ioannou Y, Eng C (2001) alpha-Galactosidase A deficiency; Fabry disease. In: Scriver CR, Beaudet 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, 3507–3534.
Zurück zum Zitat Fan J-Q, Ishii S, Asano N, Suzuki Y (1999) Accelerated transport and maturation of lysosomal α-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nature Med 5: 112–115. doi:10.1038/4801.PubMedCrossRef Fan J-Q, Ishii S, Asano N, Suzuki Y (1999) Accelerated transport and maturation of lysosomal α-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nature Med 5: 112–115. doi:10.​1038/​4801.PubMedCrossRef
Zurück zum Zitat Ioannou YA, Bishop DF, Desnick RJ (1992) Overexpression of human alpha-galactosidase A results in its intracellular aggregation, crystallization in lysosomes, and selective secretion. J Cell Biol 119: 1137–1150. doi:10.1083/jcb.119.5.1137.PubMedCrossRef Ioannou YA, Bishop DF, Desnick RJ (1992) Overexpression of human alpha-galactosidase A results in its intracellular aggregation, crystallization in lysosomes, and selective secretion. J Cell Biol 119: 1137–1150. doi:10.​1083/​jcb.​119.​5.​1137.PubMedCrossRef
Zurück zum Zitat Ioannou YA, Zeidner KM, Grace ME, Desnick R (1998) Human alpha-galactosidase A: glycosylation site 3 is essential for enzyme solubility. Biochem J 332: 789–797.PubMed Ioannou YA, Zeidner KM, Grace ME, Desnick R (1998) Human alpha-galactosidase A: glycosylation site 3 is essential for enzyme solubility. Biochem J 332: 789–797.PubMed
Zurück zum Zitat Ishii S, Chang HH, Kawasaki K, et al (2007) Mutant alpha-galacatosidase A enzymes identified in Fabry patients with residual enzyme activity: Biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin. Biochem J 406: 285–295. doi:10.1042/BJ20070479.PubMedCrossRef Ishii S, Chang HH, Kawasaki K, et al (2007) Mutant alpha-galacatosidase A enzymes identified in Fabry patients with residual enzyme activity: Biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin. Biochem J 406: 285–295. doi:10.​1042/​BJ20070479.PubMedCrossRef
Zurück zum Zitat Ishii S, Chang H, Yoshioka H, et al (2009) Preclinical efficacy and safety of 1-deoxygalactonojirimycin in mice for Fabry disease. J Pharmacol Exp Ther 328(3): 723–731.PubMedCrossRef Ishii S, Chang H, Yoshioka H, et al (2009) Preclinical efficacy and safety of 1-deoxygalactonojirimycin in mice for Fabry disease. J Pharmacol Exp Ther 328(3): 723–731.PubMedCrossRef
Zurück zum Zitat Khanna R, Benjamin ER, Soska R, et al (2007) The pharmacological chaperone AT1001 reduces globotriaosylceramide substrate levels in Fabry transgenic mice and increases α-galactosidase. A levels in vitro, in vivo and in healthy volunteers. Abstract 2250/W. Presented at the American Society of Human Genetics Conference, San Diego, October 23–27, 2007. Khanna R, Benjamin ER, Soska R, et al (2007) The pharmacological chaperone AT1001 reduces globotriaosylceramide substrate levels in Fabry transgenic mice and increases α-galactosidase. A levels in vitro, in vivo and in healthy volunteers. Abstract 2250/W. Presented at the American Society of Human Genetics Conference, San Diego, October 23–27, 2007.
Zurück zum Zitat Lemansky P, Bishop D, Desnick R, Hasilik A, von Figura K (1987) Synthesis and processing of alpha-galactosidase A in human fibroblasts. Evidence for different mutations in Fabry disease. J Biol Chem 262: 2062–2065.PubMed Lemansky P, Bishop D, Desnick R, Hasilik A, von Figura K (1987) Synthesis and processing of alpha-galactosidase A in human fibroblasts. Evidence for different mutations in Fabry disease. J Biol Chem 262: 2062–2065.PubMed
Zurück zum Zitat Matsuzawa F, Aikawa S-I, Doi H, Okumiya T, Sakuraba H (2005) Fabry disease: correlation between structural changes in α-galactosidase, and clinical and biochemical phenotypes. Hum Genet 117: 317–328. doi:10.1007/s00439-005-1300-5.PubMedCrossRef Matsuzawa F, Aikawa S-I, Doi H, Okumiya T, Sakuraba H (2005) Fabry disease: correlation between structural changes in α-galactosidase, and clinical and biochemical phenotypes. Hum Genet 117: 317–328. doi:10.​1007/​s00439-005-1300-5.PubMedCrossRef
Zurück zum Zitat Schiffmann R, Germain DP, Castelli J, et al (2008) Phase 2 clinical trials of the pharmacological chaperone AT1001 for the treatment of Fabry disease. Abstract 768/T. Presented at the American Society of Human Genetics Conference, Philadelphia, November 11–15, 2008. Schiffmann R, Germain DP, Castelli J, et al (2008) Phase 2 clinical trials of the pharmacological chaperone AT1001 for the treatment of Fabry disease. Abstract 768/T. Presented at the American Society of Human Genetics Conference, Philadelphia, November 11–15, 2008.
Zurück zum Zitat Shabbeer J, Yasuda M, Benson S, Desnick R (2006) Fabry disease: Identification of 50 novel α-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations. Hum Genomics 2: 297–309.PubMed Shabbeer J, Yasuda M, Benson S, Desnick R (2006) Fabry disease: Identification of 50 novel α-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations. Hum Genomics 2: 297–309.PubMed
Zurück zum Zitat von Scheidt W, Eng C, Fitzmaurice T, et al (1991) An atypical variant of Fabry’s disease with manifestations confined to the myocardium. N Engl J Med 324: 395–399. von Scheidt W, Eng C, Fitzmaurice T, et al (1991) An atypical variant of Fabry’s disease with manifestations confined to the myocardium. N Engl J Med 324: 395–399.
Zurück zum Zitat Yam GH, Bosshard N, Zuber C, Steinmann B, Roth J (2006) Pharmacological chaperone corrects lysosomal storage in Fabry disease caused by trafficking-incompetent variants. Am J Physiol Cell Physiol 290: C1076–1082. doi:10.1152/ajpcell.00426.2005.CrossRef Yam GH, Bosshard N, Zuber C, Steinmann B, Roth J (2006) Pharmacological chaperone corrects lysosomal storage in Fabry disease caused by trafficking-incompetent variants. Am J Physiol Cell Physiol 290: C1076–1082. doi:10.​1152/​ajpcell.​00426.​2005.CrossRef
Metadaten
Titel
The pharmacological chaperone 1-deoxygalactonojirimycin increases α-galactosidase A levels in Fabry patient cell lines
verfasst von
E. R. Benjamin
J. J. Flanagan
A. Schilling
H. H. Chang
L. Agarwal
E. Katz
X. Wu
C. Pine
B. Wustman
R. J. Desnick
D. J. Lockhart
K. J. Valenzano
Publikationsdatum
01.06.2009
Verlag
Springer Netherlands
Erschienen in
Journal of Inherited Metabolic Disease / Ausgabe 3/2009
Print ISSN: 0141-8955
Elektronische ISSN: 1573-2665
DOI
https://doi.org/10.1007/s10545-009-1077-0

Weitere Artikel der Ausgabe 3/2009

Journal of Inherited Metabolic Disease 3/2009 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.