Abstract
We compared two recombinant α-galactosidases developed for enzyme replacement therapy for Fabry disease, agalsidase alfa and agalsidase beta, as to specific α-galactosidase activity, stability in plasma, mannose 6-phosphate (M6P) residue content, and effects on cultured human Fabry fibroblasts and Fabry mice. The specific enzyme activities of agalsidase alfa and agalsidase beta were 1.70 and 3.24 mmol h−1 mg protein−1, respectively, and there was no difference in stability in plasma between them. The M6P content of agalsidase beta (3.6 mol/mol protein) was higher than that of agalsidase alfa (1.3 mol/mol protein). The administration of both enzymes resulted in marked increases in α-galactosidase activity in cultured human Fabry fibroblasts, and Fabry mouse kidneys, heart, spleen and liver. However, the increase in enzyme activity in cultured fibroblasts, kidneys, heart and spleen was higher when agalsidase beta was used. An immunocytochemical analysis revealed that the incorporated recombinant enzyme degraded the globotriaosyl ceramide accumulated in cultured Fabry fibroblasts in a dose-dependent manner, with the effect being maintained for at least 7 days. Repeated administration of agalsidase beta apparently decreased the number of accumulated lamellar inclusion bodies in renal tubular cells of Fabry mice.
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Acknowledgements
We wish to thank Dr. Ashok B. Kulkarni (Gene Targeting Facility and Functional Genomics Unit, NIDCR, NIH) for providing us with the Fabry mice, and also thank Sumitomo Pharmaceuticals for providing us with the agalsidase alfa sample. This work was partly supported by grants from the Tokyo Metropolitan Government, the Japan Society for the Promotion of Science, the Ministry of Education, Science, Sports and Culture, and the Ministry of Health, Labor and Welfare of Japan.
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Sakuraba, H., Murata-Ohsawa, M., Kawashima, I. et al. Comparison of the effects of agalsidase alfa and agalsidase beta on cultured human Fabry fibroblasts and Fabry mice. J Hum Genet 51, 180–188 (2006). https://doi.org/10.1007/s10038-005-0342-9
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DOI: https://doi.org/10.1007/s10038-005-0342-9
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