Abstract
Fabry disease is a disorder of glycosphingolipid metabolism caused by deficiency of lysosomal α–galactosidase A (α–Gal A), resulting in renal failure along with premature myocardial infarction and strokes1,2. No effective treatment of this disorder is available at present. Studies of residual activities of mutant enzymes in many Fabry patients showed that some of them had kinetic properties similar to those for normal α–Gal A, but were significantly less stable, especially in conditions of neutral pH (refs. 3,4,5 ). The biosynthetic processing was delayed in cultured fibroblasts of a Fabry patient6, and the mutant protein formed an aggregate in endoplasmic reticulum7, indicating that the enzyme deficiency in some mutants was mainly caused by abortive exit from the endoplasmic reticulum, leading to excessive degradation of the enzyme. We report here that 1–deoxy–galactonojirimycin (DGJ), a potent competitive inhibitor of α–Gal A, effectively enhanced α–Gal A activity in Fabry lymphoblasts, when administrated at concentrations lower than that usually required for intracellular inhibition of the enzyme. DGJ seemed to accelerate transport and maturation of the mutant enzyme. Oral administration of DGJ to transgenic mice overexpressing a mutant α–Gal A substantially elevated the enzyme activity in some organs. We propose a new molecular therapeutic strategy for genetic metabolic diseases of administering competitive inhibitors as 'chemical chaperons' at sub–inhibitory intracellular concentrations.
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Acknowledgements
We thank Y. Kushi and S. Handa (Tokyo Medical and Dental University) for providing CTH; M. Ito (Kyushu University) for providing sphingolipid ceramide N–deacylase; K. Mannen (Oita Medical University) for animal care; A. Oshima (National Institute of Infectious Diseases, Japan), N. Ishida, H. Kubo, and Y. Hashimoto (The Tokyo Metropolitan Institute of Medical Science) for technical advice; R.O. Brady (NIH) for discussions; Y.C. Lee (The Johns Hopkins University) for critical reading and advice on preparing the manuscript as well as suggestions; and A. Suzuki (The Tokyo Metropolitan Institute of Medical Science) for discussions. This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture and the Ministry of Health and Welfare of Japan.
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Fan, JQ., Ishii, S., Asano, N. et al. Accelerated transport and maturation of lysosomal α–galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med 5, 112–115 (1999). https://doi.org/10.1038/4801
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DOI: https://doi.org/10.1038/4801
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