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Research ArticleCELLULAR AND MOLECULAR

Preclinical Efficacy and Safety of 1-Deoxygalactonojirimycin in Mice for Fabry Disease

Satoshi Ishii, Hui-Hwa Chang, Hidekatsu Yoshioka, Tatsuo Shimada, Kazuaki Mannen, Yasunori Higuchi, Atsumi Taguchi and Jian-Qiang Fan
Journal of Pharmacology and Experimental Therapeutics March 2009, 328 (3) 723-731; DOI: https://doi.org/10.1124/jpet.108.149054
Satoshi Ishii
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Hui-Hwa Chang
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Hidekatsu Yoshioka
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Tatsuo Shimada
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Kazuaki Mannen
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Yasunori Higuchi
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Atsumi Taguchi
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Jian-Qiang Fan
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Abstract

Fabry disease is an inborn error of glycosphingolipid metabolism caused by deficiency of α-galactosidase A (α-Gal A) activity. It has been shown that protein misfolding is primarily responsible for the enzyme deficiency in a large proportion of mutations identified in Fabry patients with residual enzyme activity, and 1-deoxygalactonojirimycin (DGJ) can effectively increase the residual enzyme activity in cultured patient's cells. Herein, we demonstrate the preclinical efficacy and safety of DGJ in transgenic mice that express human mutant α-Gal A activity. α-Gal A activity in heart, kidney, spleen, and liver was increased dose- and time-dependently. The mutant α-Gal A was increased in cardiomyocytes and distal convoluted tubules of the transgenic mice in a null background after 2 weeks of DGJ treatment. Globotriaosylceramide storage was remarkably reduced in kidney of mice after a 4-week treatment at a dosage of approximately 3 mg/kg body weight/day. The half-life of DGJ was less than 1 day in all major issues and that of the enzyme synthesized during the DGJ treatment period was approximately 4 days. No abnormality of blood chemistry and pathological tissue damage was found in mice treated with DGJ at ∼30 mg/kg body weight/day for 9 weeks. Furthermore, no change was observed in appearance, growth, fertility, and life span in mice during a 2-year period of continuous administration of DGJ at the effective dosage. These preclinical results indicate that DGJ is effective in restoring mutant enzyme activity in tissues and reversing substrate storage in kidney and is well tolerated in mice.

Footnotes

  • This work was supported in part by the Ministry of Education, Science and Culture of Japan; the Ministry of Health, Labor and Welfare of Japan; Mizutani Glycoscience Foundation; Irma T. Hirschl Foundation; and American Heart Association.

  • S.I. and J.-Q.F. are coinventors of patents related to the active-site-specific chaperone technology, which is now licensed to Amicus Therapeutics, Inc., and declare competing financial interests.

  • doi:10.1124/jpet.108.149054.

  • ABBREVIATIONS: α-Gal A, α-galactosidase A; Gb3, globotriaosylceramide; ER, endoplasmic reticulum; ERAD, ER-associated degradation; ASSC, active-site-specific chaperone; DGJ, 1-deoxygalactonojirimycin; TgM mouse, transgenic mouse expressing human mutant α-Gal A (R301Q); TgM/KO mouse, transgenic mouse expressing human mutant R301Q α-Gal A in α-Gal A knockout background; Non-Tg, non-transgenic; 4MU-α-Gal, 4-methylumbelliferyl α-d-galactopyranoside; PAGE, polyacrylamide gel electrophoresis; TLC, thin layer chromatography; HPTLC, high-performance TLC; HE, hematoxylin and eosin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactic dehydrogenase; BUN, blood urea nitrogen.

    • Received November 21, 2008.
    • Accepted December 22, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 382 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 382, Issue 2
1 Aug 2022
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Research ArticleCELLULAR AND MOLECULAR

Preclinical Efficacy and Safety of 1-Deoxygalactonojirimycin in Mice for Fabry Disease

Satoshi Ishii, Hui-Hwa Chang, Hidekatsu Yoshioka, Tatsuo Shimada, Kazuaki Mannen, Yasunori Higuchi, Atsumi Taguchi and Jian-Qiang Fan
Journal of Pharmacology and Experimental Therapeutics March 1, 2009, 328 (3) 723-731; DOI: https://doi.org/10.1124/jpet.108.149054

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Research ArticleCELLULAR AND MOLECULAR

Preclinical Efficacy and Safety of 1-Deoxygalactonojirimycin in Mice for Fabry Disease

Satoshi Ishii, Hui-Hwa Chang, Hidekatsu Yoshioka, Tatsuo Shimada, Kazuaki Mannen, Yasunori Higuchi, Atsumi Taguchi and Jian-Qiang Fan
Journal of Pharmacology and Experimental Therapeutics March 1, 2009, 328 (3) 723-731; DOI: https://doi.org/10.1124/jpet.108.149054
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