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

@article{Ishii2009PreclinicalEA,
  title={Preclinical Efficacy and Safety of 1-Deoxygalactonojirimycin in Mice for Fabry Disease},
  author={Satoshi Ishii and Hui-Hwa Chang and Hidekatsu Yoshioka and Tatsuo Shimada and Kazuaki Mannen and Yasunori Higuchi and Atsumi Taguchi and Jian‐Qiang Fan},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2009},
  volume={328},
  pages={723 - 731}
}
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… 
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The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease.
TLDR
It is indicated that oral administration of DGJ increases mutant alpha-Gal A activity and reduces GL-3 in disease-relevant tissues in Tg/KO mice, and thus merits further evaluation as a treatment for Fabry disease.
A symptomatic Fabry disease mouse model generated by inducing globotriaosylceramide synthesis.
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It is suggested that Gb3 accumulation is a primary pathogenic factor in the symptomatic phenotype of G3Stg/GLAko mice, and that this mouse line is suitable for studying the pathogenesis of Fabry disease and for preclinical studies of candidate therapies.
The pharmacological chaperone 1-deoxygalactonojirimycin increases α-galactosidase A levels in Fabry patient cell lines
TLDR
The data indicate that DGJ merits further evaluation as a treatment for patients with Fabry disease with various missense mutations, and 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.
Coformulation of a Novel Human α-Galactosidase A With the Pharmacological Chaperone AT1001 Leads to Improved Substrate Reduction in Fabry Mice
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    Molecular therapy : the journal of the American Society of Gene Therapy
  • 2015
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Investigation of the effects of coformulating AT1001 with a proprietary recombinant human α-galactosidase A (ATB100) into a single intravenous formulation indicates that intravenous administration of ATB100 coformulated with AT1001 may provide an improved therapy for Fabry disease and thus warrants further investigation.
Increased globotriaosylceramide levels in a transgenic mouse expressing human alpha1,4-galactosyltransferase and a mouse model for treating Fabry disease.
TLDR
Transgenic mice expressing the human α-Gal A R301Q mutant in an α-galactosidase A-knockout background should be useful for studying active-site-specific chaperone (ASSC) therapy for Fabry disease, but the Gb3 content in the heart tissue of this mouse was too low to detect an ASSC-induced effect.
The New Pharmacological Chaperones PBXs Increase α-Galactosidase A Activity in Fabry Disease Cellular Models
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Experimental evidence suggests that PBX compounds are promising candidates for the treatment of Fabry disease caused by mutations which affect the folding of α-Galactosidase A, even for GLA variants that are not amenable to the treatment with Migalastat.
Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice
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Coadministration of the orally available, small molecule pharmacological chaperone AT1001 (GR181413A, 1-deoxygalactonojirimycin, migalastat hydrochloride) may improve the pharmacological properties of rhα-Gal A via binding and stabilization, thus warranting clinical investigation.
Review Pharmacological chaperone therapy for Fabry disease
TLDR
It is discovered that a potent ,-galactosidase A inhibitor, 1-deoxygalactonojirimycin, acts as a pharmacological chaperone to facilitate the proper folding of the mutant enzyme by binding to its active site, thereby improving its stability and trafficking to the lysosomes in mammalian cells.
Pharmacological chaperone therapy for Fabry disease
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    Proceedings of the Japan Academy. Series B, Physical and biological sciences
  • 2012
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It is discovered that a potent α-galactosidase A inhibitor, 1-deoxygalactonojirimycin, acts as a pharmacological chaperone to facilitate the proper folding of the mutant enzyme by binding to its active site, thereby improving its stability and trafficking to the lysosomes in mammalian cells.
Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates.
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