Molecular Medicine

, Volume 21, Issue 1, pp 389–399 | Cite as

Efficacy of Enzyme and Substrate Reduction Therapy with a Novel Antagonist of Glucosylceramide Synthase for Fabry Disease

  • Karen M. Ashe
  • Eva Budman
  • Dinesh S. Bangari
  • Craig S. Siegel
  • Jennifer B. Nietupski
  • Bing Wang
  • Robert J. Desnick
  • Ronald K. Scheule
  • John P. Leonard
  • Seng H. Cheng
  • John Marshall
Research Article


Fabry disease, an X-linked glycosphingolipid storage disorder, is caused by the deficient activity of α-galactosidase A (α-Gal A). This results in the lysosomal accumulation in various cell types of its glycolipid substrates, including globotriaosylceramide (GL-3) and lysoglobotriaosylceramide (globotriaosyl lysosphingolipid, lyso-GL-3), leading to kidney, heart, and cerebrovascular disease. To complement and potentially augment the current standard of care, biweekly infusions of recombinant α-Gal A, the merits of substrate reduction therapy (SRT) by selectively inhibiting glucosylceramide synthase (GCS) were examined. Here, we report the development of a novel, orally available GCS inhibitor (Genz-682452) with pharmacological and safety profiles that have potential for treating Fabry disease. Treating Fabry mice with Genz-682452 resulted in reduced tissue levels of GL-3 and lyso-GL-3 and a delayed loss of the thermal nociceptive response. Greatest improvements were realized when the therapeutic intervention was administered to younger mice before they developed overt pathology. Importantly, as the pharmacologic profiles of α-Gal A and Genz-682452 are different, treating animals with both drugs conferred the greatest efficacy. For example, because Genz-682452, but not α-Gal A, can traverse the blood-brain barrier, levels of accumulated glycosphingolipids were reduced in the brain of Genz-682452-treated but not α-Gal A-treated mice. These results suggest that combining substrate reduction and enzyme replacement may confer both complementary and additive therapeutic benefits in Fabry disease.



The authors would like to thank Leah Curtin, Erik Zarazinski, Christina Norton, Amy Allaire, JoAnne Fagan and other members of the Comparative Medicine department for animal husbandry and assistance with animal studies. We also acknowledge the members of the Histology and Pathology departments for their expertise in processing the tissue samples, Nelson Yew and Malgorzata Przybylska for Molecular Biology, and Ray Gimi, Jin Zhao, Paul Konowicz, Mike Reardon and members of Chemistry for the synthesis and purification of Genz-682452.


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Authors and Affiliations

  • Karen M. Ashe
    • 1
  • Eva Budman
    • 1
  • Dinesh S. Bangari
    • 1
  • Craig S. Siegel
    • 1
  • Jennifer B. Nietupski
    • 1
  • Bing Wang
    • 1
  • Robert J. Desnick
    • 2
  • Ronald K. Scheule
    • 1
  • John P. Leonard
    • 1
  • Seng H. Cheng
    • 1
  • John Marshall
    • 1
  1. 1.Genzyme, a Sanofi CompanyFraminghamUSA
  2. 2.Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkUSA

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