Journal of Inherited Metabolic Disease

, Volume 33, Issue 3, pp 281–289

Improved management of lysosomal glucosylceramide levels in a mouse model of type 1 Gaucher disease using enzyme and substrate reduction therapy

  • John Marshall
  • Kerry Anne McEachern
  • Wei-Lien Chuang
  • Elizabeth Hutto
  • Craig S. Siegel
  • James A. Shayman
  • Greg A. Grabowski
  • Ronald K. Scheule
  • Diane P. Copeland
  • Seng H. Cheng
Original Article


Gaucher disease is caused by a deficiency of the lysosomal enzyme glucocerebrosidase (acid β-glucosidase), with consequent cellular accumulation of glucosylceramide (GL-1). The disease is managed by intravenous administrations of recombinant glucocerebrosidase (imiglucerase), although symptomatic patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy (ERT) is not an option may also be treated by substrate reduction therapy (SRT) with miglustat. To determine whether the sequential use of both ERT and SRT may provide additional benefits, we compared the relative pharmacodynamic efficacies of separate and sequential therapies in a murine model of Gaucher disease (D409V/null). As expected, ERT with recombinant glucocerebrosidase was effective in reducing the burden of GL-1 storage in the liver, spleen, and lung of 3-month-old Gaucher mice. SRT using a novel inhibitor of glucosylceramide synthase (Genz-112638) was also effective, albeit to a lesser degree than ERT. Animals administered recombinant glucocerebrosidase and then Genz-112638 showed the lowest levels of GL-1 in all the visceral organs and a reduced number of Gaucher cells in the liver. This was likely because the additional deployment of SRT following enzyme therapy slowed the rate of reaccumulation of GL-1 in the affected organs. Hence, in patients whose disease has been stabilized by intravenously administered recombinant glucocerebrosidase, orally administered SRT with Genz-112638 could potentially be used as a convenient maintenance therapy. In patients naïve to treatment, ERT followed by SRT could potentially accelerate clearance of the offending substrate.



Central nervous system


Enzyme replacement therapy


Electrospray ionization mass spectrometry


Gaucher disease




Hematoxylin and eosin


High-performance liquid chromatography


N-butyl deoxynojirimycin


Substrate reduction therapy


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Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  • John Marshall
    • 1
  • Kerry Anne McEachern
    • 1
  • Wei-Lien Chuang
    • 1
  • Elizabeth Hutto
    • 1
  • Craig S. Siegel
    • 1
  • James A. Shayman
    • 2
  • Greg A. Grabowski
    • 3
  • Ronald K. Scheule
    • 1
  • Diane P. Copeland
    • 1
  • Seng H. Cheng
    • 1
  1. 1.Genzyme CorporationFraminghamUSA
  2. 2.University of MichiganAnn ArborUSA
  3. 3.Cincinnati Children’s Hospital Research FoundationCincinnatiUSA

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