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

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

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.

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Abbreviations

CNS:

Central nervous system

ERT:

Enzyme replacement therapy

ESI/MS:

Electrospray ionization mass spectrometry

GD:

Gaucher disease

GL-1:

Glucosylceramide

H&E:

Hematoxylin and eosin

HPLC:

High-performance liquid chromatography

NB-DNJ:

N-butyl deoxynojirimycin

SRT:

Substrate reduction therapy

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Acknowledgements

The authors thank Leah Curtin, Susan Champagne, and the Department of Comparative Medicine at Genzyme for their technical assistance with the animal studies; Jennifer Johnson and Scott Bercury for performing the histological analysis; and Joshua Pacheco for the mass spectroscopy analysis.

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Authors and Affiliations

  1. Genzyme Corporation, 49 New York Avenue, Framingham, MA, 01701-9322, USA

    John Marshall, Kerry Anne McEachern, Wei-Lien Chuang, Elizabeth Hutto, Craig S. Siegel, Ronald K. Scheule, Diane P. Copeland & Seng H. Cheng

  2. University of Michigan, Ann Arbor, MI, 48103, USA

    James A. Shayman

  3. Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH, 45229, USA

    Greg A. Grabowski

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  1. John Marshall
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  2. Kerry Anne McEachern
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Correspondence to John Marshall.

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Communicated by: Ed Wraith

Competing interests

John Marshall, Kerry Anne McEachern, Wei-Lien Chuang, Elizabeth Hutto, Craig Siegel, Ronald Scheule, Diane Copeland and Seng Cheng are all employees and stockholders of Genzyme Corporation. James Shayman has received scientific funding from Genzyme Corporation in the past. Greg Grabowski is a consultant to Genzyme Corporation and has received scientific funding from Genzyme Corporation in the past.

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Marshall, J., McEachern, K.A., Chuang, WL. et al. Improved management of lysosomal glucosylceramide levels in a mouse model of type 1 Gaucher disease using enzyme and substrate reduction therapy. J Inherit Metab Dis 33, 281–289 (2010). https://doi.org/10.1007/s10545-010-9072-z

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  • DOI: https://doi.org/10.1007/s10545-010-9072-z

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