Systemic delivery of a glucosylceramide synthase inhibitor reduces CNS substrates and increases lifespan in a mouse model of type 2 Gaucher disease

PLoS One. 2012;7(8):e43310. doi: 10.1371/journal.pone.0043310. Epub 2012 Aug 17.


Neuropathic Gaucher disease (nGD), also known as type 2 or type 3 Gaucher disease, is caused by a deficiency of the enzyme glucocerebrosidase (GC). This deficiency impairs the degradation of glucosylceramide (GluCer) and glucosylsphingosine (GluSph), leading to their accumulation in the brains of patients and mouse models of the disease. These accumulated substrates have been thought to cause the severe neuropathology and early death observed in patients with nGD and mouse models. Substrate accumulation is evident at birth in both nGD mouse models and humans affected with the most severe type of the disease. Current treatment of non-nGD relies on the intravenous delivery of recombinant human glucocerebrosidase to replace the missing enzyme or the administration of glucosylceramide synthase inhibitors to attenuate GluCer production. However, the currently approved drugs that use these mechanisms do not cross the blood brain barrier, and thus are not expected to provide a benefit for the neurological complications in nGD patients. Here we report the successful reduction of substrate accumulation and CNS pathology together with a significant increase in lifespan after systemic administration of a novel glucosylceramide synthase inhibitor to a mouse model of nGD. To our knowledge this is the first compound shown to cross the blood brain barrier and reduce substrates in this animal model while significantly enhancing its lifespan. These results reinforce the concept that systemically administered glucosylceramide synthase inhibitors could hold enhanced therapeutic promise for patients afflicted with neuropathic lysosomal storage diseases.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Central Nervous System / metabolism*
  • DNA Primers / genetics
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Gaucher Disease / drug therapy*
  • Glucosylceramides / metabolism
  • Glucosyltransferases / antagonists & inhibitors*
  • Histological Techniques
  • Injections, Intraperitoneal
  • Kaplan-Meier Estimate
  • Mice
  • Psychosine / analogs & derivatives
  • Psychosine / metabolism


  • DNA Primers
  • Enzyme Inhibitors
  • Glucosylceramides
  • Psychosine
  • sphingosyl beta-glucoside
  • Glucosyltransferases
  • ceramide glucosyltransferase

Grant support

All support for these studies was provided by Genzyme Corporation, through the employment of Mario A. Cabrera-Salazar, Matthew DeRiso, Scott D. Bercury, Lingyun Li, Nilesh Pande, William Weber, Diane Copeland, John Leonard, Seng H. Cheng and Ronald K. Scheule who contributed to all aspects of the study. The described studies were part of the drug development program at Genzyme Corporation. The internal publication review committee approved the manuscript for publication. The funders had no role in study design, data collection and analysis, or preparation of the manuscript.