An approach to treating Gaucher disease is substrate inhibition therapy which seeks to abate the aberrant lysosomal accumulation of glucosylceramide. We have identified a novel inhibitor of glucosylceramide synthase (Genz-1 12638) and assessed its activity in a murine model of Gaucher disease (D409V/null). Biochemical characterization of Genz-1 12638 showed good potency (IC50 similar to 24 nM) and specificity against the target enzyme. Mice that received drug prior to significant accumulation of substrate (10 weeks of age) showed reduced levels or glucosylceramide and number of Gaucher cells in the spleen, lung and liver when compared to age-matched control animals. Treatment of older mice that already displayed significant amounts of tissue glucosylceramide (7 months old) resulted ill arrest of further accumulation of the substrate and appearance of additional Gaucher cells in affected organs. These data indicate that substrate inhibition therapy with Genz-1 12638 represents a viable alternate approach to enzyme therapy to treat the visceral pathology in Gaucher disease. (c) 2007 Elsevier Inc. All rights reserved.

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