Niemann Pick type C (NPC) disease is a progressive
neurodegenerative disease caused by mutations in NPC1 or NPC2, the gene products of which are involved in
cholesterol transport in late endosomes. NPC is characterized by an accumulation of
cholesterol,
sphingomyelin and
glycosphingolipids in the visceral organs, primarily the liver and spleen. In the brain, there is a redistribution of unesterified
cholesterol and a concomitant accumulation of
glycosphingolipids. It has been suggested that reducing the aberrant lysosomal storage of
glycosphingolipids in the brain by a substrate reduction
therapy (SRT) approach may prove beneficial. Inhibiting
glucosylceramide synthase (GCS) using the iminosugar-based inhibitor
miglustat (NB-DNJ) has been reported to increase the survival of NPC mice. Here, we tested the effects of Genz-529468, a more potent iminosugar-based inhibitor of GCS, in the NPC mouse.
Oral administration of Genz-529468 or NB-DNJ to NPC mice improved their motor function, reduced CNS
inflammation, and increased their longevity. However, Genz-529468 offered a wider therapeutic window and better therapeutic index than NB-DNJ. Analysis of the
glycolipids in the CNS of the iminosugar-treated NPC mouse revealed that the
glucosylceramide (GL1) but not the
ganglioside levels were highly elevated. This increase in GL1 was likely caused by the off-target inhibition of the murine non-lysosomal
glucosylceramidase, Gba2. Hence, the basis for the observed effects of these inhibitors in NPC mice might be related to their inhibition of Gba2 or another unintended target rather than a result of substrate reduction.