Ashe, KM, Bangari, D, Li, L, Cabrera-Salazar, MA, Bercury, SD, Nietupski, JB et al.. Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease. PLoS ONE 6: e21758

Genzyme Corporation, Framingham, Massachusetts, United States of America.
PLoS ONE (Impact Factor: 3.53). 06/2011; 6(6):e21758. DOI: 10.1371/journal.pone.0021758
Source: PubMed

ABSTRACT The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is substrate reduction therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related glycosphingolipids that accumulate in the lysosomes. Genz-529468, a blood-brain barrier-permeant iminosugar-based GCS inhibitor, was used to evaluate this concept in a mouse model of Sandhoff disease, which accumulates the glycosphingolipid GM2 in the visceral organs and CNS. As expected, oral administration of the drug inhibited hepatic GM2 accumulation. Paradoxically, in the brain, treatment resulted in a slight increase in GM2 levels and a 20-fold increase in glucosylceramide levels. The increase in brain glucosylceramide levels might be due to concurrent inhibition of the non-lysosomal glucosylceramidase, Gba2. Similar results were observed with NB-DNJ, another iminosugar-based GCS inhibitor. Despite these unanticipated increases in glycosphingolipids in the CNS, treatment nevertheless delayed the loss of motor function and coordination and extended the lifespan of the Sandhoff mice. These results suggest that the CNS benefits observed in the Sandhoff mice might not necessarily be due to substrate reduction therapy but rather to off-target effects.

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Available from: Seng H. Cheng, Aug 23, 2015
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    • "apy with inhibitors of GlcCer synthase that are designed to lower the substrate GlcCer levels , has been investigated in clinical trials of Gaucher disease ( Cox et al . 2000 ; Lachmann and Platt 2001 ) and in the treatment of mouse models of other GSDs such as Sandhoff and Niemann - Pick C diseases ( Jeyakumar et al . 1999 ; Zervas et al . 2001 ; Ashe et al . 2011 ; Stein et al . 2012 ) . Besides this therapeutic value in substrate reduction therapy , our results revealed a novel therapeutic potential for these GlcCer synthase inhibitors – clearance of mutant a - syn , although the detailed mechanism remains to be fully determined ."
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