title: Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease.
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.
authors: Genzyme Corporation, Framingham, Massachusetts, United States of America.
authors: Karen M
authors: KM
authors: Ashe
authors: Dinesh
authors: D
authors: Bangari
authors: Lingyun
authors: L
authors: Li
authors: Mario A
authors: MA
authors: Cabrera-Salazar
authors: Scott D
authors: SD
authors: Bercury
authors: Jennifer B
authors: JB
authors: Nietupski
authors: Christopher G F
authors: CG
authors: Cooper
authors: Johannes M F G
authors: JM
authors: Aerts
authors: Edward R
authors: ER
authors: Lee
authors: Diane P
authors: DP
authors: Copeland
authors: Seng H
authors: SH
authors: Cheng
authors: Ronald K
authors: RK
authors: Scheule
authors: John
authors: J
authors: Marshall
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006028:Glycosphingolipids / Q000378:metabolism*; D050111:Imino Sugars / Q000737:chemistry*; D007150:Immunohistochemistry; D051379:Mice; D012497:Sandhoff Disease / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D006028:Glycosphingolipids; D050111:Imino Sugars; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase