title: CNS-accessible Inhibitor of Glucosylceramide Synthase for Substrate Reduction Therapy of Neuronopathic Gaucher Disease.
abstract: Gaucher disease (GD) is caused by a deficiency of glucocerebrosidase and the consequent lysosomal accumulation of unmetabolized glycolipid substrates. Enzyme-replacement therapy adequately manages the visceral manifestations of nonneuronopathic type-1 Gaucher patients, but not the brain disease in neuronopathic types 2 and 3 GD. Substrate reduction therapy through inhibition of glucosylceramide synthase (GCS) has also been shown to effectively treat the visceral disease. Here, we evaluated the efficacy of a novel small molecule inhibitor of GCS with central nervous system (CNS) access (Genz-682452) to treat the brain disease. Treatment of the conduritol β epoxide-induced mouse model of neuronopathic GD with Genz-682452 reduced the accumulation of liver and brain glycolipids (>70% and >20% respectively), extent of gliosis, and severity of ataxia. In the genetic 4L;C* mouse model, Genz-682452 reduced the levels of substrate in the brain by >40%, the extent of gliosis, and paresis. Importantly, Genz-682452-treated 4L;C* mice also exhibited an ~30% increase in lifespan. Together, these data indicate that an orally available antagonist of GCS that has CNS access is effective at attenuating several of the neuropathologic and behavioral manifestations associated with mouse models of neuronopathic GD. Therefore, Genz-682452 holds promise as a potential therapeutic approach for patients with type-3 GD.
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts, USA. Electronic address: john.marshall@genzyme.com.
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts, USA.
authors.forename: Dinesh S
authors.initials: DS
authors.lastname: Bangari
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Budman
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts, USA.
authors.forename: Hyejung
authors.initials: H
authors.lastname: Park
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts, USA.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Nietupski
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Allaire
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts, USA.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Cromwell
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA; Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, Ohio, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Grabowski
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.affiliation: Sanofi Genzyme, Framingham, Massachusetts, USA.
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002219:Carbamates / Q000008:administration & dosage* / Q000494:pharmacology; D002490:Central Nervous System / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D005776:Gaucher Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006017:Glycolipids / Q000378:metabolism*; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D011812:Quinuclidines / Q000008:administration & dosage* / Q000494:pharmacology; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D002219:Carbamates; D004791:Enzyme Inhibitors; D006017:Glycolipids; D011812:Quinuclidines; D007294:Inositol; C000608118:venglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; C011423:conduritol epoxide