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: 3.23). 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, Sep 25, 2015
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    • "Notably, systemic inhibition of ASM could negatively affect the host defense, which has been demonstrated by studies in mice that completely lack ASM and are unable to control infections [13]. Interestingly, no increased susceptibility to bacterial infections has been identified in patients affected by Gaucher disease, treated with miglustat [47] or in a mouse model of Sandhoff disease treated with Genz-529648 [48]. "
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    ABSTRACT: Current anti-inflammatory strategies for the treatment of pulmonary disease in cystic fibrosis (CF) are limited; thus, there is continued interest in identifying additional molecular targets for therapeutic intervention. Given the emerging role of sphingolipids (SLs) in various respiratory disorders, including CF, drugs that selectively target the enzymes associated with SL metabolism are under development. Miglustat, a well-characterized iminosugar-based inhibitor of β-glucosidase 2 (GBA2), has shown promise in CF treatment because it reduces the inflammatory response to infection by P. aeruginosa and restores F508del-CFTR chloride channel activity. This study aimed to probe the molecular basis for the anti-inflammatory activity of miglustat by examining specifically the role of GBA2 following the infection of CF bronchial epithelial cells by P. aeruginosa. We also report the anti-inflammatory activity of another potent inhibitor of GBA2 activity, namely N-(5-adamantane-1-yl-methoxy)pentyl)-deoxynojirimycin (Genz-529648). In CF bronchial cells, inhibition of GBA2 by miglustat or Genz-529648 significantly reduced the induction of IL-8 mRNA levels and protein release following infection by P. aeruginosa. Hence, the present data demonstrate that the anti-inflammatory effects of miglustat and Genz-529648 are likely exerted through inhibition of GBA2.
    PLoS ONE 08/2014; 9(8):e104763. DOI:10.1371/journal.pone.0104763 · 3.23 Impact Factor
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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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    ABSTRACT: Aggregate-prone mutant proteins, such as α-synuclein and huntingtin, play a prominent role in the pathogenesis of various neurodegenerative disorders; thus, it has been hypothesized that reducing the aggregate-prone proteins may be a beneficial therapeutic strategy for these neurodegenerative disorders. Here, we identified two previously described glucosylceramide (GlcCer) synthase inhibitors, DL-threo-1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) and Genz-123346(Genz), as enhancers of autophagy flux. We also demonstrate that GlcCer synthase inhibitors exert their effects on autophagy by inhibiting AKT-mTOR signaling. More importantly, siRNA knock down of GlcCer synthase had the similar effect as pharmacological inhibition, confirming the on-target effect. In addition, we discovered that inhibition of GlcCer synthase increased the number and size of lysosomal/late endosomal structures. Although inhibition of GlcCer synthase decreases levels of mutant α-synuclein in neurons, it does so, according to our data, through autophagy-independent mechanisms. Our findings demonstrate a direct link between glycosphingolipid biosynthesis and autophagy in primary neurons, which may represent a novel pathway with potential therapeutic value for the treatment of Parkinson's disease. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 02/2014; 129(5). DOI:10.1111/jnc.12672 · 4.28 Impact Factor
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    • "Miglustat, a marketed, non specific glucosylceramide synthase inhibitor (GSI) which crosses the BBB does not appear to address the neuropathic symptoms of nGD. To this point, we have shown in a mouse model of Sandhoff disease [14] that NB-DNJ (active ingredient in miglustat) counterintuitively increases brain GluCer levels, while GZ 112638 a specific GSI in clinical trials, which does not cross the BBB, has no effect as expected. To identify a glucocerebroside synthase (GCS) inhibitor with the ability to cross the BBB, we screened a series of novel synthetic compounds, resulting in the nomination of GZ 161 as a potential therapeutic. "
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    ABSTRACT: Neuropathic Gaucher disease (nGD), also known as type 2 or type 3 Gaucher disease, is caused by a deficiency of the enzyme glucocerebrosidase (GC). This deficiency impairs the degradation of glucosylceramide (GluCer) and glucosylsphingosine (GluSph), leading to their accumulation in the brains of patients and mouse models of the disease. These accumulated substrates have been thought to cause the severe neuropathology and early death observed in patients with nGD and mouse models. Substrate accumulation is evident at birth in both nGD mouse models and humans affected with the most severe type of the disease. Current treatment of non-nGD relies on the intravenous delivery of recombinant human glucocerebrosidase to replace the missing enzyme or the administration of glucosylceramide synthase inhibitors to attenuate GluCer production. However, the currently approved drugs that use these mechanisms do not cross the blood brain barrier, and thus are not expected to provide a benefit for the neurological complications in nGD patients. Here we report the successful reduction of substrate accumulation and CNS pathology together with a significant increase in lifespan after systemic administration of a novel glucosylceramide synthase inhibitor to a mouse model of nGD. To our knowledge this is the first compound shown to cross the blood brain barrier and reduce substrates in this animal model while significantly enhancing its lifespan. These results reinforce the concept that systemically administered glucosylceramide synthase inhibitors could hold enhanced therapeutic promise for patients afflicted with neuropathic lysosomal storage diseases.
    PLoS ONE 08/2012; 7(8):e43310. DOI:10.1371/journal.pone.0043310 · 3.23 Impact Factor
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