New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat

Wraith, J. E.; Imrie, Jackie

doi:10.2147/tcrm.s5777

Cited by 66 publications

(43 citation statements)

References 60 publications

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“…Clinically, N-butyldeoxynojirimycin (NB-DNJ, Zavesca, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland; Fig. 1D) ameliorates the pathological manifestations in type 1 Gaucher patients (52,53) and restricts disease advancement in patients with Niemann-Pick type C1 disease (54,55). Alkylated imino sugars thus can modulate the levels of glucosylceramide and complex GSLs, are currently in clinical use, and may be developed for additional indications (17, 56 -61).…”

Section: Glucosylceramide (Glccer)mentioning

confidence: 99%

β-Glucosidase 2 (GBA2) Activity and Imino Sugar Pharmacology

Ridley

Thur

Shanahan

et al. 2013

Journal of Biological Chemistry

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Background: GBA2 and GBA are both ␤-glucosidases that degrade glucosylceramide. Results: Conduritol B epoxide inactivates both GBA and GBA2, whereas the imino sugar NB-DGJ selectively inhibits GBA2. Conclusion: NB-DGJ is a suitable reagent to distinguish GBA2 from GBA. Significance: This study redefines GBA2 activity, which is relevant for clinical GBA2 measurements and imino sugar pharmacology.

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Section: Glucosylceramide (Glccer)mentioning

confidence: 99%

β-Glucosidase 2 (GBA2) Activity and Imino Sugar Pharmacology

Ridley

Thur

Shanahan

et al. 2013

Journal of Biological Chemistry

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“…This drug is in Phase 3 trials for Sandhoff disease ( 158 ) and for NPC1; miglustat has been approved by EMEA ( 305 ). The therapeutic effects of NB-DNJ are less than achieved with intravenous ERT using mannoseterminated GCase ( 304 ).…”

Section: Treatments By Decreasing Gsl Synthesismentioning

confidence: 99%

Multi-system disorders of glycosphingolipid and ganglioside metabolism

Xu¹,

Barnes²,

Sun³

et al. 2010

Journal of Lipid Research

148

121

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important to a variety of cellular functions. GSLs and gangliosides are synthesized at the endoplasmic reticulum (ER) and are remodeled during transit from cis to trans Golgi by a series of glycosyl-and sialyl-transferases. These are then transported to the intracellular compartments and the plasma membrane where they become enriched in microdomains and membrane bilayers. During plasma membrane turnover, GSLs and gangliosides can be internalized and partially or completely degraded in the endosomal/lysosomal system to sphingosine and free fatty acids that are then transported or fl ipped across late endosomal and lysosomal membranes for recycling or for use as signaling molecules ( 2, 3 ). GSL metabolic pathwaysGSL biosynthesis begins with condensation of serine and palmitoyl-CoA catalyzed by serine-palmitoyltransferase (SPT) on the cytoplasmic face of the ER, leading to de novo biosynthesis of ceramide, the core of GSLs (

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“…The morphogenetic process of epiboly involves coordinated movements of each of the embryonic cell layers that are present during late blastula ( 1 ): the deep cell layer, which gives rise to the embryo proper ( 2 ); the enveloping layer (EVL), an extraembryonic superfi cial epithelial layer covering the deep cells; and ( 3 ) the yolk syncytial layer (YSL), an extra-embryonic cytoplasmic cell layer within the yolk cell ( 38,39 ). Epiboly commences when the yolk cell bulges toward the animal pole and the deep cell blastomeres radially intercalate.…”

Section: This Work Was Supported By a Ruth L Kirschtein Predoctoral mentioning

confidence: 99%

“…

This article is available online at http://www.jlr.org ( 1,2 ). NP-C symptoms typically appear in childhood, although infant onsets are possible.

…”

mentioning

confidence: 99%

Requirement of Npc1 and availability of cholesterol for early embryonic cell movements in zebrafish

Schwend

Loucks

Snyder

et al. 2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org ( 1,2 ). NP-C symptoms typically appear in childhood, although infant onsets are possible. By the time the disorder's symptoms manifest, signifi cant cellular damage has already occurred. At the cellular level, NP-C is characterized by an aberrant accumulation of unesterifi ed cholesterol and glycolipids in the late endosomes and lysosomes of the endocytotic pathway ( 3-6 ). The disease is caused by mutations in one of two genes, Niemann-Pick disease, type C1 ( NPC1 ), which accounts for 95% of cases, or NiemannPick disease, type C2 ( NPC2 ), which accounts for 4% of cases. The remaining 1% of cases involves patients with confi rmed biochemical defects without an accompanying identifi ed mutation ( 7-10 ).The function of NPC1 involves regulating the movement of LDL-derived cholesterol and plasma-derived glycolipids from the endocytotic pathway to the endoplasmic reticulum/trans-Golgi network (ER/TGN) and the mitochondrial membrane ( 11-15 ). Despite reductions in sterol exit from the endocytotic pathway, NPC1-defi cient cells display normal sterol uptake, proper sterol delivery to the endocytotic organelles, and unperturbed levels of cholesterol ester hydrolysis ( 3,16,17 ). Excessive sterol content in the liver and spleen likely accounts for reports of hepato-splenomegaly, whereas sterol accumulation in the brain may contribute to the neurological deterioration in NP-C patients ( 16,(18)(19)(20).Abstract Niemann-Pick disease, type C (NP-C), often associated with Niemann-Pick disease, type C1 (NPC1) mutations, is a cholesterol-storage disorder characterized by cellular lipid accumulation, neurodegeneration, and reduced steroid production. To study NPC1 function in vivo, we cloned zebrafi sh npc1 and analyzed its gene expression and activity by reducing Npc1 protein with morpholino (MO)-oligonucleotides. Filipin staining in npc1-morphant cells was punctate, suggesting abnormal accumulation of cholesterol. Developmentally, reducing Npc1 did not disrupt early cell fate or survival; however, early morphogenetic movements were delayed, and the actin cytoskeleton network was abnormal. MO-induced defects were rescued with ectopic expression of mouse NPC1 , demonstrating functional gene conservation, and by treatments with steroids pregnenolone or dexamethasone, suggesting that reduced steroidogenesis contributed to abnormal cell movements. Cell death was found in anterior tissues of npc1 morphants at later stages, consistent with fi ndings in mammals. Collectively, these studies show that npc1 is required early for proper cell movement and cholesterol localization and later for cell survival. -Schwend, T., E. J. Loucks, D. Snyder, and S. C. Ahlgren. Requirement of Npc1 and availability of cholesterol for early embryonic cell movements in zebrafi sh. J.

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New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat

Cited by 66 publications

References 60 publications

β-Glucosidase 2 (GBA2) Activity and Imino Sugar Pharmacology

β-Glucosidase 2 (GBA2) Activity and Imino Sugar Pharmacology

Multi-system disorders of glycosphingolipid and ganglioside metabolism

Requirement of Npc1 and availability of cholesterol for early embryonic cell movements in zebrafish

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