Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gaucher disease (GD) is a disorder of glycosphinglipid metabolism caused by deficiency of lysosomal acid beta-glucosidase (GC), resulting in progressive deposition of glucosylceramide in macrophages. The glucose analogue, N-butyl-deoxynojirimycin (NB-DNJ, Miglustat), is an inhibitor of the ceramide-specific glucosyltransferase (CSG) which catalyzes the first step of glycosphingolipids biosynthesis and is currently approved for the oral treatment of type 1 GD. Using site-directed mutagenesis, we constructed plasmids containing wild-type and several mutations in glucocerebrosidase (GBA) gene. The plasmids were transfected into COS-7 cells and stable transfected cell lines were obtained by geneticin (G418) selection. Cells were cultured during 6 days with medium with or without 10 microM NB-DNJ. The addition of NB-DNJ to COS-7 cell medium leads to 1.3-, 2.1-, 2.3-, 3.6-, and 9.9-fold increase in the activity of S364R, wild-type, N370S, V15M, and M123T GC, respectively. However, no significant changes were observed in the activity of the L444P, L336P, and S465del mutated proteins, but a small decrease in the rare P266L variant was observed. These results suggest that NB-DNJ, in addition to the inhibitory effect on CSG, also works as a "chemical chaperone", increasing the activity of acid beta-glucosidase of wild-type and several GC mutated proteins, including the most frequent N370S mutation. The specific location of the Miglustat binding site in GC is unknown. Potential binding sites in the enzyme have been searched for using computational molecular docking. The searching strategy identified three potential GC binding sites for Miglustat, one being the substrate-binding site of the enzyme, which was the best-ranked site by AutoDock program. Therefore, it is possible that Miglustat exerts its chaperoning activity on acid beta-glucosidase by acting as an inhibitor bound at the active site. This increase on the activity of the acid beta-glucosidase would imply that Miglustat is not only a substrate reducer but also an inhibitor of the GC degradation, with very promising clinical implications for the treatment of GD patients.
Blood Cells Mol Dis
PMID:Miglustat (NB-DNJ) works as a chaperone for mutated acid beta-glucosidase in cells transfected with several Gaucher disease mutations. 1603 81

Imino sugars are used to treat type 2 diabetes mellitus [miglitol (Glyset)] and lysosomal storage disorders [miglustat (Zavesca)] based on the inhibition of alpha-glucosidases and glucosyltransferases. In this substrate specificity study, we examined the interactions of imino sugars with a novel human glucose sensor, sodium/glucose cotransporter type 3 (hSGLT3), using expression in Xenopus laevis oocytes and electrophysiology. The results for hSGLT3 are compared with those for alpha-glucosidases and human SGLT type 1 (hSGLT1), a well characterized sodium/glucose cotransporter of the SGLT family. In general, substrates have lower apparent affinities (K0.5) for hSGLT3 than hSGLT1 (D-glucose, alpha-methyl-D-glucose, 1-deoxy-D-glucose, and 4-deoxy-4-fluoro-D-glucose exhibit K0.5 values of 19, 21, 43, and 17 mM, respectively, for hSGLT3, and 0.5, 0.7, 10, and 0.07 mM, respectively, for hSGLT1). However, specificity of hSGLT3 binding is greater (D-galactose and 4-deoxy-4-fluoro-D-galactose are not hSGLT3 substrates, but have hSGLT1 K0.5 values of 0.6 and 1.3 mM). An important deviation from this trend is potent hSGLT3 activation by the imino sugars 1-deoxynojirimycin (DNJ), N-hydroxylethyl-1-deoxynojirimycin (miglitol), N-butyl-1-deoxynojirimycin (miglustat), N-ethyl-1-deoxynojirimycin, and 1-deoxynojirimycin-1-sulfonic acid, with K0.5 values of 0.5 to 9 microM. The diastereomer 1-deoxygalactonojirimycin activates hSGT3 with a K0.5 value of 11 mM, a 3000-fold less potent interaction than is observed for DNJ (4 microM). These imino sugar binding characteristics are similar to those for alpha-glucosidases, but there are no interactions with hSGLT1. This work provides insights into hSGLT3 and -1 substrate binding interactions, establishes a pharmacological profile to study endogenous hSGLT3, and may have important ramifications for the clinical application of imino sugars.
Mol Pharmacol 2007 Feb
PMID:Imino sugars are potent agonists of the human glucose sensor SGLT3. 1711 May 2

GM1 gangliosidosis is an inherited neurodegenerative disorder caused by lysosomal beta-galactosidase deficiency, resulting in the storage of GM1 and GA1, primarily in the central nervous system. This disease typically afflicts infants and young children and there is currently no effective therapy. Substrate reduction therapy (SRT) could be of potential benefit. The imino sugars N-butyldeoxynojirimycin (NB-DNJ, miglustat, Zavesca) and N-butyldeoxygalactonojirimycin (NB-DGJ) used for SRT inhibit glucosylceramide synthase (GlcCerS) that catalyses the first committed step in glycosphingolipid biosynthesis. We have compared the efficacy and tolerability of NB-DNJ and NB-DGJ in the beta-galactosidase knockout mouse. NB-DGJ was better tolerated than NB-DNJ, due to intrinsic gastrointestinal tract dysfunction that was exacerbated by NB-DNJ. However, functional improvement was greatest with NB-DNJ treatment which may potentially be caused by novel anti-inflammatory properties of NB-DNJ.
Mol Genet Metab 2008 Jun
PMID:Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis. 1838 28

The role of CFTR deficiency in promoting inflammation remains unclear. Perez et al. [A. Perez, A.C. Issler, C.U. Cotton, T.J. Kelley, A.S. Verkman and P.B. Davis, CFTR inhibition mimics the cystic fibrosis inflammatory profile. Am J Physiol Lung Cell Mol Physiol 2007; 292:L383-L395.] recently demonstrated that the inhibition of function of w/t CFTR produces an inflammatory profile that resembles that observed in CF patients, whereas we found that correction of F508del-CFTR function with MPB-07 down-modulates the inflammatory response to P. aeruginosa in CF bronchial cells [M.C. Dechecchi, E. Nicolis, V. Bezzerri, A. Vella, M. Colombatti, B.M. Assael, et al., MPB-07 reduces the inflammatory response to Pseudomonas aeruginosa in cystic fibrosis bronchial cells. Am J Respir Cell Mol Biol 2007; 36, 615-624.]. Since both evidence support a link between CFTR function and inflammation, we extended our investigation to other F508del-CFTR correctors, such as miglustat (Norez, 2006), an approved drug for Gaucher disease, in comparison with the galactose analogue NB-DGJ. We report here that miglustat but not NB-DGJ restores F508del-CFTR function in CF bronchial epithelial IB3-1 and CuFi-1 cells. Miglustat and NB-DGJ reduce the inflammatory response to P. aeruginosa in both CF and non-CF bronchial cells, indicating that the anti-inflammatory effect is independent of the correction of F508del-CFTR function. Miglustat also inhibits the inflammatory response induced by the supernatant of mucopurulent material obtained from the lower airway tract of cystic fibrosis patients with chronic bacterial colonization (Ribeiro, 2005). Both compounds do not interfere with the adherence of P. aeruginosa to the cells and reduce the expression of IL-8 not only after challenge with P. aeruginosa but also after exposure to TNF alpha or IL-1 beta, suggesting an effect on transduction proteins downstream and in common with different receptors for pathogens. Finally, miglustat has no major effects on overall binding activity of transcription factors NF-kappaBNF-kB and AP-1. Since miglustat is an approved drug, it could be investigated as a novel anti-inflammatory molecule to ameliorate lung inflammation in CF patients.
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PMID:Anti-inflammatory effect of miglustat in bronchial epithelial cells. 1881 75

Niemann-Pick C (NPC) is a fatal progressive neurolipidosis. Miglustat, an inhibitor of glycosphingolipid synthesis, has been proposed to treat patients but questions remain regarding its efficacy. A major problem has been the lack of suitable objective efficacy endpoints. Three adults with NPC were treated with miglustat for 24 months. Efficacy of treatment was assessed clinically and using brain magnetic resonance spectroscopy. All patients reported mild clinical improvement or stabilization. Furthermore, a sustained decrease in the choline/creatine ratio was observed in all three patients over time. Although these preliminary results require confirmation on a larger cohort of patients, they suggest that miglustat has some beneficial effect on brain dysfunction in NPC and that MRS could be used routinely as a non invasive surrogate marker of treatment efficacy.
Mol Genet Metab 2009 Feb
PMID:24 month-treatment with miglustat of three patients with Niemann-Pick disease type C: follow up using brain spectroscopy. 1901 89

Cystic fibrosis (CF) is a fatal, autosomal and recessive genetic disease that is mainly due to inactivating mutations in the chloride channel CF transmembrane conductance regulator (CFTR). Sodium hyperabsorption by the airways, profound lung inflammation, and dysregulation of calcium homeostasis, are presumably causally related to loss of CFTR-dependent chloride function in patients with CF. Miglustat (N-butyldeoxynojirimycin, Zavesca), an inhibitor of the alpha-1,2 glucosidase, has been proposed for clinical use in CF because of its effect as a corrector of the defective trafficking of F508del-CFTR. In the present study, we show that daily treatment for 2 months with low concentrations of miglustat on the human CF nasal epithelial cell line, JME/CF15 (F508del/F508del-CFTR), results in progressive, stable, reversible, and sustained correction of F508del-CFTR trafficking, down-regulation of sodium hyperabsorption, and regulation of the calcium homeostasis. In conclusion, we provide here the first evidence that a respiratory CF cell can acquire a non-CF-like phenotype when chronically treated with low concentrations of a pharmacological drug.
Am J Respir Cell Mol Biol 2009 Aug
PMID:A cystic fibrosis respiratory epithelial cell chronically treated by miglustat acquires a non-cystic fibrosis-like phenotype. 1913 42

GM2 gangliosidosis (GM2g) is an inherited neurodegenerative disorder caused by deficiency of lysosomal beta-hexosaminidase A, resulting in accumulation of GM2 ganglioside, principally in the brain. Substrate reduction therapy is currently under investigation as a treatment. The study investigated the pharmacokinetics and safety of miglustat given as single and multiple doses in infantile and juvenile GM2g patients for 6- and 24-months, respectively. Eleven patients with infantile (n = 6) and juvenile (n = 5) GM2g received oral miglustat at 30-200 mg t.i.d. adjusted to the body surface area. Patients underwent pharmacokinetic assessments on day 1 and at month 3. The pharmacokinetics of miglustat were described by a 2-compartmental model with a lag time, median time to maximum concentration of 2.5 h, and terminal half-life of about 10 h. The pharmacokinetics were time-independent, and did not differ between infantile and juvenile cohorts. The accumulation index was 1.7. Among infantile GM2g patients, the major drug-related adverse events (DRAEs) were abdominal discomfort and flatulence. In the juvenile group, however, the major DRAEs observed were diarrhea and weight loss. One juvenile patient developed peripheral neuropathy, and others showed progression of already established neuropathy, which was judged to be part of the natural progression of the disease. Some mild laboratory abnormalities observed were either transient or attributable to concomitant medications. Miglustat showed similar pharmacokinetic parameters in all patients, with no specific difference between infantile and juvenile forms. Miglustat was shown to be a safe drug, with mild to moderate diarrhea, as an age-dependent DRAE, which was controlled by dietary modification.
Mol Genet Metab 2009 Aug
PMID:Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis. 1944 53

Miglustat has been shown to stabilize disease progression in children, juveniles and adults with Niemann-Pick disease type C (NP-C), a rare genetic disorder characterized by progressive neurological deterioration. We report findings from a retrospective observational cohort study assessing the effects of miglustat on neurological disease progression in patients treated in the clinical practice setting. Data from all NP-C patients prescribed miglustat at 25 expert centers were evaluated using a disease disability scale. The scale analyzed four key parameters of neurological disease progression in NP-C (ambulation, manipulation, language, swallowing). Mean individual parameter scores and a composite score were calculated at baseline (time of diagnosis) and up to 4 follow-up visits. Overall, 66 patients were included (mean [SD] age at diagnosis, 9.7 [7.6] years, and at treatment start, 12.8 [9.5] years). The median (range) miglustat exposure was 1.46 (0.05-4.51) years. Mean annual progression was +0.11 score units/year from diagnosis to treatment start, indicating disease progression prior to therapy, and decreasing to -0.01 score units/year from treatment start to last clinic visit, indicating stabilization. Stabilization of neurological disease on miglustat was observed in all age groups, but the magnitude of the effect was greater in patients diagnosed in late childhood and in juveniles and adults. Stabilization of neurological disease was also observed in a subset of 19 patients with extended pre-treatment information. Overall, these data support previous clinical trial findings indicating clinically relevant beneficial effects of miglustat on neurological disease progression in patients with NP-C.
Mol Genet Metab 2009 Nov
PMID:Miglustat in patients with Niemann-Pick disease Type C (NP-C): a multicenter observational retrospective cohort study. 1965 3

New treatment options for Niemann-Pick Type C (NPC) have recently become available. To assess the efficiency and efficacy of these new treatment markers for disease status and progression are needed. Both the diagnosis and the monitoring of disease progression are challenging and mostly rely on clinical impression and functional testing of horizontal eye movements. Diffusion tensor imaging (DTI) provides information about the microintegrity especially of white matter. We show here in a case report how DTI and measures derived from this imaging method can serve as adjunct quantitative markers for disease management in Niemann-Pick Type C. Two approaches are taken--first, we compare the fractional anisotropy (FA) in the white matter globally between a 29-year-old NPC patient and 18 healthy age-matched controls and show the remarkable difference in FA relatively early in the course of the disease. Second, a voxelwise comparison of FA values reveals where white matter integrity is compromised locally and demonstrate an individualized analysis of FA changes before and after 1year of treatment with Miglustat. This method might be useful in future treatment trials for NPC to assess treatment effects.
Mol Genet Metab 2010 Mar
PMID:Eye movement and diffusion tensor imaging analysis of treatment effects in a Niemann-Pick Type C patient. 1993 18

A randomized, controlled trial of miglustat indicated that miglustat (Zavesca) stabilized neurological disease over 12 months in adult and juvenile patients with Niemann-Pick disease type C (NP-C). We report data from a non-controlled, open-label extension to this initial randomized trial. All patients completing the randomized trial were allowed to continue treatment in a 12-month, non-controlled open-label extension. Those completing 12 months of extension therapy could continue further on miglustat in a 'continued extension' phase. From a total of 29 patients in the randomized phase (mean [+/-SD] age 24.6+/-9.1 ears; 52% female), 21 completed 12 months of therapy with miglustat (17 of whom received miglustat in the initial randomized phase, and four in the extension phase), and 15 patients (all from the miglustat-randomized group) completed 24 months on miglustat. Mean horizontal saccadic eye movement velocity (HSEM-alpha) indicated improvement in the 12-month miglustat group, and stabilization in the 24-month group; swallowing was improved or stable in 86% and in up to 93%, respectively. Ambulation was stabilized in both the 12- and 24-month groups. In an exploratory disease stability analysis of prospective data on key parameters of disease progression (HSEM-alpha, swallowing, ambulation and cognition), 13/19 (68%) patients receiving >or= 12 months' miglustat therapy had stable disease. Among all patients receiving >or= 1 dose of miglustat (n=28), the most frequent adverse events were diarrhoea, weight decrease, flatulence and tremor. Overall, these data suggest that long-term miglustat therapy stabilizes neurological disease and is well tolerated in adult and juvenile patients with NP-C.
Mol Genet Metab 2010 Apr
PMID:Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial. 2004 66


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