| Reference | 1. FEBS Lett. 2006 Apr 3;580(8):2081-6. Epub 2006 Mar 10.
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Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by
the alpha-glucosidase inhibitor miglustat.
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Norez C(1), Noel S, Wilke M, Bijvelds M, Jorna H, Melin P, DeJonge H, Becq F.
<br>
Author information: <br>
(1)Institut de Physiologie et Biologie Cellulaires, CNRS UMR 6187, Université de
Poitiers, 40 avenue du recteur Pineau, Poitiers 86022, France.
[email protected]
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In the disease cystic fibrosis (CF), the most common mutation delF508 results in
endoplasmic reticulum retention of misfolded CF gene proteins (CFTR). We show
that the alpha-1,2-glucosidase inhibitor miglustat (N-butyldeoxynojirimycin,
NB-DNJ) prevents delF508-CFTR/calnexin interaction and restores cAMP-activated
chloride current in epithelial CF cells. Moreover, miglustat rescues a mature and
functional delF508-CFTR in the intestinal crypts of ileal mucosa from delF508
mice. Since miglustat is an orally active orphan drug (Zavesca) prescribed for
the treatment of Gaucher disease, our findings provide the basis for future
clinical evaluation of miglustat in CF patients.
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2. Recent Pat CNS Drug Discov. 2006 Jan;1(1):77-82.
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Miglustat: substrate reduction therapy for lysosomal storage disorders associated
with primary central nervous system involvement.
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Pastores GM(1).
<br>
Author information: <br>
(1)Neurogenetics Unit, Department of Neurology and Pediatrics, New York
University School of Medicine, New York, NY, USA. [email protected]
<br>
Difficulties with delivery of functional enzyme to the brain limit the ability to
modify neurologic outcome in patients with neuronopathic forms of the lysosomal
storage diseases. In a subset of these disorders, which result from a disruption
of glycosphingolipid metabolism, the use of a small molecule inhibitor of
substrate precursor synthesis may reduce the amount of brain tissue lipid
deposition and lead to amelioration of disease. The efficacy of this approach,
termed substrate reduction therapy, has been demonstrated in several animal
models; with resultant reduction of ganglioside storage in the brain, delayed
onset of symptoms and prolonged survival. This pre-clinical ‘proof of therapeutic
concept’ served as the rationale for proceeding with trials in humans using
miglustat; an imino-sugar inhibitor of ceramide-specific glucosytransferase (the
catalyst for the first committed step in glycosphingolipid synthesis). The
glycosphingolipidoses are rare ‘orphan’ disorders; the limited number of suitable
study subjects and the paucity of information on the natural history of these
disorders represent major hurdles in the conduct of clinical trials. As treatment
potentially constitutes lifelong administration, there will be a need to identify
any potential safety considerations attendant to the use of these agents. With
greater understanding of disease mechanism, adjunctive therapies may be
identified; offering the prospect of modifying these otherwise relentlessly
progressive neurodegenerative diseases.
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3. Blood Cells Mol Dis. 2005 Sep-Oct;35(2):268-76.
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Miglustat (NB-DNJ) works as a chaperone for mutated acid beta-glucosidase in
cells transfected with several Gaucher disease mutations.
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Alfonso P(1), Pampín S, Estrada J, Rodríguez-Rey JC, Giraldo P, Sancho J, Pocoví
M.
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Author information: <br>
(1)Departamento de Bioquímica y Biología Molecular y Celular, Facultad de
Ciencias, Universidad de Zaragoza, Plaza San Francisco s/n, 50009 Zaragoza,
Spain.
<br>
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.
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4. J Inherit Metab Dis. 2003;26(6):513-26.
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The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management
of type I (non-neuronopathic) Gaucher disease: a position statement.
<br>
Cox TM(1), Aerts JM, Andria G, Beck M, Belmatoug N, Bembi B, Chertkoff R, Vom
Dahl S, Elstein D, Erikson A, Giralt M, Heitner R, Hollak C, Hrebicek M, Lewis S,
Mehta A, Pastores GM, Rolfs A, Miranda MC, Zimran A; Advisory Council to the
European Working Group on Gaucher Disease.
<br>
Author information: <br>
(1)Department of Medicine, University of Cambridge, Addenbrooke’s Hospital,
Cambridge, UK. [email protected]
<br>
N-Butyldeoxynojirimycin (NB-DNJ, miglustat ‘Zavesca’) is an orally active
iminosugar which inhibits the biosynthesis of macromolecular substrates that
accumulate pathologically in glycosphingolipidoses. Clinical trials of NB-DNJ in
patients with Gaucher’s disease demonstrate the therapeutic potential of such
substrate inhibitors in the glycolipid storage disorders. However,
macrophage-targetted enzyme replacement using intravenous mannose-terminated
human glucocerebrosidase (imiglucerase, Cerezyme) is highly effective in
ameliorating many of the manifestations of Gaucher’s disease and is a treatment
in widespread use. Given that imiglucerase and miglustat are now both licensed
for the treatment of Gaucher’s disease, there is a need to review their
therapeutic status. Here the treatment of type 1 (non-neuronopathic) Gaucher
disease is evaluated with particular reference to the emerging role of oral
N-butyldeoxynojirimycin (miglustat) as a substrate-reducing agent. This position
statement represents the consensus viewpoint of an independent international
advisory council to the European Working Group on Gaucher Disease.
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