<i>In vitro</i> inhibition and intracellular enhancement of lysosomal α‐galactosidase A activity in Fabry lymphoblasts by 1‐deoxygalactonojirimycin and its derivatives

Asano, Naoki; Ishii, Satoshi; Kizu, Haruhisa; Ikeda, Kyoko; Yasuda, Kayo; Kato, Atsushi; Martin, Olivier R.; Fan, Jintu

doi:10.1046/j.1432-1327.2000.01457.x

Cited by 231 publications

(143 citation statements)

References 35 publications

Supporting

Mentioning

137

Contrasting

Unclassified

Order By: Relevance

“…1). Interestingly, while DGJ was a low μM inhibitor of α-Gal (~20-fold stronger than for β-Gal), NB-DGJ was a poor inhibitor, as previously reported [35,41], and no significant inhibitory effect on the enzyme was detected in the presence of up to 340 μM NN-DGJ. On the other hand NN-DGJ was found to be an ~30-fold better inhibitor of β-Gal than NB-DGJ.…”

Section: In Vitro Characterization Of Nn-dgj As a Competitive Inhibitsupporting

confidence: 74%

“…This class of compounds is of particular interest to LSDs as some have been shown to be effective for SRT; e.g. N-butyl-deoxygalactonojirimycin (NB-DGJ) for Gaucher Disease, which is more specific and thus has fewer side effects [33] than the only currently approved SRT-agent NB-DNJ (Zavesca or Miglustat) [34], and others acting as PCs for EET, e.g., DGJ for Fabry disease caused by deficiencies in α-galactosidase (α-Gal) [35].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evaluation of N-nonyl-deoxygalactonojirimycin as a pharmacological chaperone for human GM1 gangliosidosis leads to identification of a feline model suitable for testing enzyme enhancement therapy

Rigat

Tropak

Buttner

et al. 2012

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

Deficiencies of lysosomal β-D-galactosidase can result in GM1 gangliosidosis, a severe neurodegenerative disease characterized by massive neuronal storage of GM1 ganglioside in the brain. Currently there are no available therapies that can even slow the progression of this disease. Enzyme enhancement therapy utilizes small molecules that can often cross the blood brain barrier, but are also often competitive inhibitors of their target enzyme. It is a promising new approach for treating diseases, often caused by missense mutations, associated with dramatically reduced levels of functionally folded enzyme. Despite a number of positive reports based on assays performed with patient cells, skepticism persists that an inhibitor-based treatment can increase mutant enzyme activity in vivo. To date no appropriate animal model, i.e., one that recapitulates a responsive human genotype and clinical phenotype, has been reported that could be used to validate enzyme enhancement therapy. In this report, we identify a novel enzyme enhancementagent, N-nonyl-deoxygalactonojirimycin, that enhances the mutant β-galactosidase activity in the lysosomes of a number of patient cell lines containing a variety of missense mutations. We then demonstrate that treatment of cells from a previously described, naturally occurring feline model (that biochemically, clinically and molecularly closely mimics GM1 gangliosidosis in humans) with this molecule, results in a robust enhancement of their mutant lysosomal β-galactosidase activity. These data indicate that the feline model could be used to validate this therapeutic

show abstract

Section: In Vitro Characterization Of Nn-dgj As a Competitive Inhibitsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Evaluation of N-nonyl-deoxygalactonojirimycin as a pharmacological chaperone for human GM1 gangliosidosis leads to identification of a feline model suitable for testing enzyme enhancement therapy

Rigat

Tropak

Buttner

et al. 2012

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

show abstract

“…Gene therapy is another promising approach for the potential treatment of neurodegenerative diseases that are caused by a single-gene defect, but this method is still in the experimental stage. Recently, the effects of a molecular approach, i.e., chemical chaperone therapy, for restoration of mutant α-galactosidase in Fabry disease (Fan et al, 1999;Asano et al, 2000) and mutant β-galactosidase in GM1 gangliosidosis (Matsuda et al, 2003) were reported. These novel therapies are expected to be effective and safe, but all of these therapies need further investigation using appropriate animal models prior to application to humans.…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid biomarkers showing neurodegeneration in dogs with GM1 gangliosidosis: Possible use for assessment of a therapeutic regimen

et al. 2007

View full text Add to dashboard Cite

gangliosidosis and preliminarily evaluated the efficacy of long-term glucocorticoid therapy for GM1 gangliosidosis using the biomarkers identified here. GM1 gangliosidosis, a lysosomal storage disease that affects the brain and multiple systemic organs, is due to an autosomal recessively inherited deficiency of acid β-galactosidase activity. Pathogenesis of GM1 gangliosidosis may include neuronal apoptosis and abnormal axoplasmic transport and inflammatory response, which are perhaps consequent to massive neuronal storage of GM1 ganglioside. In the present study, we assessed some possible CSF biomarkers, such as GM1 ganglioside, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), neuron-specific enolase (NSE) and myelin basic protein (MBP). Periodic studies demonstrated that GM1 ganglioside concentration, activities of AST and LDH, and concentrations of NSE and MBP in CSF were significantly higher in dogs with GM1 gangliosidosis than those in control dogs, and their changes were well related with the months of age and clinical course. In conclusion, GM1 ganglioside, AST, LDH, NSE and MBP could be utilized as CSF biomarkers showing CNS degeneration in dogs with GM1 gangliosidosis to evaluate the efficacy of novel therapies proposed for this disease. In addition, we preliminarily treated an affected dog with long-term oral administration of prednisolone and evaluated the efficacy of this therapeutic trial using CSF biomarkers determined in the present study. However, this treatment did not change either the clinical course or the CSF biomarkers of the affected dog, suggesting that glucocorticoid therapy would not be effective for treating GM1 gangliosidosis.3

show abstract

“…To analyze the mutant α-galactosidase A activities, we transfected COS-7 cells with the mutant GLAs. In addition, since 1-deoxygalactonojirimycin (DGJ) stabilizes the α-galactosidase A conformation and improves its stability (Asano et al, 2000;Ishii et al, 2000;Yam et al, 2006), we added DGJ to the incubation medium and examined its effect on the mutant α-galactosidase A activities. …”

mentioning

confidence: 99%

Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone

et al. 2008

Self Cite

View full text Add to dashboard Cite

Fabry disease is an X-linked recessive inborn metabolic disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (EC 3.2. throughout the 7 exons of the α-galactosidase A gene (GLA). Mutation hotspots for Fabry disease do not exist. We examined 62 Fabry patients in Japan and found 24 GLA mutations, including 11 novel ones. A potential treatment reported for Fabry disease is active site specific chaperone (ASSC) therapy using 1-deoxygalactonojirimycin (DGJ), an inhibitor of α-galactosidase A, at subinhibitory concentrations. We transfected COS-7 cells with the 24 mutant GLAs and analyzed the α-galactosidase A activities. We then treated the transfected COS-7 cells with DGJ and analyzed its effect on the mutant enzyme activities. The activity of 11 missense mutants increased significantly with DGJ. Although ASSC therapy is useful only for misfolding mutants and therefore not applicable to all cases, it may be useful for treating many Japanese patients with Fabry disease. © 2007 Wiley-Liss, Inc.KEY WORDS: α-galactosidase A; GLA; lysosomal storage disease; 1-deoxygalactonojirimycin; chaperone therapy INTRODUCTIONFabry disease (FD; MIM# 301500) is a pan-ethnic, X-linked, lysosomal storage disorder caused by a deficiency in the lysosomal enzyme α-galactosidase A (EC 3.2.1.22) (Brady et al., 1967). Human α-galactosidase A is a homodimeric glycoprotein with three N-linked oligosaccharide chains on each subunit. Enzyme deficiency results in a systemic lysosomal accumulation of glycolipids, primarily globotriosylceramide (Gb3), in the vascular endothelium and other tissues. In the classical form of the disease, the patient develops angiokeratoma, hypohidrosis, and episodic pain crises in the extremities during childhood or adolescence. With advancing age, the morbidity of renal failure, cardiac disease, and early onset of stroke increases. The severity of the clinical manifestations depends on the amount of residual α-galactosidase A activity. Hemizygous male patients with no or very low α-galactosidase A activity usually have severe clinical symptoms and die as young adults. Heterozygous female Fabry patients exhibit a wide range of severity, from a virtually symptom-free course (Marguery et al., 1993) to one comparable to that of their male counterparts (Whybra et al., 2001), although they usually have no symptoms or very mild manifestations.We examined Fabry patients in Japan and sequenced the patients' α-galactosidase A gene (GLA) (MIM# 300644). To analyze the mutant α-galactosidase A activities, we transfected COS-7 cells with the mutant GLAs. In addition, since 1-deoxygalactonojirimycin (DGJ) stabilizes the α-galactosidase A conformation and improves its stability (Asano et al., 2000;Ishii et al., 2000;Yam et al., 2006), we added DGJ to the incubation medium and examined its effect on the mutant α-galactosidase A activities. MATERIALS AND METHODS PatientsWe examined 62 Fabry patients from 31 unrelated families. Diagnosis was based on reduced or absent α-galactosidase A activity and typical signs an...

show abstract

In vitro inhibition and intracellular enhancement of lysosomal α‐galactosidase A activity in Fabry lymphoblasts by 1‐deoxygalactonojirimycin and its derivatives

Cited by 231 publications

References 35 publications

Evaluation of N-nonyl-deoxygalactonojirimycin as a pharmacological chaperone for human GM1 gangliosidosis leads to identification of a feline model suitable for testing enzyme enhancement therapy

Evaluation of N-nonyl-deoxygalactonojirimycin as a pharmacological chaperone for human GM1 gangliosidosis leads to identification of a feline model suitable for testing enzyme enhancement therapy

Cerebrospinal fluid biomarkers showing neurodegeneration in dogs with GM1 gangliosidosis: Possible use for assessment of a therapeutic regimen

Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone

Contact Info

Product

Resources

About