Galactonojirimycin derivatives restore mutant human β-galactosidase activities expressed in fibroblasts from enzyme-deficient knockout mouse

Tominaga, Lika; Ogawa, Yasuko; Taniguchi, Megumi; Ohno, Kousaku; Matsuda, Junichiro; Oshima, Akihiro; Suzuki, Yoshiyuki; Nanba, Eiji

doi:10.1016/s0387-7604(01)00216-9

Cited by 61 publications

(52 citation statements)

References 9 publications

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“…They are D332N (type 1) and W509C (type 3), which we now report as being responsive, and R148S (type 1/2) and R482H (common in Italian type 1 patients), which we find to be nonresponsive. In agreement with others, we found that R201C/H (common in Japanese type 2 patients) is responsive, while W273L (common in Caucasian Morquio B patients) is nonresponsive [25,40,42]. Of the 11 mutations associated with Morquio B mapped to the new crystal structure of β-Gal by Ohto et al [30], only two were found to be involved in ligand binding, W273L and Y83C/H.…”

Section: Nn-dgj Treatment Of Patient Fibroblasts Shows An Additive Efsupporting

confidence: 92%

“…Since DGJ, as well as its N-butyl derivative, NB-DGJ, have been shown to be inhibitors of β-Gal with IC50s ~25 μM [40], we decided to test and compare another commercially available derivative of DGJ, N-nonyl-DGJ (NN-DGJ), as an inhibitor of β-Gal. These three derivatives were first tested in vitro using a glycoprotein-enriched Concanavalin A fraction of a human placental extract high in lysosomal enzymes such as α-Gal and β-Gal [36,37].…”

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

confidence: 99%

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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

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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

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Section: Nn-dgj Treatment Of Patient Fibroblasts Shows An Additive Efsupporting

confidence: 92%

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

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

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“…Assuming that CNS GA1 in the mutant mouse is derived largely from GM1 desialylation, it is interesting that NB-DGJ treatment, which reduced GM1 content, did not also reduce GA1 content. Recent studies showed that NB-DGJ could enhance lysosomal enzyme activity through chaperone effects (7,65). Further studies will be needed to assess possible NB-DGJ chaperone effects and the relationship between GM1, GA1, and sialidase activity in the control and NB-DGJ-treated ␤-gal Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

“…N -acetylneuraminic acid (Sigma, St. Louis, MO) was used as an external standard. Samples were dissolved in 1 ml of resorcinol reagent/dH 2 O (1:1, v/v), boiled for 15 min, and then by guest, on May 7, 2018 www.jlr.org Downloaded from cooled in an ice bath. Butyl acetate/1-butanol (1.5 ml; 85:15, v/v) was then added, and the samples were vortexed and centrifuged at 1,200 g .…”

Section: Lipid Isolation Purification and Quantitationmentioning

confidence: 99%

Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice

Kasperzyk

d’Azzo

Platt

et al. 2005

Journal of Lipid Research

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“…Fibroblasts from human patients with G M1 -gangliosidosis or Morquio B disease were kindly provided by colleagues in Japan and other countries or purchased from Coriell Institute for Medical Research (Camden, NJ). Mouse fibroblast lines expressing mutant human ␤-galactosidase were established as reported (14). They were cultured in DMEM with 10% FCS and antibiotics.…”

Section: Methodsmentioning

confidence: 99%

Chemical chaperone therapy for brain pathology in G _M1 -gangliosidosis

Matsuda

Сузукі²,

Oshima³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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253

204

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We synthesized a galactose derivative, N-octyl-4-epi-␤-valienamine (NOEV), for a molecular therapy (chemical chaperone therapy) of a human neurogenetic disease, ␤-galactosidosis (GM1-gangliosidosis and Morquio B disease). It is a potent inhibitor of lysosomal ␤-galactosidase in vitro. Addition of NOEV in the culture medium restored mutant enzyme activity in cultured human or murine fibroblasts at low intracellular concentrations, resulting in a marked decrease of intracellular substrate storage. Short-term oral administration of NOEV to a model mouse of juvenile G M1-gangliosidosis, expressing a mutant enzyme protein R201C, resulted in significant enhancement of the enzyme activity in the brain and other tissues. Immunohistochemical stain revealed a decrease in the amount of G M1 and GA1 in neuronal cells in the fronto-temporal cerebral cortex and brainstem. However, mass biochemical analysis did not show the substrate reduction observed histochemically in these limited areas in the brain probably because of the brief duration of this investigation. Chemical chaperone therapy may be useful for certain patients with ␤-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.

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Galactonojirimycin derivatives restore mutant human β-galactosidase activities expressed in fibroblasts from enzyme-deficient knockout mouse

Cited by 61 publications

References 9 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

Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice

Chemical chaperone therapy for brain pathology in G _M1 -gangliosidosis

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Galactonojirimycin derivatives restore mutant human β-galactosidase activities expressed in fibroblasts from enzyme-deficient knockout mouse

Cited by 61 publications

References 9 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

Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice

Chemical chaperone therapy for brain pathology in G M1 -gangliosidosis

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Chemical chaperone therapy for brain pathology in G _M1 -gangliosidosis