Therapeutic strategies to ameliorate lysosomal storage disorders – a focus on Gaucher disease

Sawkar, Anu R.; D’Haeze, Wim; Kelly, Jeffery W.

doi:10.1007/s00018-005-5437-0

Cited by 120 publications

(129 citation statements)

References 91 publications

(110 reference statements)

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“…Cell biology studies examining the trafficking and folding of different mutant forms of the enzyme may also prove valuable. Other forms of therapy that might provide less expensive, more convenient, and possibly mutation-specific treatment of GD, such as substrate reduction, gene therapy, and small molecule chaperones, are being developed or refined [Aerts et al, 2006;Beck 2007;Sawkar et al, 2006;Sidransky et al, 2007;Zheng et al, 2007].…”

Section: Future Prospectsmentioning

confidence: 99%

Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

et al. 2008

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Communicated by William S. SlyGaucher disease (GD) is an autosomal recessive disorder caused by the deficiency of glucocerebrosidase, a lysosomal enzyme that catalyses the hydrolysis of the glycolipid glucocerebroside to ceramide and glucose. Lysosomal storage of the substrate in cells of the reticuloendothelial system leads to multisystemic manifestations, including involvement of the liver, spleen, bone marrow, lungs, and nervous system. Patients with GD have highly variable presentations and symptoms that, in many cases, do not correlate well with specific genotypes. Almost 300 unique mutations have been reported in the glucocerebrosidase gene (GBA), with a distribution that spans the gene. These include 203 missense mutations, 18 nonsense mutations, 36 small insertions or deletions that lead to either frameshifts or in-frame alterations, 14 splice junction mutations, and 13 complex alleles carrying two or more mutations in cis. Recombination events with a highly homologous pseudogene downstream of the GBA locus also have been identified, resulting from gene conversion, fusion, or duplication. In this review we discuss the spectrum of GBA mutations and their distribution in the patient population, evolutionary conservation, clinical presentations, and how they may affect the structure and function of glucocerebrosidase.

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Section: Future Prospectsmentioning

confidence: 99%

Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

et al. 2008

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“…Deficient GlcCerase activity results in the storage of glucosylceramide within macrophages leading to hepatosplenomegaly, anemia, bone lesions and, in some instances, central nervous system involvement [3]. The more severe types of the disease (classified as type 2 or 3) are characterized by central nervous system impairment and early onset.…”

Section: Introductionmentioning

confidence: 99%

“…Intravenous infusions of recombinant human GlcCerase (enzyme replacement therapy, ERT) and inhibition of glucosylceramide biosynthesis (substrate reduction therapy, SRT) are currently the only available treatment options for Gaucher disease [3]. While effective in managing the visceral symptoms of the disease, enzyme replacement therapy is expensive and cannot address the neurological defects because the replacement enzyme is unable to cross the blood-brain barrier [4].…”

Section: Introductionmentioning

confidence: 99%

Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase

Steet

Chung

Lee

et al. 2007

Biochemical Pharmacology

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Gaucher disease is a lysosomal glycolipid storage disorder characterized by defects in acid-β-glucosidase (GlcCerase), the enzyme responsible for the catabolism of glucosylceramide. We recently demonstrated that isofagomine (IFG), an iminosugar that binds to the active site of GlcCerase, enhances the folding, transport and activity of the N370S mutant form of GlcCerase. In this study we compared the effects of IFG on a number of other glucosidases and glucosyltransferases. We report that IFG has little or no inhibitory activity towards intestinal disaccharidase enzymes, ER α-glucosidase II or glucosylceramide synthase at concentrations previously shown to enhance N370S GlcCerase folding and trafficking in Gaucher fibroblasts. Furthermore, treatment of wild type fibroblasts with high doses of IFG did not alter the processing of newly synthesized N-linked oligosaccharides. These findings support further evaluation of IFG as a potential therapeutic agent in the treatment of some forms of Gaucher disease.

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“…[10,11] Among the Asian population, L444P (Type II, neurological) and F213I (Type I) have been identified as the first and second most frequent mutations. N370S is associated with impaired intracellular trafficking resulting in a reduction in lysosomal concentrations of GCase.…”

mentioning

confidence: 99%

Isofagomine Induced Stabilization of Glucocerebrosidase

Kornhaber¹,

Tropak

Maegawa

et al. 2008

ChemBioChem

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Structurally destabilizing mutations in acid β-glucosidase (GCase) can result in Gaucher disease (GD). The iminosugar isofagomine (IFG), a competitive inhibitor and a potential pharmacological chaperone of GCase, is currently undergoing clinical evaluation for the treatment of GD. An X-ray crystallographic study of the GCase-IFG complex revealed a hydrogen bonding network between IFG and certain active site residues. It was suggested that this network may translate into greater global stability. Here it is demonstrated that IFG does increase the global stability of wild-type GCase, shifting its melting curve by ~15 °C and that it enhances mutant GCase activity in pretreated N370S/N370S and F213I/L444P patient fibroblasts. Additionally, amide hydrogen/ deuterium exchange mass spectroscopy (H/D-Ex) was employed to identify regions within GCase that undergo stabilization upon IFG-binding. H/D-Ex data indicate that the binding of IFG not only restricts the local protein dynamics of the active site, but also propagates this effect into surrounding regions.

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Therapeutic strategies to ameliorate lysosomal storage disorders – a focus on Gaucher disease

Cited by 120 publications

References 91 publications

Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase

Isofagomine Induced Stabilization of Glucocerebrosidase

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