Modifying exogenous glucocerebrosidase for effective replacement therapy in Gaucher disease

Brady, Roscoe O.; Murray, Gary J.; Barton, Norman W.

doi:10.1007/bf00711365

Cited by 48 publications

(30 citation statements)

References 30 publications

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“…Similar to the already mentioned relevance of endocytosis receptors for routing determinants such as GalNAc-4-SO 4 on the terminal part of N-glycan antennae of a limited set of glycoproteins [37], the occurrence of pattern-recognizing lectins in host defense attests how meaningful messages of the glycocode can be deciphered to the benefit of the organism. As likewise emphasized, therapeutic routing has also been beneficially exploited in enzyme replacement therapy involving the C-type tandem-repeat mannose receptor of macrophages [298,335,449,451]. These examples and further information given in table 2 make easily understandable why current research activities on lectins and glycoconjugates touch on various disciplines from the realms of basic and applied science ( fig.…”

Section: Review Articlementioning

confidence: 90%

“…Such a case has already been discussed for autosomal recessive Morbus Gaucher by the targeted enzyme (i.e. i-glucocerebrosidase) replacement [449,451,497].…”

Section: Review Articlementioning

confidence: 95%

“…Accumulation of glycolipids due to defective degradation can be alleviated by therapeutically routing enzymes to the badly afflicted cell types such as macrophages, an approach termed enzyme replacement therapy, with the enzyme's trimmed complex-type N-glycans as a routing signal to the C-type lectins of the target cells [298,449]. Instead of exoglycosidase treatment of the naturally occurring i-glucocerebrosidase or expression in GlcNAc-transferase I-deficient mammalian cells, insect cells may also be a source of mannose-presenting enzymes, as explained in the section on N-glycans [450,451]. This example again emphasizes the role of glycans in cell-targeted delivery.…”

Section: G Reuter and H-j Gabiusmentioning

confidence: 98%

See 2 more Smart Citations

Eukaryotic glycosylation: whim of nature or multipurpose tool?

Reuter¹,

Gabius²

1999

Cellular and Molecular Life Sciences (CMLS)

214

141

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Protein and lipid glycosylation is a ubiquitous phenomenon. The task of cataloguing the great structural variety of the glycan part has demanded considerable efforts over decades. This patient endeavor was imperative to discern the inherent rules of glycosylation which cannot affirm assumptions on a purely coincidental nature of this type of protein and lipid modification. These results together with theoretical considerations uncover a salient property of oligosaccharides. In comparison with amino acids and nucleotides, monosaccharides excel in their potential to serve as units of hardware for storing biological information. Thus, the view that glycan chains exclusively affect physiochemical properties of the conjugates is indubitably flawed. This original concept has been decisively jolted by the discovery of endogenous receptors (lectins) for distinct glycan epitopes which are as characteristic as a fingerprint or a signature for a certain protein (class) or cell type. Recent evidence documents that these binding proteins are even endowed with the capacity to select distinct low-energy conformers of the often rather flexible oligosaccharides, granting entry to a new level of regulation of ligand affinity by shifting conformer equilibria. The assessment of the details of this recognition by X-ray crystallography, nuclear magnetic resonance spectroscopy, microcalorimetry and custom-made derivatives is supposed to justify a guarded optimism in satisfying the need for innovative drug design in antiadhesion therapy, for example against viral or bacterial infections and unwanted inflammation. This review presents a survey of the structural aspects of glycosylation and of evidence to poignantly endorse the notion that carrier-attached glycan chains can partake in biological information transfer at the level of cell compartments, cells and organs.

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Section: Review Articlementioning

confidence: 90%

“…Such a case has already been discussed for autosomal recessive Morbus Gaucher by the targeted enzyme (i.e. i-glucocerebrosidase) replacement [449,451,497].…”

Section: Review Articlementioning

confidence: 95%

Section: G Reuter and H-j Gabiusmentioning

confidence: 98%

See 1 more Smart Citation

Eukaryotic glycosylation: whim of nature or multipurpose tool?

Reuter¹,

Gabius²

1999

Cellular and Molecular Life Sciences (CMLS)

214

141

View full text Add to dashboard Cite

show abstract

“…[1][2][3] Enzyme bioprocesses are important industrially in the food, beverage, and detergent fields. It is usually desirable to separate the enzyme and its product efficiently, to recover the product, plus, in some cases, to reuse the enzyme.…”

Section: Introductionmentioning

confidence: 99%

Unusual properties of thermally sensitive oligomer-enzyme conjugates of poly(N-isopropylacrylamide)-trypsin

Ding¹,

Chen²,

Hoffman³

1998

J. Biomed. Mater. Res.

104

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Reversible soluble-insoluble oligomer-enzyme conjugates have been prepared by conjugating a thermally sensitive oligomer, poly(N-isopropylacrylamide) [poly(NIPAAm)] to trypsin. The conjugates can catalyze enzymatic reactions in solution and then may be separated from the solution by thermal precipitation. One special feature of the conjugates is that every poly(NIPAAm) chain has only one end attachment to the enzyme, so that the loss of enzymatic activity due to steric hindrance should be minimized. Conjugates with various numbers of oligomer chains per trypsin molecule were prepared. Surprisingly, the conjugates increased in enzymatic activity with increasing oligomer conjugation to the native trypsin. The trypsin active sites in the conjugates were accessible to large molecules, such as soybean trypsin inhibitor (MW = 21,500). The enzyme conjugates were more stable than native trypsin, both in solution and in the precipitated phase. On the other hand, the conjugates lost enzymatic activity faster than native trypsin when the temperature was repeatedly cycled through the lower critical solution temperature (LCST) of the poly(NIPAAm). The recovery of the conjugates by thermal precipitation in each cycle was over 95% even after 14 cycles through the LCST.

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“…Similar material enabled pathologists to extract the stored lipid and ultimately determine its structure (Aghion 1934). Later it was the living tissue taken opportunistically during the course of clinical work that enabled Dr Brady and others to identify the metabolic defect (Brady et al 1965 Indeed, after many years, scientific access to patients became essential for clinical trials of enzyme therapy, bone marrow transplantation and, latterly, substrate reduction therapy (as described by Dr Brady, Dr Moyses and Dr Zimran (Ringdén et al 1988;Brady et al 1994;Brady 1997;Cox et al 2000)). …”

Section: The Study Of Rare Variantsmentioning

confidence: 99%

Future perspectives for glycolipid research in medicine

Cox

2003

Phil. Trans. R. Soc. Lond. B

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Medical interest in glycolipids has been mainly directed to the rare and complex glycosphingolipid storage disorders that are principally caused by unitary deficiencies of lysosomal acid hydrolases. However, glycolipids are critical components of cell membranes and occur within newly described membrane domains known as lipid rafts. Glycolipids are components of important antigen systems and membrane receptors; they participate in intracellular signalling mechanisms and may be presented to the immune system in the context of the novel CD1 molecules present on T lymphocytes. A knowledge of their mechanism of action in the control of cell growth and survival as well as developmental pathways is likely to shed light on the pathogenesis of the glycosphingolipid storage disorders as well as the role of lipid second messengers in controlling cell mobility and in the mobilization of intracellular calcium stores (a biological role widely postulated particularly for the lysosphingolipid metabolite sphingosine 1-phosphate). Other sphingolipid metabolites such as ceramide 1-phosphate may be involved in apoptotic responses and in phagocytosis and synaptic vesicle formation. The extraordinary pharmaceutical success of enzymatic complementation for Gaucher's disease using macrophage-targeted human glucocerebrosidase has focused further commercial interest in other glycolipid storage diseases: the cost of targeted enzyme therapy and its failure to restore lysosomal enzymatic deficiencies in the brain has also stimulated interest in the concept of substrate reduction therapy using diffusible inhibitory molecules. Successful clinical trials of the iminosugar Nbutyldeoxynojirimycin in type 1 Gaucher's disease prove the principle of substrate reduction therapy and have attracted attention to this therapeutic method. They will also foster important further experiments into the use of glycolipid synthesis inhibitors for the severe neuronopathic glycosphingolipidoses, for which no definitive treatment is otherwise available. Future glycolipid research in medicine will be directed to experiments that shed light on the role of sphingolipids in signalling pathways, and in the comprehensive characterization and their secretory products in relation to the molecular pathogenesis of the storage disorders; experiments of use to improve the efficiency of complementing enzymatic delivery to the lysosomal compartment of storage cells are also needed. Further systematic screening for inhibitory compounds with specific actions in the pathways of glycosphingolipid biosynthesis will undoubtedly lead to clinical trials in the neuronopathic storage disorders and to wider applications in the fields of immunity and cancer biology.

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Modifying exogenous glucocerebrosidase for effective replacement therapy in Gaucher disease

Cited by 48 publications

References 30 publications

Eukaryotic glycosylation: whim of nature or multipurpose tool?

Eukaryotic glycosylation: whim of nature or multipurpose tool?

Unusual properties of thermally sensitive oligomer-enzyme conjugates of poly(N-isopropylacrylamide)-trypsin

Future perspectives for glycolipid research in medicine

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