The Role of Mannosylated Enzyme and the Mannose Receptor in Enzyme Replacement Therapy

Du, Hong; Levine, Mark; Ganesa, Chandrashekar; Witte, David P.; Cole, Edward S.; Grabowski, Gregory A.

doi:10.1086/498652

Cited by 63 publications

(72 citation statements)

References 36 publications

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“…) showed therapeutic effects in both Kupffer cells and hepatocytes, suggesting a MMR-independent uptake system in vivo (15). chLAL has posttranslational modifications with complex glycosylations.…”

Section: /2mentioning

confidence: 97%

“…chLAL has posttranslational modifications with complex glycosylations. Repeated intraperitoneal injections of chLAL into lal 2/2 mice showed lipid reductions in liver macrophages and hepatocytes (15). In comparison, a single intravenous injection of an adenovirus containing the hLAL cDNA into lal 2/2 mice showed significant corrections of lipid storage in the liver (Kupffer cells and hepatocytes), and peripheral uptake of hLAL in spleen and small intestine (13).…”

Section: /2mentioning

confidence: 98%

“…Peritoneal administration of hLAL, expressed in Pichia pastoris (phLAL), into lal 2/2 mice resulted in significant reductions of hepatomegaly and lipid storage in the liver, spleen, and small intestine. Chinese hamster ovary (CHO)-produced LAL (chLAL) showed similar results (15). However, with phLAL, the hepatic reduction of lipid storage was primarily in Kupffer cells, whereas the lipid storage in the hepatic parenchymal cells was unchanged (14).…”

mentioning

confidence: 88%

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Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice

Cameron²,

Garger

et al. 2008

Journal of Lipid Research

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Section: /2mentioning

confidence: 97%

Section: /2mentioning

confidence: 98%

mentioning

confidence: 88%

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Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice

Cameron²,

Garger

et al. 2008

Journal of Lipid Research

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“…injection. These observations led them (23) to propose an uptake mechanism in hepatocytes, independent of the classical MR and MPR, which remains to be identified. This system was observable only if the rapid clearance by the MR was eliminated.…”

Section: Comparison Of Effectiveness Of P-gus In Reducing Lysosomal Smentioning

confidence: 99%

Enzyme therapy in mannose receptor-null mucopolysaccharidosis VII mice defines roles for the mannose 6-phosphate and mannose receptors

Sly¹,

Vogler²,

Grubb³

et al. 2006

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

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Enzyme replacement therapy (ERT) is available for several lysosomal storage diseases. Except for Gaucher disease, for which an enzyme with exposed mannosyl residues targets mannose receptors (MR) on macrophages, ERT targets primarily the mannose 6-phosphate receptor (MPR). Most recombinant lysosomal enzymes contain oligosaccharides with both terminal mannosyl and mannose 6-phosphate residues. Effective MPR-mediated delivery may be compromised by rapid clearance of infused enzyme by the MR on fixed tissue macrophages, especially Kupffer cells. To evaluate the impact of this obstacle to ERT, we introduced the MR-null mutation onto the mucopolysaccharidosis type VII (MPS VII) background and produced doubly deficient MR ؊/؊ MPS VII mice. The availability of both MR ؉/؉ and MR ؊/؊ mice allowed us to study the effects of eliminating the MR on MR-and MPR-mediated plasma clearance and tissue distribution of infused phosphorylated (P) and nonphosphorylated (NP) forms of human ␤-glucuronidase (GUS). In MR ؉/؉ MPS VII mice, the MR clearance system predominated at doses up to 6.4 mg͞kg P-GUS. Genetically eliminating the MR slowed plasma clearance of both P-and NP-GUS and enhanced the effectiveness of P-GUS in clearing storage in kidney, bone, and retina. Saturating the MR clearance system by high doses of enzyme also improved targeting to MPR-containing tissues such as muscle, kidney, heart, and hepatocytes. Although ablating the MR clearance system genetically is not practical clinically, blocking the MR-mediated clearance system with high doses of enzyme is feasible. This approach delivers a larger fraction of enzyme to MPR-expressing tissues, thus enhancing the effectiveness of MPRtargeted ERT.␤-glucuronidase deficiency ͉ immune tolerance ͉ lysosomal storage disease T he mucopolysacchridoses (MPS) are a group of lysosomal storage diseases (LSDs) in which a deficiency of one or more lysosomal enzymes interferes with the degradation of glycosaminoglycans (GAGs), resulting in their storage in the lysosome. Accumulated GAG storage in lysosomes results in progressive cellular and organ dysfunction (1). In recent years, advances have been made in the treatment of several LSDs (2-5). In these diseases, lysosomal storage can be partially or completely reversed in many target tissues by i.v. infusion of the missing lysosomal enzyme. Traditionally, it was assumed that lysosomal enzymes would be delivered to target tissues so long as the enzymes contained the mannose 6-phosphate (M6P) recognition marker (6). However, other factors can influence the delivery of lysosomal enzymes to target tissues. Among these is the presence of nonphosphorylated oligosaccharides on the enzymes and the extent to which these have been processed from high mannose to complex-type oligosaccharides (7). The latter determines the number of exposed mannose residues on the enzyme, which can target the enzyme preferentially to the mannose receptor (MR). In addition, the distribution of the MR and the mannose 6-phosphate receptor (MPR) and their relative abund...

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“…This cross-correction experiment takes advantage of the general property of lysosomal enzymes to be taken up by cells, primarily via the endocytic mechanism involving a mannose 6-phosphate receptor (53). Cross-correction using this approach has been well established with a significant number of lysosomal enzymes, including ASA (54).…”

Section: Pdgfr␣ Is Secreted Via Exosomalmentioning

confidence: 99%

Dysfunction of Platelet-derived Growth Factor Receptor α (PDGFRα) Represses the Production of Oligodendrocytes from Arylsulfatase A-deficient Multipotential Neural Precursor Cells

Pituch

Moyano

Lopez-Rosas

et al. 2015

Journal of Biological Chemistry

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Background: PDGFR␣ is a key signaling component in oligodendrogenesis. Results: Multipotential Neural precursors (NPs) deficient in arylsulfatase A (ASA) show a higher ratio of long versus short fatty acid sulfatides, reduction in PDGFR␣, decreased AKT phosphorylation, and increased exosomal shedding of PDGFR␣. Conclusion: Sulfatides are regulators of NP response to PDGF-AA. Significance: A novel regulatory mechanism of PDGFR␣ signaling is described.

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The Role of Mannosylated Enzyme and the Mannose Receptor in Enzyme Replacement Therapy

Cited by 63 publications

References 36 publications

Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice

Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice

Enzyme therapy in mannose receptor-null mucopolysaccharidosis VII mice defines roles for the mannose 6-phosphate and mannose receptors

Dysfunction of Platelet-derived Growth Factor Receptor α (PDGFRα) Represses the Production of Oligodendrocytes from Arylsulfatase A-deficient Multipotential Neural Precursor Cells

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