Active site mutant transgene confers tolerance to human β-glucuronidase without affecting the phenotype of MPS VII mice

Sly, William S.; Vogler, Carole; Grubb, Jeffrey H.; Zhou, Mi; Jiang, Jinxing; Zhou, Xiao Yan; Tomatsu, Shunji; Bi, Yanhua; Snella, Elizabeth M.

doi:10.1073/pnas.051623698

Cited by 36 publications

(33 citation statements)

References 44 publications

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“…The efficacy of the infused enzyme depends on its delivery to cell-surface receptors in a range of tissues in which the storage products accumulate. Thus, demonstration that a potential therapeutic enzyme is delivered effectively to target tissues is a good predictor of the likely clinical effectiveness of the therapy (31). We report here that the GILT tag is effective at delivering the chimeric protein hGUS-GILT to a wide range of tissues and cell types that exceeds the range of cell types targeted by native hGUS at the same dose.…”

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confidence: 86%

“…In these studies, MPS VII͞E540A tg mice were used (31). These mice carry an hGUS transgene that encodes an inactive enzyme, which induces immunotolerance to the human protein.…”

Section: Expression Of Recombinant Proteins In Chinese Hamster Ovary mentioning

confidence: 99%

“…Although the number of human patients suffering from MPS VII is very small, well characterized animal models are available that have been studied extensively (29)(30)(31). MPS VII mice lack the lysosomal enzyme mGUS and display a disease progression that is similar to the disease progression observed in human patients lacking human GUS (hGUS).…”

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confidence: 99%

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Glycosylation-independent targeting enhances enzyme delivery to lysosomes and decreases storage in mucopolysaccharidosis type VII mice

LeBowitz

Grubb

Maga

et al. 2004

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

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Enzyme-replacement therapy is an established means of treating lysosomal storage diseases. Infused therapeutic enzymes are targeted to lysosomes of affected cells by interactions with cellsurface receptors that recognize carbohydrate moieties, such as mannose and mannose 6-phosphate, on the enzymes. We have tested an alternative, peptide-based targeting system for delivery of enzymes to lysosomes in a murine mucopolysaccharidosis type VII (MPS VII) model. This strategy depends on the interaction of a fragment of insulin-like growth factor II (IGF-II), with the IGF-II binding site on the bifunctional, IGF-II cation-independent mannose 6-phosphate receptor. A chimeric protein containing a portion of mature human IGF-II fused to the C terminus of human ␤-glucuronidase was taken up by MPS VII fibroblasts in a mannose 6-phosphate-independent manner, and its uptake was inhibited by the addition of IGF-II. Furthermore, the tagged enzyme was delivered effectively to clinically significant tissues in MPS VII mice and was effective in reversing the storage pathology. The tagged enzyme was able to reduce storage in glomerular podocytes and osteoblasts at a dose at which untagged enzyme was much less effective. This peptide-based, glycosylation-independent lysosomal targeting system may enhance enzyme-replacement therapy for certain human lysosomal storage diseases.␤-glucuronidase ͉ IGF-II͞Man6-P receptor ͉ receptor-mediated endocytosis ͉ enzyme-replacement therapy ͉ lysosomal storage disease

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confidence: 86%

“…In these studies, MPS VII͞E540A tg mice were used (31). These mice carry an hGUS transgene that encodes an inactive enzyme, which induces immunotolerance to the human protein.…”

Section: Expression Of Recombinant Proteins In Chinese Hamster Ovary mentioning

confidence: 99%

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Glycosylation-independent targeting enhances enzyme delivery to lysosomes and decreases storage in mucopolysaccharidosis type VII mice

LeBowitz

Grubb

Maga

et al. 2004

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

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“…modified this model by making it immunologically tolerant to human ␤-glucuronidase (hGUS; ref. 9). This reduces the risk of complications from an immune response when hGUS is infused repeatedly in ERT.…”

Section: Fig 1 Plasma Clearance Of P-and Np-gus (A) or Ap-and Np-gumentioning

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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“…In this paper, we describe the generation of a novel immune‐tolerant mouse model for alpha‐mannosidosis showing histopathological, biochemical and behavioral characteristics comparable to the conventional alpha‐mannosidase knockout mice 15. A similar approach, describing the successful induction of immune tolerance by transgenic expression of an active site mutant in various LSD mouse models has been used by others 25, 26, 27. Immune‐tolerant mice were instrumental in investigating the effect of long‐term ERT in other LSDs such as Pompe disease,28 mucopolysaccharidosis‐type VII (MPSVII),26 and metachromatic leukodystrophy 25.…”

Section: Discussionmentioning

confidence: 99%

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Damme

Lüdemann

Rothaug

et al. 2015

Ann Clin Transl Neurol

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ObjectiveThe lysosomal storage disease alpha‐mannosidosis is caused by the deficiency of the lysosomal acid hydrolase alpha‐mannosidase (LAMAN) leading to lysosomal accumulation of neutral mannose‐linked oligosaccharides throughout the body, including the brain. Clinical findings in alpha‐mannosidosis include skeletal malformations, intellectual disabilities and hearing impairment. To date, no curative treatment is available. We previously developed a beneficial enzyme replacement therapy (ERT) regimen for alpha‐mannosidase knockout mice, a valid mouse model for the human disease. However, humoral immune responses against the injected recombinant human alpha‐mannosidase (rhLAMAN) precluded long‐term studies and chronic treatment.MethodsHere, we describe the generation of an immune‐tolerant alpha‐mannosidosis mouse model that allowed chronic injection of rhLAMAN by transgenic expression of a catalytically inactive variant of human LAMAN in the knockout background.ResultsChronic ERT of rhLAMAN revealed pronounced effects on primary substrate storage throughout the brain, normalization of lysosomal enzyme activities and morphology as well as a decrease in microglia activation. The positive effect of long‐term ERT on neuronal lysosomal function was reflected by an improvement of cognitive deficits and exploratory activity. in vivo and in vitro uptake measurements indicate rapid clearance of rhLAMAN from circulation and a broad uptake into different cell types of the nervous system.InterpretationOur data contribute to the understanding of neurological disorders treatment by demonstrating that lysosomal enzymes such as rhLAMAN can penetrate into the brain and is able to ameliorate neuropathology.

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Active site mutant transgene confers tolerance to human β-glucuronidase without affecting the phenotype of MPS VII mice

Cited by 36 publications

References 44 publications

Glycosylation-independent targeting enhances enzyme delivery to lysosomes and decreases storage in mucopolysaccharidosis type VII mice

Glycosylation-independent targeting enhances enzyme delivery to lysosomes and decreases storage in mucopolysaccharidosis type VII mice

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

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

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