Overcoming the blood-brain barrier with high-dose enzyme replacement therapy in murine mucopolysaccharidosis VII

Vogler, Carole; Levy, Beth; Grubb, Jeffrey H.; Galvin, Nancy; Tan, Yun Long; Kakkis, Emil; Pavloff, Nadine; Sly, William S.

doi:10.1073/pnas.0506892102

Cited by 157 publications

(130 citation statements)

References 35 publications

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“…This is in agreement with our previous studies16 showing that high enzyme doses are necessary to get sufficient amounts of enzyme into the CNS leading to a substantial reduction of brain storage when applied short term, suggesting a dose‐dependent uptake of the recombinant enzyme into the brain. Our studies are in agreement with other preclinical ERT studies in LSD animal models showing mostly beneficial effects of high‐dose injections of recombinant enzymes on primary lysosomal storage reduction and improvement of secondary pathological alterations such as neuroinflammation and behavioral deficits 29, 30, 31, 32, 33. Of note, in our preclinical study, the beneficial effect of ERT was most prominent for the 500 U/kg dosage but still significant at 125 U/kg for most of the parameters analyzed, suggesting that chronic treatment can at least to some extent compensate for lower enzyme activity.…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Damme

Lüdemann

Rothaug

et al. 2015

Ann Clin Transl Neurol

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“…Novel potential therapy for mucopolysaccharidoses E Piotrowska et al demonstrated recently that using very high doses of recombinant human b-glucuronidase, it is possible to deliver small amounts of the enzyme to brains of MPS VII mice; 28 however, it is not clear whether this partial overcoming of the blood -brain barrier might be sufficient to cause significant therapeutic effects in mice. Even if so, one might easily imagine various problems (both medical and economical) with provision of very high amounts of the enzyme to human patients suffering from MPS VII and other MPS types.…”

Section: Discussionmentioning

confidence: 99%

Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses

et al. 2006

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Mucopolysaccharidoses (MPS) are inherited, severe, progressive, metabolic disorders caused by deficiencies in different enzymes involved in degradation of glycosaminoglycans (GAGs). Although enzyme replacement therapy (ERT) has recently been available for MPS type I, and clinical trials have been performed in ERT for MPS II and MPS VI, there is little chance that this kind of treatment may be effective for neurodegenerative forms of MPS (due to inefficient delivery of enzymes to central nervous system through the blood -brain barrier), hence currently there is no effective therapy available for them. Therefore, we aim to develop an alternative therapy for these diseases. We found that genistein (4 0 ,5, 7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) inhibits synthesis of GAGs considerably in cultures of fibroblasts of MPS patients (types I, II, IIIA and IIIB were tested). Prolonged cultivation of these cells in the presence of genistein resulted in reduction of GAG accumulation and normalization of cells as estimated by biochemical tests and electron microscopic analysis, respectively. As genistein inhibits kinase activity of epidermal growth factor receptor, which is required for full expression of genes coding for enzymes involved in GAG production, we propose to consider a substrate reduction therapy for MPS, which is referred to as 'gene expression-targeted isoflavone therapy'.

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“…Recombinant phosphorylated hGUS (P-GUS) was produced in CHO cells, and enzyme secreted into conditioned medium was collected and purified as described (18). This enzyme contains showed no enzyme activity in kidney.…”

Section: Methodsmentioning

confidence: 99%

“…Seven days after the last infusion, mice were killed, tissues for GUS assay were frozen in liquid nitrogen, and the samples were processed for histochemical analysis for GUS activity and histological analysis of lysosomal storage (6,18).…”

Section: Methodsmentioning

confidence: 99%

“…Using a high enough dose of recombinant enzyme might be a nontoxic way to saturate the MR clearance system and enhance MPR-mediated enzyme delivery. Favorable effects in overcoming the blood-brain barrier to ERT in certain parts of the CNS with high doses of infused GUS may have been partially attributable to saturation of the MR clearance system (18)(19)(20)(21).…”

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

confidence: 99%

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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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Overcoming the blood-brain barrier with high-dose enzyme replacement therapy in murine mucopolysaccharidosis VII

Cited by 157 publications

References 35 publications

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses

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

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