Enzyme replacement therapy in a feline model of Maroteaux-Lamy syndrome.

Crawley, Allison C.; Brooks, Doug A.; Muller, Vivienne; Petersen, Birgit A.; Isaac, Elizabeth; Bielicki, Julie; King, Barbara; Boulter, Christine D.; Moore, Abby; Fazzalari, N.L.; Anson, Donald S.; Byers, Sharon; Hopwood, John J.

doi:10.1172/jci118617

Cited by 126 publications

(100 citation statements)

References 35 publications

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“…Biochemical, histological, and clinical analysis of these cats suggests that the entire range of MPS VI phenotypes from severe to mild are clustered within a narrow range of residual 4S activity in cultured skin fibroblasts from 0.5% to 4.6% of normal levels. L476P homozygous cats, which display a clinically severe MPS VI phenotype, contain very low levels of 4S activity in cultured skin fibroblasts (Table I), excrete substantially elevated levels of DS in their urine, show extensive lysosomal vacuolation in a large number of tissues including chondrocytes, and display severe degenerative joint disease (5,8). Despite the presence of residual 4S activity (approximately 3.1% of normal 4S activity levels in cultured skin fibroblasts, Table I), adult D520N/L476P compound heterozygous cats contain marginally elevated levels of DS in their urine and increased lysosomal vacuolation in most chondrocytes, which is associated with variable degrees of degenerative joint disease.…”

Section: Discussionmentioning

confidence: 99%

“…The intravenous administration of recombinant human 4S (rh4S) to severely affected MPS VI cats has been shown to dramatically reduce disease progression in a dose-dependent manner (6, 7). However, three cats placed on enzyme replacement therapy dis-played significant antibody titers to the human enzyme, which may have reduced the availability and subsequent efficacy of 4S (8,9). When using animal models to evaluate therapy protocols, it may be advantageous to use species-specific material in an attempt to avoid the complication of immunological responses to foreign proteins.…”

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Mild Feline Mucopolysaccharidosis Type VI

Yogalingam

Hopwood

Crawley

et al. 1998

Journal of Biological Chemistry

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The missense mutation, L476P, in the N-acetylgalactosamine 4-sulfatase (4S) gene, has previously been shown to be associated with a severe feline mucopolysaccharidosis type VI (MPS VI) phenotype. The present study describes a second mutation, D520N, in the same MPS VI cat colony, which is inherited independently of L476P and is associated with a clinically mild MPS VI phenotype in D520N/L476P compound heterozygous cats. Biochemical and clinical assessment of L476P homozygous, D520N/L476P compound heterozygous, and D520N homozygous cats demonstrated that the entire range of clinical phenotypes, from severe MPS VI, to mild MPS VI, to normal are clustered within a narrow range of residual 4S activity from 0.5% to 4.6% of normal levels. When overexpressed in CHO-KI cells, the secreted form of D520N 4S was inactivated in neutral pH conditions. In addition, intracellular D520N 4S protein was rapidly degraded and corresponded to 37%, 14.5%, and 0.67% of normal 4S protein levels in the microsomal, endosomal, and lysosomal compartments, respectively. However, the specific activity of lysosomal D520N 4S was elevated 22.5-fold when compared with wild-type 4S. These results suggest that the D520N mutation causes a rapid degradation of 4S protein. The effect of this is partially ameliorated as a result of a significant elevation in the specific activity of mutant D520N 4S reaching the lysosomal compartment. The mucopolysaccharidoses (MPS)1 are a group of lysosomal storage disorders that involve the deficiency of specific enzymes required for the degradation of glycosaminoglycans (GAG). MPS VI is characterized by a deficiency of N-acetylgalactosamine 4-sulfatase (4S), which leads to the lysosomal accumulation and urinary excretion of the GAG dermatan sulfate (DS) (1). The severe MPS VI phenotype is characterized by growth retardation, coarse facial features, joint stiffness, corneal clouding, skeletal deformities, and organ and soft tissue involvement. As a result of DS storage in the heart valve and lung, the normal function of these organs is often compromised, leading to early death in affected individuals. The central nervous system does not appear to be affected, even in individuals with clinically severe MPS VI (2).Patients with MPS VI are diagnosed by elevated levels of DS in their urine and a substantial reduction or lack of 4S activity in cells such as peripheral blood leukocytes and cultured skin fibroblasts. The clinical phenotype of MPS VI patients ranges from severe to relatively mild and has generally been shown to correlate with urinary DS and residual 4S activity levels (2). Generally, patients manifest symptomology associated with MPS VI when their 4S protein and activity levels are 5% or less of normal controls (3).Currently, there is no safe and effective treatment available for MPS patients other than surgical intervention to alleviate symptoms whenever possible. MPS VI is a good candidate for both enzyme and gene replacement therapy protocols for a number of reasons. First, the complication of targeting r...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Mild Feline Mucopolysaccharidosis Type VI

Yogalingam

Hopwood

Crawley

et al. 1998

Journal of Biological Chemistry

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“…Enzyme replacement therapy (ERT) has proven effective in preventing or reversing lysosomal storage in patients and animal models with several lysosomal storage diseases (LSDs) [22][23][24][25][26][27][28]. Tremendous progress in the development of ERT has been made in the last three decades.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of drug delivery to bone: Characterization of human tissue-nonspecific alkaline phosphatase tagged with an acidic oligopeptide

Nishioka

Tomatsu

Gutiérrez

et al. 2006

Molecular Genetics and Metabolism

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Hypophosphatasia is caused by deficiency of activity of the tissue-nonspecific alkaline phosphatase (TNSALP), resulting in a defect of bone mineralization. Enzyme replacement therapy (ERT) with partially purified plasma enzyme was attempted but with little clinical improvement. Attaining clinical effectiveness with ERT for hypophosphatasia may require delivering functional TNSALP enzyme to bone. We tagged the C-terminal-anchorless TNSALP enzyme with an acidic oligopeptide (a six or eight residue stretch of L-Asp), and compared the biochemical properties of the purified tagged and untagged enzymes derived from Chinese hamster ovary cell lines. The specific activities of the purified enzymes tagged with the acidic oligopeptide were the same as the untagged enzyme. In vitro affinity experiments showed the tagged enzymes had 30-fold higher affinity for hydroxyapatite than the untagged enzyme. Lectin affinity chromatography for carbohydrate structure showed little difference among the three enzymes. Biodistribution pattern from single infusion of the fluorescence-labeled enzymes into mice showed delayed clearance from the plasma up to 18h post infusion and the amount of tagged enzyme retained in bone was 4-fold greater than that of the untagged enzyme. In vitro mineralization assays with the bone marrow from a hypophosphatasia patient using each of the three enzymes in the presence of high concentrations of pyrophosphate provided evidence of bone mineralization. These results show the anchorless enzymes tagged with an acidic oligopeptide are delivered efficiently to bone and function bioactively in bone mineralization, at least in vitro. They suggest potential advantages for use of these tagged enzymes in ERT for hypophosphatasia, which should be explored.

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“…ERT has been approved for human use in the lysosomal storage disorders Gaucher disease, Fabry disease, and MPS I. [11][12][13][14] Application of ERT with recombinant human ASB (rhASB) in a feline model for MPS VI disease demonstrated clearance of GAG from storage organs and improved joint mobility in juvenile affected cats 15 and in prevention or slowing of skeletal dysplasia in affected cats that were treated from birth. 16,17 These studies supported investigation of ERT in humans in a phase 1/2 randomized, double-blind, 2-dose (0.2 and 1 mg/kg) study in 6 patients with varying severity of MPS VI.…”

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confidence: 99%