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Molecular Therapy. Methods & Clinical... Jun 2023Mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by dysfunction of α-L-iduronidase (IDUA), is characterized by the deposition of dermatan sulfate...
Mucopolysaccharidosis I (MPS I), a lysosomal storage disease caused by dysfunction of α-L-iduronidase (IDUA), is characterized by the deposition of dermatan sulfate (DS) and heparan sulfate (HS) throughout the body, which causes several somatic and central nervous symptoms. Although enzyme-replacement therapy (ERT) is currently available to treat MPS I, it does not alleviate central nervous disorders, as it cannot penetrate the blood-brain barrier. Here we evaluate the brain delivery, efficacy, and safety of JR-171, a fusion protein comprising humanized anti-human transferrin receptor antibody Fab and IDUA, using monkeys and MPS I mice. Intravenously administered JR-171 was distributed in major organs, including the brain, and reduced DS and HS concentrations in the central nervous system and peripheral tissues. JR-171 exerted similar effects on peripheral disorders similar to conventional ERT and further reversed brain pathology in MPS I mice. We found that JR-171 improved spatial learning ability, which was seen to deteriorate in the vehicle-treated mice. Further, no safety concerns were noted in repeat-dose toxicity studies in monkeys. This study provides nonclinical evidence that JR-171 might potentially prevent and even improve disease conditions in patients with neuronopathic MPS I without serious safety concerns.
PubMed: 37251981
DOI: 10.1016/j.omtm.2023.05.010 -
Pediatrics International : Official... Feb 2016Carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase-1 (CHST14/D4ST1) deficiency represents a specific form of Ehlers-Danlos syndrome (EDS) caused by recessive... (Review)
Review
Carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase-1 (CHST14/D4ST1) deficiency represents a specific form of Ehlers-Danlos syndrome (EDS) caused by recessive loss-of-function mutations in CHST14. The disorder has been independently termed "adducted thumb-clubfoot syndrome", "EDS, Kosho type", and "EDS, musculocontractural type". To date, 31 affected patients from 21 families have been described. Clinically, CHST14/D4ST1 deficiency is characterized by multiple congenital malformations (craniofacial features including large fontanelle, hypertelorism, short and downslanting palpebral fissures, blue sclerae, short nose with hypoplastic columella, low-set and rotated ears, high palate, long philtrum, thin upper lip vermilion, small mouth, and micro-retrognathia; multiple congenital contractures including adduction-flexion contractures and talipes equinovarus as well as other visceral or ophthalmological malformations) and progressive multisystem fragility-related complications (skin hyperextensibility, bruisability, and fragility with atrophic scars; recurrent dislocations; progressive talipes or spinal deformities; pneumothorax or pneumohemothorax; large subcutaneous hematomas; and diverticular perforation). Etiologically, multisystem fragility is presumably caused by impaired assembly of collagen fibrils resulting from loss of dermatan sulfate (DS) in the decorin glycosaminoglycan side chain that promotes electrostatic binding between collagen fibrils. This is the first reported human disorder that specifically affects biosynthesis of DS. Its clinical characteristics indicate that CHST14/D4ST1 and, more fundamentally, DS, play a critical role in fetal development and maintenance of connective tissues in multiple organs. Considering that patients with CHST14/D4ST1 deficiency develop progressive multisystem fragility-related manifestations, establishment of a comprehensive and detailed natural history and health-care guidelines as well as further elucidation of the pathophysiology in view of future etiology-based therapy are crucial.
Topics: Adolescent; Animals; Child; Child, Preschool; Dermatan Sulfate; Ehlers-Danlos Syndrome; Female; Humans; Infant; Male; Mutation; Sulfotransferases; Young Adult
PubMed: 26646600
DOI: 10.1111/ped.12878 -
International Journal of Molecular... Jul 2022The crucial roles of dermatan sulfate (DS) have been demonstrated in tissue development of the cutis, blood vessels, and bone through construction of the extracellular... (Review)
Review
The crucial roles of dermatan sulfate (DS) have been demonstrated in tissue development of the cutis, blood vessels, and bone through construction of the extracellular matrix and cell signaling. Although DS classically exerts physiological functions via interaction with collagens, growth factors, and heparin cofactor-II, new functions have been revealed through analyses of human genetic disorders as well as of knockout mice with loss of DS-synthesizing enzymes. Mutations in human genes encoding the epimerase and sulfotransferase responsible for the biosynthesis of DS chains cause connective tissue disorders including spondylodysplastic type Ehlers-Danlos syndrome, characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. DS-deficient mice show perinatal lethality, skin fragility, vascular abnormalities, thoracic kyphosis, myopathy-related phenotypes, acceleration of nerve regeneration, and impairments in self-renewal and proliferation of neural stem cells. These findings suggest that DS is essential for tissue development in addition to the assembly of collagen fibrils in the skin, and that DS-deficient knockout mice can be utilized as models of human genetic disorders that involve impairment of DS biosynthesis. This review highlights a novel role of DS in tissue development studies from the past decade.
Topics: Animals; Collagen; Dermatan Sulfate; Ehlers-Danlos Syndrome; Female; Glycosaminoglycans; Mice; Mice, Knockout; Pregnancy; Sulfotransferases
PubMed: 35806490
DOI: 10.3390/ijms23137485 -
Current Opinion in Structural Biology Oct 2015Recent functional studies on chondroitin sulfate-dermatan sulfate (CS-DS) demonstrated its indispensable roles in various biological events including brain development... (Review)
Review
Recent functional studies on chondroitin sulfate-dermatan sulfate (CS-DS) demonstrated its indispensable roles in various biological events including brain development and cancer. CS-DS proteoglycans exert their physiological activity through interactions with specific proteins including growth factors, cell surface receptors, and matrix proteins. The characterization of these interactions is essential for regulating the biological functions of CS-DS proteoglycans. Although amino acid sequences on the bioactive proteins required for these interactions have already been elucidated, the specific saccharide sequences involved in the binding of CS-DS to target proteins have not yet been sufficiently identified. In this review, recent findings are described on the interaction between CS-DS and some proteins which are especially involved in the central nervous system and cancer development/metastasis.
Topics: Animals; Chondroitin Sulfates; Dermatan Sulfate; Extracellular Matrix Proteins; Humans; Intercellular Signaling Peptides and Proteins; Neoplasm Metastasis; Neoplasms; Neuronal Plasticity; Neurons; Protein Binding; Receptor for Advanced Glycation End Products; Receptors, Cell Surface; Wnt Signaling Pathway
PubMed: 26164146
DOI: 10.1016/j.sbi.2015.06.004 -
Methods in Molecular Biology (Clifton,... 2022Glycosaminoglycans (GAGs) such as heparan sulfates (HS) or chondroitin sulfates (CS) are long unbranched polymers of a disaccharide comprised of hexuronic acid and...
Glycosaminoglycans (GAGs) such as heparan sulfates (HS) or chondroitin sulfates (CS) are long unbranched polymers of a disaccharide comprised of hexuronic acid and hexosamine. Attached to a protein backbone via a characteristic tetrasaccharide, the GAG chains are non-uniformly modified by sulfations, epimerizations, and deacetylations. The resultant glycan chains contain highly modified domains, separated by sections of sparse or no modifications. These GAG domains are central to the role of glycans in binding to proteins and mediating protein-protein interactions. Since HS and CS domains are not genetically encoded, they cannot be visualized and studied with conventional methods in vivo. We describe a transgenic approach using single chain variable fragment (scFv) antibodies that bind HS or CS. By transgenically expressing fluorescently tagged scFv antibodies, we can directly visualize both HS and CS domains in live Caenorhabditis elegans revealing unprecedented cellular specificity and evolutionary conservation (Attreed et al., Nat Methods 9(5): 477-479, 2012; Attreed et al., Glycobiology 26(8): 862-870, 2016) (unpublished). The approach allows concomitant co-labeling of multiple GAG domains, the study of GAG dynamics, and could lend itself to a genetic analysis of GAG domain biosynthesis or function.
Topics: Animals; Animals, Genetically Modified; Caenorhabditis elegans; Chondroitin Sulfates; Disaccharides; Glycosaminoglycans; Heparitin Sulfate; Single-Chain Antibodies
PubMed: 34626406
DOI: 10.1007/978-1-0716-1398-6_42 -
Metabolites Aug 2014Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiency of the lysosomal enzymes essential for catabolism of glycosaminoglycans... (Review)
Review
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiency of the lysosomal enzymes essential for catabolism of glycosaminoglycans (GAGs). Accumulation of undegraded GAGs results in dysfunction of multiple organs, resulting in distinct clinical manifestations. A range of methods have been developed to measure specific GAGs in various human samples to investigate diagnosis, prognosis, pathogenesis, GAG interaction with other molecules, and monitoring therapeutic efficacy. We established ELISA, liquid chromatography tandem mass spectrometry (LC-MS/MS), and an automated high-throughput mass spectrometry (HT-MS/MS) system (RapidFire) to identify epitopes (ELISA) or disaccharides (MS/MS) derived from different GAGs (dermatan sulfate, heparan sulfate, keratan sulfate, and/or chondroitin sulfate). These methods have a high sensitivity and specificity in GAG analysis, applicable to the analysis of blood, urine, tissues, and cells. ELISA is feasible, sensitive, and reproducible with the standard equipment. HT-MS/MS yields higher throughput than conventional LC-MS/MS-based methods while the HT-MS/MS system does not have a chromatographic step and cannot distinguish GAGs with identical molecular weights, leading to a limitation of measurements for some specific GAGs. Here we review the advantages and disadvantages of these methods for measuring GAG levels in biological specimens. We also describe an unexpected secondary elevation of keratan sulfate in patients with MPS that is an indirect consequence of disruption of catabolism of other GAGs.
PubMed: 25116756
DOI: 10.3390/metabo4030655 -
Genes Feb 2023Dermatan sulfate (DS) and its proteoglycans are essential for the assembly of the extracellular matrix and cell signaling. Various transporters and biosynthetic enzymes... (Review)
Review
Dermatan sulfate (DS) and its proteoglycans are essential for the assembly of the extracellular matrix and cell signaling. Various transporters and biosynthetic enzymes for nucleotide sugars, glycosyltransferases, epimerase, and sulfotransferases, are involved in the biosynthesis of DS. Among these enzymes, dermatan sulfate epimerase (DSE) and dermatan 4--sulfotranserase (D4ST) are rate-limiting factors of DS biosynthesis. Pathogenic variants in human genes encoding DSE and D4ST cause the musculocontractural type of Ehlers-Danlos syndrome, characterized by tissue fragility, joint hypermobility, and skin hyperextensibility. DS-deficient mice exhibit perinatal lethality, myopathy-related phenotypes, thoracic kyphosis, vascular abnormalities, and skin fragility. These findings indicate that DS is essential for tissue development as well as homeostasis. This review focuses on the histories of DSE as well as D4ST, and their knockout mice as well as human congenital disorders.
Topics: Pregnancy; Female; Humans; Animals; Mice; Dermatan Sulfate; Ehlers-Danlos Syndrome; Phenotype; Sulfotransferases; Racemases and Epimerases
PubMed: 36833436
DOI: 10.3390/genes14020509 -
Carbohydrate Polymers Jun 2021Crude anionic polysaccharides extracted from the Pacific starfish Lysastrosoma anthosticta were separated by anion-exchange chromatography into fractions LA-F1 and...
Crude anionic polysaccharides extracted from the Pacific starfish Lysastrosoma anthosticta were separated by anion-exchange chromatography into fractions LA-F1 and LA-F2. The main fraction LA-F1 was solvolytically desulfated giving rise to preparation LA-F1-DS with a structure of dermatan core [→3)-β-d-GalNAc-(1→4)-α-l-IdoA-(1→]. Reduction of LA-F1 afforded preparation LA-F1-RED composed mainly of the repeating disaccharide units →3)-β-d-GalNAc4R-(1→4)-α-l-Ido2S3S-(1→, where R was SO- or H. Analysis of the NMR spectra of the parent fraction LA-F1 led to determine the main component as the oversulfated dermatan sulfate LA-Derm bearing sulfate groups at O-2 and O-3 of α-l-iduronic acid, as well as at O-4 of some N-acetyl-d-galactosamine residues. The minor fraction LA-F2 contained a mixture of LA-Derm and heparinoid LA-Hep, the latter being composed of the fragments →4)-α-d-GlcNS3S6S-(1→4)-α-l-IdoA2S3S-(1→ and →4)-α-d-GlcNS3S-(1→4)-α-l-IdoA2S3S-(1→. The presence of 2,3-di-O-sulfated iduronic acid residues is very unusual both for natural dermatan sulfate and heparinoid. Preparations LA-F1, LA-F2 and LA-F1-RED demonstrated significant anticoagulant effect in vitro.
Topics: Animals; Anticoagulants; Blood Coagulation; Carbohydrate Sequence; Dermatan Sulfate; Heparinoids; Molecular Structure; Partial Thromboplastin Time; Polysaccharides; Starfish; Sulfates
PubMed: 33766355
DOI: 10.1016/j.carbpol.2021.117867 -
Marine Drugs Dec 2023Glycosaminoglycans (GAGs) with unique structures from marine animals show intriguing pharmacological activities and negligible biological risks, providing more options...
Glycosaminoglycans (GAGs) with unique structures from marine animals show intriguing pharmacological activities and negligible biological risks, providing more options for us to explore safer agents. The swim bladder is a tonic food and folk medicine, and its GAGs show good anticoagulant activity. In this study, two GAGs, CMG-1.0 and GMG-1.0, were extracted and isolated from the swim bladder of and . The physicochemical properties, precise structural characteristics, and anticoagulant activities of these GAGs were determined for the first time. The analysis results of the CMG-1.0 and GMG-1.0 showed that they were chondroitin sulfate (CS)/dermatan sulfate (DS) hybrid chains with molecular weights of 109.3 kDa and 123.1 kDa, respectively. They were mainly composed of the repeating disaccharide unit of -{IdoA-α1,3-GalNAc-β1,4-}- (DS-A). The DS-B disaccharide unit of -{IdoA-α1,3-GalNAc-β1,4-}- also existed in both CMG-1.0 and GMG-1.0. CMG-1.0 had a higher proportion of CS-O disaccharide unit -{-GlcA-β1,3-GalNAc-β1,4-}- but a lower proportion of CS-E disaccharide unit -{-GlcA-β1,3-GalNAc-β1,4-}- than GMG-1.0. The disaccharide compositions of the GAGs varied in a species-specific manner. Anticoagulant activity assay revealed that both CMG-1.0 and GMG-1.0 had potent anticoagulant activity, which can significantly prolong activated partial thromboplastin time. GMG-1.0 also can prolong the thrombin time. CMG-1.0 showed no intrinsic tenase inhibition activity, while GMG-1.0 can obviously inhibit intrinsic tenase with EC of 58 nM. Their significantly different anticoagulant activities may be due to their different disaccharide structural units and proportions. These findings suggested that swim bladder by-products of fish processing of these two marine organisms may be used as a source of anticoagulants.
Topics: Animals; Chondroitin Sulfates; Dermatan Sulfate; Urinary Bladder; Glycosaminoglycans; Anticoagulants; Disaccharides
PubMed: 38276647
DOI: 10.3390/md22010009