Pentosan Polysulfate: A Novel Therapy for the Mucopolysaccharidoses

Schuchman, Edward H.; Ge, Yi; Lai, Alon; Borisov, Yury; Faillace, Meghan E.; Eliyahu, Efrat; He, Xingxing; Iatridis, James C.; Vlassara, Helen; Striker, Gary E.; Simonaro, Calogera M.

doi:10.1371/journal.pone.0054459

Cited by 87 publications

(96 citation statements)

References 39 publications

(52 reference statements)

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“…Schuchman et al also reported that oral and subcutaneous administration of PPS reduced inflammation and improved skeletal pathology, bone mineral density, and mobility of joints in MPS VI rats [39,139,140]. Ghosh et al reported that PPS promotes proliferation, and chondrogenic differentiation of adult human bone marrow-derived mesenchymal precursor cells [139]. In our preliminary experiment, PPS suppressed GAG accumulation in fibroblasts of several types of MPS patients.…”

Section: Anti-inflammatory Drugssupporting

confidence: 61%

“…Successively, clinical trials of PPS in patients with knee osteoarthritis provided significant reduction in pain [138]. Schuchman et al also reported that oral and subcutaneous administration of PPS reduced inflammation and improved skeletal pathology, bone mineral density, and mobility of joints in MPS VI rats [39,139,140]. Ghosh et al reported that PPS promotes proliferation, and chondrogenic differentiation of adult human bone marrow-derived mesenchymal precursor cells [139].…”

Section: Anti-inflammatory Drugsmentioning

confidence: 99%

“…The efficacy of ERT alone and combined treatment using ERT and anti-inflammatory drug was also tested [37]. An anti-inflammatory treatment should be evaluated alone or in combined therapy with ERT, HSCT, or future gene therapy for MPSs [38,39].…”

Section: Introductionmentioning

confidence: 99%

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Therapies for the bone in mucopolysaccharidoses

Tomatsu

Barrera

Alméciga-Díaz

et al. 2015

Molecular Genetics and Metabolism

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Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis, leading to 1) stenosis of the upper cervical region, 2) restrictive small lung, 3) hip dysplasia, 4) restriction of joint movement, and 5) surgical complications. Patients often need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy through their lifetime. Current measures to intervene in bone disease progression are not perfect and palliative, and improved therapies are urgently required.Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzyme to bone, especially avascular cartilage, to prevent or ameliorate the devastating skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion, and damage since the severity of skeletal dysplasia is associated with level of activity during daily life.This review illustrates a current overview of therapies and their impact for bone lesions in MPS including ERT, HSCT, gene therapy, and anti-inflammatory drugs.

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Section: Anti-inflammatory Drugssupporting

confidence: 61%

Section: Anti-inflammatory Drugsmentioning

confidence: 99%

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Therapies for the bone in mucopolysaccharidoses

Tomatsu

Barrera

Alméciga-Díaz

et al. 2015

Molecular Genetics and Metabolism

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“…Enzyme replacement therapy (ERT) [3][4][5], hematopoietic stem cell transplantation (HSCT) [6][7][8][9], substrate reduction therapy (SRT) [10,11], gene therapy [12,13], and anti-inflammatory drugs [14,15] are in clinical use or being investigated under clinical trials for patients with some types of MPS. Initiating these treatments at birth or during early stages provides most benefits in the clinical improvement of the disease.…”

Section: Introductionmentioning

confidence: 99%

Establishment of glycosaminoglycan assays for mucopolysaccharidoses

Tomatsu

Shimada

Mason

et al. 2015

Molecular Genetics and Metabolism

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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 OPEN ACCESSMetabolites 2014, 4 656 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.

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“…Aldouronates, acidic xylooligosaccharides (U-XOS and U-AXOS, where U represents uronate) in which some xylose (X) residues are substituted with ␣-1,2-linked 4-O-methylglucuronate (MeG), have been shown to exhibit anti-inflammatory and other immunomodulating activities (5). These acidic forms comprise a portion of the pentosans that are used for the preparation of pentosan polysulfates (PPSs), which have several medical applications, including the treatment of interstitial cystitis, mucopolysaccharidoses, and osteoarthritis (6)(7)(8). The generation of different forms of XOS and AXOS or U-XOS and U-AXOS results from the depolymerization of both methylglucuronoxylans (MeGX n ) and methylglucuronoarabinoxylans (MeGAX n ), the predominant polymers comprising the hemicellulose fractions of lignocellulosics derived from most species of dicots and monocots, respectively (9,10).…”

mentioning

confidence: 99%

Engineering the Xylan Utilization System in Bacillus subtilis for Production of Acidic Xylooligosaccharides

Rhee

Sawhney

et al. 2014

Appl Environ Microbiol

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cXylans are the predominant polysaccharides in hemicelluloses and an important potential source of biofuels and chemicals. The ability of Bacillus subtilis subsp. subtilis strain 168 to utilize xylans has been ascribed to secreted glycoside hydrolase family 11 (GH11) and GH30 endoxylanases, encoded by the xynA and xynC genes, respectively. Both of these enzymes have been defined with respect to structure and function. In this study, the effects of deletion of the xynA and xynC genes, individually and in combination, were evaluated for xylan utilization and formation of acidic xylooligosaccharides. Parent strain 168 depolymerizes methylglucuronoxylans (MeGX n ), releasing the xylobiose and xylotriose utilized for growth and accumulating the aldouronate methylglucuronoxylotriose (MeGX 3 ) with some methylglucuronoxylotetraose (MeGX 4 ). The combined GH11 and GH30 activities process the products generated by their respective actions on MeGX n to release a maximal amount of neutral xylooligosaccharides for assimilation and growth, at the same time forming MeGX 3 in which the internal xylose is substituted with methylglucuronate (MeG). Deletion of xynA results in the accumulation of ␤-1,4-xylooligosaccharides with degrees of polymerization ranging from 4 to 18 and an average degree of substitution of 1 in 7.2, each with a single MeG linked ␣-1,2 to the xylose penultimate to the xylose at the reducing terminus. Deletion of the xynC gene results in the accumulation of aldouronates comprised of 4 or more xylose residues in which the MeG may be linked ␣-1,2 to the xylose penultimate to the nonreducing xylose. These B. subtilis lines may be used for the production of acidic xylooligosaccharides with applications in human and veterinary medicine.

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Pentosan Polysulfate: A Novel Therapy for the Mucopolysaccharidoses

Cited by 87 publications

References 39 publications

Therapies for the bone in mucopolysaccharidoses

Therapies for the bone in mucopolysaccharidoses

Establishment of glycosaminoglycan assays for mucopolysaccharidoses

Engineering the Xylan Utilization System in Bacillus subtilis for Production of Acidic Xylooligosaccharides

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