Pentosan Polysulfate Treatment of Mucopolysaccharidosis Type IIIA Mice

Mucopolysaccharidoses are lysosomal storage disorders characterised by accumulation of abnormal pathological glycosaminoglycans, cellular dysfunction and widespread inflammation, resulting in progressive cognitive and motor decline. Lysosomes are important mediators of immune cell function, and therefore accumulation of glycosaminoglycans (GAGs) and other abnormal substrates could affect immune function and directly impact on disease pathogenesis. This review summarises current knowledge with regard to inflammation in mucopolysaccharidosis, with an emphasis on the brain and outlines a potential role for GAGs in induction of inflammation. We propose a model by which the accumulation of GAGs and other factors may impact on innate immune signalling with particular focus on the Toll‐like receptor 4 pathway. Innate immunity appears to have a dominating role in mucopolysaccharidosis; however, furthering understanding of innate immune signalling would have significant impact on highlighting novel anti‐inflammatory therapeutics for use in mucopolysaccharide diseases. https://onlinelibrary.wiley.com/page/journal/14714159/homepage/virtual_issues.htm.

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“…Alternatively, it may be able to exert an effect just through reducing peripheral cytokine levels (Guo et al . ).…”

Section: Anti‐inflammatory Treatments In Mpsmentioning

confidence: 97%

The role of innate immunity in mucopolysaccharide diseases

Parker

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2018

Journal of Neurochemistry

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“…Glycosaminoglycan (GAG) storage, which induces a complex sequence of molecular changes leading to inflammation, synovial hyperplasia, and cartilage apoptosis [ 8 ], is assumed to play a major role in joint and bone pathologies in MPS diseases. Animal and human studies investigating the treatment effects of anti-inflammatory drugs such as pentosan polysulfate (PPS) on skeletal pathologies in MPS III are under investigation [ 21 ]. In addition to inflammation, many studies in various MPS animal models have reported early abnormalities of chondrocyte organization in the growth plate and architecture of cortical bone which could be a trigger for abnormal bone modeling and remodeling leading to secondary hip deformities [ 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Hip pathologies in mucopolysaccharidosis type III

et al. 2021

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Background Mucopolysaccharidosis type III (MPS III) comprises a group of rare lysosomal storage diseases. Although musculoskeletal symptoms are less pronounced than in other MPS subtypes, pathologies of hip and spine have been reported in MPS III patients. The purpose of this study was to describe hip pathologies and influencing parameters in MPS III patients. Methods A retrospective chart review was performed for 101 MPS III patients. Thirty-two patients met the inclusion criteria of enzymatically or genetically confirmed diagnosis and anteroposterior radiograph of the hips. Modified Ficat classification, Wiberg’s center-edge angle, and Reimer’s migration percentage were measured. Results The mean age at data assessment was 11.0 years (SD 5.7). Osteonecrosis of the femoral head was observed in 17/32 patients. No statistically significant association was found between these changes and age, sex, or MPS III subtype. Patients with a severe phenotype showed significantly higher rates of osteonecrosis (14/17) than patients with an intermediate phenotype. Hip dysplasia was present in 9/32 patients and was significantly associated with osteonecrosis of the femoral head (p = 0.04). Conclusions The present study demonstrates a high rate of hip pathologies in MPS III patients. Hip dysplasia and severe phenotype were significantly correlated with osteonecrosis of the femoral head. Therefore, radiographs of the hips are highly recommended in baseline and follow-up assessments of MPS III patients. Trial registration Retrospectively registered.

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“…The anti-inflammatory effects of PPS have been extensively documented, and broad anti-inflammatory effects were previously studied in three MPS animal models [52][53][54]56], and also in cells from Fabry and Gaucher disease patients treated with PPS [55]. Several cytokines related to inflammation were also measured during the current trial.…”

Section: Discussionmentioning

confidence: 99%

“…Among the various experimental therapies being studied in MPS, PPS is somewhat unique since it not only reduces GAG storage but also significantly reduces inflammatory cytokines in MPS animal models. It also appears to cross the blood-brain barrier, although this has only been studied in the context of one neurological MPS model (MPS IIIA) [56]. There is extensive clinical data in different diseases showing the safety of PPS administration in humans, and now seven MPS patients of two different types have been treated (4 MPS I and 3 MPS II) without serious, drug-related adverse events.…”

Section: Discussionmentioning

confidence: 99%

“…However, in the MPS disorders, models [52][53][54], as well as IL-1β, TNF-α, and interleukin-6 (IL-6) in in vitro models of Gaucher Disease and Fabry Disease [55]. Treatment with PPS also led to a significant reduction of GAG levels and alleviated MPS pathology in MPS I dogs [54], MPS VI rats [52,53], and MPS IIIA mice [56]. Currently, the mechanism of how PPS leads to GAG reduction in MPS is unknown, but this was observed in multiple animal model studies and in multiple tissues.…”

Section: Introductionmentioning

confidence: 99%

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Safety study of sodium pentosan polysulfate for adult patients with mucopolysaccharidosis type II

Tomatsu¹,

Orii²,

Lim³

et al. 2020

Molecular Genetics and Metabolism

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Current therapies for the mucopolysaccharidoses (MPS) do not effectively address skeletal and neurological manifestations. Pentosan polysulfate (PPS) is an alternative treatment strategy that has been shown to improve bone architecture, mobility, and neuroinflammation in MPS animals. The aims of this study were to a) primarily establish the safety of weekly PPS injections in attenuated MPS II, b) assess the efficacy of treatment on MPS pathology, and c) define appropriate clinical endpoints and biomarkers for future clinical trials. Subcutaneous injections were administered to three male Japanese patients for 12 weeks. Enzyme replacement therapy was continued in two of the patients while they received PPS and halted for two months in one patient before starting PPS. During treatment, one patient experienced an elevation of alanine transaminase, and another patient experienced convulsions; however, these incidences were non-cumulative and unrelated to PPS administration, respectively. Overall, the drug was well-tolerated in all patients, and no serious drug-related adverse events were noted. Generally, PPS treatment led to an increase in several parameters of shoulder range of motion and decrease of the inflammatory cytokines, MIF and TNF-α, which are potential clinical endpoints and biomarkers, respectively. Changes in urine and serum glycosaminoglycans were inconclusive. Overall, this study demonstrates the safety of using PPS in adults with MPS II and suggests the efficacy of PPS on MPS pathology with the identification of potential clinical endpoints and biomarkers.

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Pentosan Polysulfate Treatment of Mucopolysaccharidosis Type IIIA Mice

Cited by 16 publications

References 43 publications

The role of innate immunity in mucopolysaccharide diseases

The role of innate immunity in mucopolysaccharide diseases

Hip pathologies in mucopolysaccharidosis type III

Safety study of sodium pentosan polysulfate for adult patients with mucopolysaccharidosis type II

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