Treatment with pentosan polysulphate in patients with MPS I: results from an open label, randomized, monocentric phase II study

Hennermann, Julia B.; Gökce, Seyfullah; Sólyom, Alexander; Mengel, Eugen; Schuchman, Edward H.; Simonaro, Calogera M.

doi:10.1007/s10545-016-9974-5

Cited by 40 publications

(42 citation statements)

References 19 publications

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“…Many other compounds (e.g. the antiinflammatory drug pentosan polysulfate for treating mucopolysaccharidoses, or arimoclomol, a small‐molecule inducer of the heat shock protein for NPC) have been developed and will be or are already applied in clinical trials. Based on positive effects in animal models, cyclodextrin, a cyclic oligosaccharide, was used as an experimental drug in patients with NPC, although its mechanism of action is not yet fully understood.…”

Section: Other Novel Therapiesmentioning

confidence: 99%

Treatment strategies for lysosomal storage disorders

Beck

2017

Develop Med Child Neuro

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Over the past several years the number of treatments available for patients with lysosomal storage disorders has rapidly increased. Haematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction, and chaperone therapies are currently available, and gene therapies and other treatments are rapidly advancing. Despite remarkable advances, the efficacy of most of these therapies is limited, particularly because the treatments are usually initiated when organ damage has already occurred. To circumvent this limitation, screening in newborn infants for lysosomal storage disorders has been introduced in many countries. However, this screening is complicated by the broad clinical variability of the disorders and the fact that many individuals who will be detected as having an enzyme deficiency will develop symptoms very late or never in their life. This paper provides an overview of available therapies for lysosomal storage disorders and describes those treatments that are under development. What this paper adds For a few lysosomal storage disorders, new therapies are available or under development. These therapies include enzyme replacement therapy, small molecules, and gene therapy. The new therapies cannot cure patients, but can stabilize organ function or slow progression.

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Section: Other Novel Therapiesmentioning

confidence: 99%

Treatment strategies for lysosomal storage disorders

Beck

2017

Develop Med Child Neuro

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“…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. Furthermore, Hennermann et al demonstrated the safety of PPS in four adult MPS I patients and showed a reduction in urinary GAGs and some clinical improvements over a six month study period [57]. Each of these patients had received ERT for over one year prior to PPS and was maintained on ERT during the six-month study.…”

Section: Introductionmentioning

confidence: 99%

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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“…Immunomodulating or immunosuppressive therapies are presently applied to decrease allergic reactions . Immunomodulation has been reported in patients with Pompe disease and Gaucher's disease, with variable success, and temporary depletion of B cells (anti‐CD20) has been mostly used . However, only bone marrow transplantation in patients with mucopolysaccharidosis type I (another type of LSD) resulted in a decrease in antibody formation .…”

Section: Introductionmentioning

confidence: 99%

“…Although effective for an umber of LSDs, substantial problems and limitations are caused by the raising of antibodies upon ERT.ERT can trigger the formation of specific IgE antibodies, which may be associated with allergicr eactions ranging from mild symptomst oa naphylactics hock. [5][6][7][8][9] Moreover,E RT can result in the productiono fn eutralizing IgG antibodies that bind to the infused enzymes and might impair or even diminish the clinical effectiveness of ERT. [6] The emergence of neutralizinga nti-aGal-A antibodies in FD patients treated with agalsidase-a or agalsidase-b has been reported in severals tudies.…”

mentioning

confidence: 99%

“…[6,7] Immunomodulation has been reported in patients with Pompe disease and Gaucher's disease, with variable success, and temporary depletion of Bcells (anti-CD20) has been mostly used. [8][9][10] However, only bone marrow transplantation in patients with mucopolysaccharidosis type I( another type of LSD) resulted in ad ecrease in antibody formation. [1,2] Thus, the development of alternative treatments by identification of antibody-specific epitopes and application of peptide epitopes capable of blocking antibodies represents ar elevant clinicalgoal.…”

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confidence: 99%

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Antibody Epitope of Human α‐Galactosidase A Revealed by Affinity Mass Spectrometry: A Basis for Reversing Immunoreactivity in Enzyme Replacement Therapy of Fabry Disease

et al. 2018

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α-Galactosidase (αGal) is a lysosomal enzyme that hydrolyses the terminal α-galactosyl moiety from glycosphingolipids. Mutations in the encoding genes for αGal lead to defective or misfolded enzyme, which results in substrate accumulation and subsequent organ dysfunction. The metabolic disease caused by a deficiency of human α-galactosidase A is known as Fabry disease or Fabry-Anderson disease, and it belongs to a larger group known as lysosomal storage diseases. An effective treatment for Fabry disease has been developed by enzyme replacement therapy (ERT), which involves infusions of purified recombinant enzyme in order to increase enzyme levels and decrease the amounts of accumulated substrate. However, immunoreactivity and IgG antibody formation are major, therapy-limiting, and eventually life-threatening complications of ERT. The present study focused on the epitope determination of human α-galactosidase A against its antibody formed. Here we report the identification of the epitope of human αGal(309-332) recognized by a human monoclonal anti-αGal antibody, using a combination of proteolytic excision of the immobilized immune complex and surface plasmon resonance biosensing mass spectrometry. The epitope peptide, αGal(309-332), was synthesized by solid-phase peptide synthesis. Determination of its affinity by surface plasmon resonance analysis revealed a high binding affinity for the antibody (K =39×10 m), which is nearly identical to that of the full-length enzyme (K =16×10 m). The proteolytic excision affinity mass spectrometry method is shown here to be an efficient tool for epitope identification of an immunogenic lysosomal enzyme. Because the full-length αGal and the antibody epitope showed similar binding affinities, this provides a basis for reversing immunogenicity upon ERT by: 1) treatment of patients with the epitope peptide to neutralize antibodies, or 2) removal of antibodies by apheresis, and thus significantly improving the response to ERT.

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Treatment with pentosan polysulphate in patients with MPS I: results from an open label, randomized, monocentric phase II study

Cited by 40 publications

References 19 publications

Treatment strategies for lysosomal storage disorders

Treatment strategies for lysosomal storage disorders

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

Antibody Epitope of Human α‐Galactosidase A Revealed by Affinity Mass Spectrometry: A Basis for Reversing Immunoreactivity in Enzyme Replacement Therapy of Fabry Disease

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