A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA

Jones, Simon A.; Breen, Catherine; Heap, Fiona; Rust, Stewart; Ruijter, Jessica de; Tump, Evelien; Marchal, Jan Pieter; Pan, Luying; Qiu, Yongchang; Chung, Jou-Ku; Nair, Nitin; Haslett, Patrick; Barbier, Ann; Wijburg, Frits A.

doi:10.1016/j.ymgme.2016.05.006

Cited by 90 publications

(56 citation statements)

References 13 publications

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“…There are very few reports of CSF GAG evaluation in patients afflicted with a mucopolysaccharidosis diagnosis282930, and we believe this is the first study to evaluate non-reduced ends (NREs) and HS levels in the CSF of MPS-IH patients. Clinical trials investigating the use of anti-inflammatory agents are being developed in MPS-I and other MPS subtypes for the purpose of ameliorating joint and bone disease25.…”

Section: Discussionmentioning

confidence: 99%

Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H

Raymond

Pasquali

Polgreen

et al. 2016

Sci Rep

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Mucopolysaccharidosis (MPS) type-IH is a lysosomal storage disease that results from mutations in the IDUA gene causing the accumulation of glycosaminoglycans (GAGs). Historically, children with the severe phenotype, MPS-IH (Hurler syndrome) develop progressive neurodegeneration with death in the first decade due to cardio-pulmonary complications. New data suggest that inflammation may play a role in MPS pathophysiology. To date there is almost no information on the pathophysiologic changes within the cerebral spinal fluid (CSF) of these patients. We evaluated the CSF of 25 consecutive patients with MPS-IH. While CSF glucose and total protein were within the normal range, we found a significantly mean elevated CSF opening pressure at 24 cm H2O (range 14–37 cm H2O). We observed a 3-fold elevation in CSF heparan sulfate and a 3–8 fold increase in MPS-IH specific non-reducing ends, I0S0 and I0S6. Cytokine analyses in CSF of children with MPS-IH showed significantly elevated inflammatory markers including: MCP-1 SDF-1a, IL-Ra, MIP-1b, IL-8, and VEGF in comparison to unaffected children. This is the largest report of CSF characteristics in children with MPS-IH. Identification of key biomarkers may provide further insight into the inflammatory-mediated mechanisms related to MPS diseases and perhaps lead to improved targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H

Raymond

Pasquali

Polgreen

et al. 2016

Sci Rep

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“…Haematopoietic stem cell transplantation (HSCT) is not effective in MPS III [35, 36], even when performed before the onset of neurological manifestations [37]. Numerous treatment approaches are under investigation in animal models and humans, including CNS-directed ERT [38–41]; substrate reduction therapy (SRT) [42, 43] and gene therapy [44–53], with several progressing to clinical trial [38, 51, 54–56] (Table 1). …”

Section: Introductionmentioning

confidence: 99%

“…Numerous treatment approaches are under investigation in animal models and humans, including CNS-directed ERT [38–41]; substrate reduction therapy (SRT) [42, 43] and gene therapy [44–53], with several progressing to clinical trial [38, 51, 54–56] (Table 1). …”

Section: Introductionmentioning

confidence: 99%

Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III

Ghosh

Shapiro

Rust

et al. 2017

Orphanet J Rare Dis

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BackgroundMucopolysaccharidosis type III is a progressive, neurodegenerative lysosomal storage disorder for which there is currently no effective therapy. Though numerous potential therapies are in development, there are several challenges to conducting clinical research in this area. We seek to make recommendations on the approach to clinical research in MPS III, including the selection of outcome measures and trial endpoints, in order to improve the quality and impact of research in this area.ResultsAn international workshop involving academic researchers, clinical experts and industry groups was held in June 2015, with presentations and discussions on disease pathophysiology, biomarkers, potential therapies and clinical outcome measures. A set of recommendations was subsequently prepared by a working group and reviewed by all delegates. We present a series of 11 recommendations regarding the conduct of clinical research, outcome measures and management of natural history data in Mucopolysaccharidosis type III.ConclusionsImproving the quality of clinical research in Mucopolysaccharidosis type III will require an open, collaborative and systematic approach between academic researchers, clinicians and industry. Natural history data should be published as soon as possible and ideally collated in a central repository. There should be agreement on outcome measures and instruments for evaluation of clinical outcomes to maximise the effectiveness of current and future clinical research.

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“…Crawley et al 2011;M a r s h a l le ta l2015). This strategy has undergone investigational evaluation in MPS IIIA patients (Jones et al 2016). The treatment has also been explored in other LSD models, progressing to human clinical trial in MPS I (Kakkis et al 2004;reviewed in Dickson and Chen 2011]; NCT#00852358), MPS II (Calias et al 2012;NCT#00920647;#01506141), Batten's disease (Chang et al 2008;NCT#01907087) and metachromatic leukodystrophy patients (Stroobants et al 2011;NCT#01510028;NCT#01887938).…”

Section: Introductionmentioning

confidence: 99%

Slow, continuous enzyme replacement via spinal CSF in dogs with the paediatric‐onset neurodegenerative disease, MPS IIIA

King

Marshall

Hassiotis

et al. 2016

J of Inher Metab Disea

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Intra-cerebrospinal fluid (CSF) injection of recombinant human lysosomal enzyme is a potential treatment strategy for several neurodegenerative lysosomal storage disorders including Sanfilippo syndrome (Mucopolysaccharidosis type IIIA; MPS IIIA). Here we have utilised the MPS IIIA Huntaway dog model to compare the effectiveness of the repeated intermittent bolus injection strategy being used in the trials with an alternate approach; slow, continual infusion of replacement enzyme (recombinant human sulphamidase; rhSGSH) into the spinal CSF using a SynchroMed II® pump attached to a spinal infusion cannula. The ability of each enzyme delivery strategy to ameliorate lesions in MPS IIIA brain was determined in animals treated from ∼three- to six-months of age. Controls received buffer or no treatment. Significant reductions in heparan sulphate (primary substrate) were observed in brain samples from dogs treated via either cisternal or lumbar spinal CSF bolus injection methods and also in slow intra-spinal CSF infusion-treated dogs. The extent of the reduction differed regionally. Pump-delivered rhSGSH was less effective in reducing secondary substrate (G ganglioside) in deeper aspects of cerebral cortex, and although near-amelioration of microglial activation was seen in superficial (but not deep) layers of cerebral cortex in both bolus enzyme-treated groups, pump-infusion of rhSGSH had little impact on microgliosis. While continual low-dose infusion of rhSGSH into MPS IIIA dog CSF reduces disease-based lesions in brain, it was not as efficacious as repeated cisternal or spinal CSF bolus infusion of rhSGSH over the time-frame of these experiments.

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A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA

Cited by 90 publications

References 13 publications

Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H

Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H

Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III

Slow, continuous enzyme replacement via spinal CSF in dogs with the paediatric‐onset neurodegenerative disease, MPS IIIA

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