Advertisement

pp 1-16 | Cite as

Pentosan Polysulfate Treatment of Mucopolysaccharidosis Type IIIA Mice

  • Ningning Guo
  • Victor DeAngelis
  • Changzhi Zhu
  • Edward H. Schuchman
  • Calogera M. Simonaro
Research Report
Part of the JIMD Reports book series

Abstract

Overall Goal: This study was designed to evaluate the impact of pentosan polysulfate (PPS) treatment on mice with mucopolysaccharidosis (MPS) type IIIA (Sanfilippo A syndrome; OMIM 252900).

Protocol: Three groups of MPS IIIA mice were evaluated: 1-week-old mice treated with subcutaneous (subQ) PPS at 25 mg/kg once weekly for 31 weeks (group 1); 5-month-old mice treated with subQ PPS once weekly at 50 mg/kg for 12 weeks (group 2); and 5-week-old mice treated by continual intracerebroventricular (ICV) PPS infusion for 11 weeks (60 μg/kg/day). Treated MPS IIIA mice and controls were assessed by measuring plasma cytokine levels, histologic analyses of systemic organs, and analyses of various neuroinflammatory, neurodegenerative, and lysosomal disease markers in their brains. Neurobehavioral testing also was carried out.

Results: As seen in other MPS animal models, subQ PPS treatment reduced plasma cytokine levels and macrophage infiltration in systemic tissues. ICV administration did not elicit these systemic effects. SubQ PPS administration also significantly impacted brain neuropathology, inflammation, and behavior. The effect of early subQ treatment was more significant than dose. Surprisingly, ICV PPS treatment had intermediate effects on most of these brain markers, perhaps due to the limited dose and/or duration of treatment. Consistent with these neuropathological findings, we also observed significant improvements in the hyperactivity/anxiety and learning behaviors of the MPS IIIA mice treated with early subQ PPS.

Keywords

Central nervous system Mucopolysaccharidosis type IIIA Neuroinflammation Pentosan polysulfate 

Abbreviations

BBB

Blood brain barrier

BSA

Bovine serum albumin

CNS

Central nervous system

CSF

Cerebral spinal fluid

DAB

Diaminobenzidine

ELISA

Enzyme-linked immunosorbent assays

GAG

Glycosaminoglycan

GCS-F

Granulocyte colony stimulating factor

GFAP

Glial fibrillary acidic protein

GM3

Monosialodihexosylganglioside

HS

Heparan sulfate

HSCT

Hematopoietic stem cell transplantation

ICV

Intracerebroventricular

IL1α

Interleukin-1 alpha

IL-B4

Isolectin B4

kg

Kilogram

Limp-2

Lysosomal integral membrane protein-2

LSD

Lysosomal storage disorder

MCP-1

Monocyte chemoattractant protein-1

mg

Milligram

MIP-1α

Macrophage inflammatory protein-1 alpha

MPS

Mucopolysaccharidosis

PBS

Phosphate buffered saline

PPS

Pentosan polysulfate

subQ

Subcutaneous

Notes

Acknowledgements

The research was funded by the Stop Sanfilippo Foundation.

Supplementary material

8904_2018_96_MOESM1_ESM.pptx (33 kb)
Supplementary Fig. 1 Semi-quantitative assessment of storage vacuoles in the livers, spleens, and kidneys of MPS IIIA mice treated by subQ PPS. Scoring was performed by three independent laboratory technicians who were blinded to the treatment groups. The scoring system is described in the Materials and Methods. At least three slides were scored per tissue per mouse. *p = <0.001 compared treated to age-matched untreated mice (PPTX 34 kb)
8904_2018_96_MOESM2_ESM.pptx (35 kb)
Supplementary Fig. 2 Total GAG analysis of liver, spleen, and kidney extracts of MPS IIIA mice treated by subQ PPS. Total GAGs were determined by the Blyscan method using tissue extracts prepared from each mouse. n = 10 per group (PPTX 36 kb)

References

  1. Archer LD, Langford-Smith KJ, Bigger BW, Fildes JE (2014) Mucopolysaccharide diseases: a complex interplay between neuroinflammation, microglial activation and adaptive immunity. J Inherit Metab Dis 37(1):1–12.  https://doi.org/10.1007/s10545-013-9613-3CrossRefGoogle Scholar
  2. Beard H, Hassiotis S, Gai WP, Parkinson-Lawrence E, Hopwood JJ, Hemsley KM (2017) Axonal dystrophy in the brain of mice with Sanfilippo syndrome. Exp Neurol 295:243–255.  https://doi.org/10.1016/j.expneurol.2017.06.010CrossRefGoogle Scholar
  3. Bhaumik M, Muller VJ, Rozaklis T (1999) A mouse model for mucopolysaccharidosis type III A (Sanfilippo syndrome). Glycobiology 9(12):1389–1396Google Scholar
  4. Boelens JJ, Prasad VK, Tolar J, Wynn RF, Peters C (2010) Current international perspectives on hematopoietic stem cell transplantation for inherited metabolic disorders. Pediatr Clin N Am 1:123–145.  https://doi.org/10.1016/j.pcl.2009.11.004CrossRefGoogle Scholar
  5. Boivin JR, Piekarski DJ, Wahlberg JK, Wilbrecht L (2017) Age, sex, and gonadal hormones differently influence anxiety- and depression-related behavior during puberty in mice. Psychoneuroendocrinology 85:78–87.  https://doi.org/10.1016/j.psyneuen.2017.08.009CrossRefGoogle Scholar
  6. Bone L, Belton L, Walker AS, Darbyshire J (2008) Intraventricular pentosan polysulphate in human prion diseases: an observational study in the UK. Eur J Neurol 15(5):458–464.  https://doi.org/10.1111/j.1468-1331.2008.02108.xCrossRefGoogle Scholar
  7. Dawson G, Fuller M, Helmsley KM, Hopwood JJ (2012) Abnormal gangliosides are localized in lipid rafts in Sanfilippo (MPS3a) mouse brain. Neurochem Res 37(6):1372–1380.  https://doi.org/10.1007/s11064-012-0761-xCrossRefGoogle Scholar
  8. Farquhar C, Dickinson A, Bruce M (1999) Prophylactic potential of pentosan polysulphate in transmissible spongiform encephalopathies. Lancet 353(9147):117Google Scholar
  9. Frohbergh M, Ge Y, Meng F et al (2014) Dose responsive effects of subcutaneous pentosan polysulfate injection in mucopolysaccharidosis type VI rats and comparison to oral treatment. PLoS One 9(6):e100882.  https://doi.org/10.1371/journal.pone.0100882CrossRefGoogle Scholar
  10. Gaffke L, Pierzynowska K, Piotrowska E, Węgrzyn G (2017) How close are we to therapies for Sanfilippo disease? Metab Brain Dis.  https://doi.org/10.1007/s11011-017-0111-4. E pub ahead of printGoogle Scholar
  11. Garbuzova-Davis S, Louis MK, Haller EM, Derasari HM, Rawls AE, Sanberg PR (2011) Blood-brain barrier impairment in an animal model of MPS IIIB. PLoS One 6(3):e16601.  https://doi.org/10.1371/journal.pone.0016601CrossRefGoogle Scholar
  12. Garbuzova-Davis S, Mirtyl S, Sallot SA, Hernandez-Ontiveros DG, Haller E, Sanberg PR (2013) Blood-brain barrier impairment in MPS III patients. BMC Neurol 13:174.  https://doi.org/10.1186/1471-2377-13-174CrossRefGoogle Scholar
  13. Gliddon BL, Hopwood JJ (2004) Enzyme-replacement therapy from birth delays the development of behavior and learning problems in mucopolysaccharidosis type IIIA mice. Pediatr Res 56(1):65–72Google Scholar
  14. Greenslade D, Ward J, Hopkins R (1983) (3H)-sodium pentosan polysulfate (SP 54): a study of the elimination of radioactivity following subcutaneous administration to the rat. Report No. 3484-218/5, Hazleton Laboratories EuropeGoogle Scholar
  15. Hardi P, Nagy T, Fazekas G et al (2016) Sodium pentosan polysulfate reduced renal ischemia-reperfusion-induced oxidative stress and inflammatory responses in an experimental animal model. J Vasc Res 53(3–4):230–242.  https://doi.org/10.1159/000452246CrossRefGoogle Scholar
  16. Hennermann JB, Gökce S, Solyom A, Mengel E, Schuchman EH, Simonaro CM (2016) Treatment with pentosan polysulphate in patients with MPS I: results from an open label, randomized, monocentric phase II study. J Inherit Metab Dis 39(6):831–837.  https://doi.org/10.1016/j.bbacli.2017.02.001CrossRefGoogle Scholar
  17. Herrero LJ, Foo SS, Sheng KC, Chen W, Forwood MR, Bucala R et al (2015) Pentosan polysulfate: a novel glycosaminoglycan-like molecule for effective treatment of alphavirus-induced cartilage destruction and inflammatory disease. J Virol 89(15):8063–8076.  https://doi.org/10.1128/JVI.00224-15CrossRefGoogle Scholar
  18. Honda H, Sasaki K, Minaki H, Masui K, Suzuki SO et al (2012) Proteaseresistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion. Neuropathology 32(2):124–132. PMID: 21801238Google Scholar
  19. Jones SA, Breen C, Heap F et al (2016) A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA. Mol Genet Metab 118(3):198–205.  https://doi.org/10.1016/j.ymgme.2016.05.006CrossRefGoogle Scholar
  20. King B, Marshall N, Beard H et al (2015) Evaluation of enzyme dose and dose-frequency in ameliorating substrate accumulation in MPS IIIA huntaway dog brain. J Inherit Metab Dis 38(2):341–350.  https://doi.org/10.1007/s10545-014-9790-8CrossRefGoogle Scholar
  21. King B, Marshall NR, Hassiotis S et al (2017) Slow, continuous enzyme replacement via spinal CSF in dogs with the paediatric-onset neurodegenerative disease, MPS IIIA. J Inherit Metab Dis 40(3):443–453.  https://doi.org/10.1007/s10545-016-9994-1CrossRefGoogle Scholar
  22. Klein U, Kresse H, von Figura K (1978) Sanfilippo syndrome type C: deficiency of acetyl-CoA: alpha-glucosaminide N-acetyltransferase in skin fibroblasts. Proc Natl Acad Sci U S A 75(10):5185–5189Google Scholar
  23. Kresse H (1973) Mucopolysaccharidosis 3A (Sanfilippo A disease): deficiency of a heparin sulfamidase in skin fibroblasts and leucocytes. Biochem Biophys Res Commun 54(3):1111–1118Google Scholar
  24. Kresse H, Paschke E, von Figura K, Gilberg W, Fuchs W (1980) Sanfilippo disease type D: deficiency of N-acetylglucosamine-6-sulfate sulfatase required for heparan sulfate degradation. Proc Natl Acad Sci U S A 77(11):6822–6826Google Scholar
  25. Larramendy-Gozalo C, Barret A, Daudigeous E et al (2013) Comparison of CR36, a new heparin mimetic, and pentosan polysulfate in the treatment of therapies for human prion diseases. Am J Neurodegener Dis 2(3):176–186.  https://doi.org/10.1099/vir.0.82286-0CrossRefGoogle Scholar
  26. Love S, Bridges LR, Case CP (1995) Neurofibrillary tangles in Niemann-Pick disease type C. Brain 118(Pt 1):119–129Google Scholar
  27. Martins C, Hůlková H, Dridi L et al (2015) Neuroinflammation, mitochondrial defects and neurodegeneration in mucopolysaccharidosis III type C mouse model. Brain 138(Pt 2):336–355.  https://doi.org/10.1093/brain/awu355CrossRefGoogle Scholar
  28. Ohmi K, Kudo LC, Ryazantsev S, Zhao HZ, Karsten SL, Neufeld EF (2009) Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy. Proc Natl Acad Sci U S A 106(20):8332–8337.  https://doi.org/10.1073/pnas.0903223106CrossRefGoogle Scholar
  29. Orii K, Tomatsu S, Suzuki Y et al (2016) Safety study of sodium pentosan polysulfate for adult patients with mucopolysaccharidosis type II. Mol Genet Metab 117(2):S88.  https://doi.org/10.1016/j.ymgme.2015.12.384CrossRefGoogle Scholar
  30. Reczek D, Schwake M, Schröder J et al (2007) LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell 131(4):770–783Google Scholar
  31. Ryazantsev S, Yu WH, Zhao HZ, Neufeld EF, Ohmi K (2007) Lysosomal accumulation of SCMAS (subunit c of mitochondrial ATP synthase) in neurons of the mouse model of mucopolysaccharidosis III B. Mol Genet Metab 90(4):393–401Google Scholar
  32. Sakurai-Yamashita Y, Kinugawa H, Niwa M (2006) Neuroprotective effect of pentosan polysulphate on ischemia-related neuronal death of the hippocampus. Neurosci Lett 409(1):30–34.  https://doi.org/10.1016/j.neulet.2006.09.041CrossRefGoogle Scholar
  33. Sanden C, Mori M, Jogdand P et al (2017) Broad Th2 neutralization and anti-inflammatory action of pentosan polysulfate sodium in experimental allergic rhinitis. Immun Inflamm Dis 5(3):300–309.  https://doi.org/10.1002/iid3.164CrossRefGoogle Scholar
  34. Schuchman EH, Ge Y, Lai A et al (2013) Pentosan polysulfate: a novel therapy for the mucopolysaccharidoses. PLoS One 8:e54459.  https://doi.org/10.1371/journal.pone.0054459CrossRefGoogle Scholar
  35. Shiotsuki H, Yoshimi K, Shimo Y et al (2010) A rotarod test for evaluation of motor skill learning. J Neurosci Methods 189(2):180–185.  https://doi.org/10.1016/j.jneumeth.2010.03.026CrossRefGoogle Scholar
  36. Simonaro CM, Tomatsu S, Sikora T et al (2016) Pentosan polysulfate: oral versus subcutaneous injection in mucopolysaccharidosis type I dogs. PLoS One 11(4):e0153136.  https://doi.org/10.1371/journal.pone.0153136CrossRefGoogle Scholar
  37. Tardieu M, Zérah M, Gougeon ML et al (2017) Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial. Lancet Neurol 16(9):712–720.  https://doi.org/10.1016/S1474-4422(17)30169-2CrossRefGoogle Scholar
  38. Terada T, Tsuboi Y, Obi T et al (2010) Less protease-resistant PrP in a patient with sporadic CJD treated with intraventricular pentosan polysulphate. Acta Neurol Scand 121(2):127–130.  https://doi.org/10.1111/j.1600-0404.2009.01272.xCrossRefGoogle Scholar
  39. Thomas A, Burant A, Bui N, Graham D, Yuva-Paylor LA, Paylor R (2009) Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology 204(2):361–373.  https://doi.org/10.1007/s00213-009-1466-yCrossRefGoogle Scholar
  40. von Figura K (1977) Human alpha-n-acetylglucosaminidase. 2. Activity towards natural substrates and multiple recognition forms. Eur J Biochem 80(2):535–542Google Scholar
  41. Wilkinson FL, Holley RJ, Langford-Smith KJ et al (2012) Neuropathology in mouse models of mucopolysaccharidosis type I, IIIA and IIIB. PLoS One 7(4):e35787.  https://doi.org/10.1371/journal.pone.0035787CrossRefGoogle Scholar
  42. Wu J, Guan TJ, Zheng S et al (2011) Inhibition of inflammation by pentosan polysulfate impedes the development and progression of severe diabetic nephropathy in aging C57B6 mice. Lab Investig 91(10):1459–1471.  https://doi.org/10.1038/labinvest.2011.93CrossRefGoogle Scholar

Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  • Ningning Guo
    • 1
  • Victor DeAngelis
    • 1
  • Changzhi Zhu
    • 1
  • Edward H. Schuchman
    • 1
  • Calogera M. Simonaro
    • 1
  1. 1.Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkUSA

Personalised recommendations