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.
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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
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The research was funded by the Stop Sanfilippo Foundation.
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Communicated by: Jrn Oliver Sass
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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)
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)
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Synopsis of Article
Subcutaneous pentosan polysulfate treatment reduces neuroinflammation and neurodegeneration in the brain of MPS IIIA mice.
Conflict of Interest
Calogera M. Simonaro: inventor on patent related to the use of pentosan polysulfate for the treatment of lysosomal storage disorders; licensed to Plexcera Therapeutics.
Calogera M. Simonaro has received a research grant from the Stop Sanfilippo Foundation (Spain).
Edward H. Schuchman: inventor on patent related to the use of pentosan polysulfate for the treatment of lysosomal storage disorders; licensed to Plexcera Therapeutics.
Edward H. Schuchman: co-founder and owns equity in Plexcera Therapeutics.
Ningning Guo, Victor A. DeAngelis and Changzhi Zhu declare that they have no conflict of interest.
Animal Rights
All institutional and national guidelines for the care and use of laboratory animals were followed. All animal protocols were approved by the Mount Sinai Institutional Animal Care and Use Committee (protocol #08-0108), and were performed in accordance with NIH guidelines.
Contributions of Individual Authors
Calogera M. Simonaro: concept and design, analysis and interpretation of data, drafting of article, revising of article for important intellectual content. Corresponding author.
Edward H. Schuchman: concept and design, analysis and interpretation of data, drafting of article, revising of article for important intellectual content.
Ningning Guo: conducting experiments, analysis and interpretation of data, and drafting of article.
Victor A. DeAngelis: conducting experiments and analysis of data.
Changzi Zhu: conducting experiments and analysis of data.
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Guo, N., DeAngelis, V., Zhu, C., Schuchman, E.H., Simonaro, C.M. (2018). Pentosan Polysulfate Treatment of Mucopolysaccharidosis Type IIIA Mice. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 43. JIMD Reports, vol 43. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2018_96
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DOI: https://doi.org/10.1007/8904_2018_96
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