Continual low-dose infusion of sulfamidase is superior to intermittent high-dose delivery in ameliorating neuropathology in the MPS IIIA mouse brain

Helen Beard, Sofia Hassiotis, Amanda J. Luck, Tina Rozaklis, John J. Hopwood, Kim M. Hemsley

Research output: Chapter in Book/Report/Conference proceedingChapter

4 Citations (Scopus)

Abstract

Mucopolysaccharidosis IIIA (MPS IIIA) is a neurodegenerative lysosomal storage disorder characterised by progressive loss of learned skills, sleep disturbance and behavioural problems. Reduced activity of lysosomal sulfamidase results in accumulation of heparan sulfate and secondary storage of glycolipids in the brain. Intra-cisternal sulfamidase infusions reduce disease-related neuropathology; however, repeated injections may subject patients to the risk of infection and tissue damage so alternative approaches are required. We undertook a proof-of-principle study comparing the ability of slow/continual or repeat/bolus infusion to ameliorate neuropathology in MPS IIIA mouse brain. Six-week-old MPS IIIA mice were implanted with subcutaneously located mini-osmotic pumps filled with recombinant human sulfamidase (rhSGSH) or vehicle, connected to lateral ventricle-directed cannulae. Pumps were replaced at 8 weeks of age. Additional MPS IIIA mice received intra-cisternal bolus infusions of the same amount of rhSGSH (or vehicle), at 6 and 8 weeks of age. Unaffected mice received vehicle via each strategy. All mice were euthanised at 10 weeks of age and the brain was harvested to assess the effect of treatment on neuropathology. Mice receiving pump-delivered rhSGSH exhibited highly significant reductions in lysosomal storage markers (lysosomal integral membrane protein-2, GM3 ganglioside and filipin-positive lipids) and neuroinflammation (isolectin B4-positive microglia, glial fibrillary acidic protein-positive astroglia). MPS IIIA mice receiving rhSGSH via bolus infusion displayed reductions in these markers, but the effectiveness of the strategy was inferior to that seen with slow/pump-based delivery. Continual low-dose infusion may therefore be a more effective strategy for enzyme delivery in MPS IIIA.

Original languageEnglish
Title of host publicationJIMD Reports
EditorsEva Morava, Matthias Baumgartner, Marc Patterson, Shamima Rahman, Johannes Zschocke, Verena Peters
PublisherSpringer Berlin Heidelberg
Pages59-68
Number of pages10
Volume29
ISBN (Electronic)9783662532782
ISBN (Print)9783662532775
DOIs
Publication statusPublished - 8 Sep 2016
Externally publishedYes

Publication series

NameJIMD Reports
Volume29
ISSN (Print)2192-8304
ISSN (Electronic)2192-8312

Keywords

  • Bolus Delivery
  • Filipin Staining
  • Inferior Colliculus
  • Metachromatic Leukodystrophy
  • Sandhoff Disease

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    Beard, H., Hassiotis, S., Luck, A. J., Rozaklis, T., Hopwood, J. J., & Hemsley, K. M. (2016). Continual low-dose infusion of sulfamidase is superior to intermittent high-dose delivery in ameliorating neuropathology in the MPS IIIA mouse brain. In E. Morava, M. Baumgartner, M. Patterson, S. Rahman, J. Zschocke, & V. Peters (Eds.), JIMD Reports (Vol. 29, pp. 59-68). (JIMD Reports; Vol. 29). Springer Berlin Heidelberg. https://doi.org/10.1007/8904_2015_495