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Published in: Journal of Inherited Metabolic Disease 2/2015

01-03-2015 | Original Article

Evaluation of enzyme dose and dose-frequency in ameliorating substrate accumulation in MPS IIIA Huntaway dog brain

Authors: Barbara King, Neil Marshall, Helen Beard, Sofia Hassiotis, Paul J. Trim, Marten F. Snel, Tina Rozaklis, Robert D. Jolly, John J. Hopwood, Kim M. Hemsley

Published in: Journal of Inherited Metabolic Disease | Issue 2/2015

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Abstract

Intracerebrospinal fluid (CSF) infusion of replacement enzyme is under evaluation for amelioration of disease-related symptoms and biomarker changes in patients with the lysosomal storage disorder mucopolysaccharidosis type IIIA (MPS IIIA; www.​clinicaltrials.​gov; NCT#01155778; #01299727). Determining the optimal dose/dose-frequency is important, given the invasive method for chronically supplying recombinant protein to the brain, the main site of symptom generation. To examine these variables, we utilised MPS IIIA Huntaway dogs, providing recombinant human sulphamidase (rhSGSH) to young pre-symptomatic dogs from an age when MPS IIIA dog brain exhibits significant accumulation of primary (heparan sulphate) and secondary (glycolipid) substrates. Enzyme was infused into CSF via the cisterna magna at one of two doses (3 mg or 15 mg/infusion), with the higher dose supplied at two different intervals; fortnightly or monthly. Euthanasia was carried out 24 h after the final injection. Dose- and frequency-dependent reductions in heparan sulphate were observed in CSF and deeper layers of cerebral cortex. When we examined the amount of immunostaining of the general endo/lysosomal marker, LIMP-2, or quantified activated microglia, the higher fortnightly dose resulted in superior outcomes in affected dogs. Secondary lesions such as accumulation of GM3 ganglioside and development of GAD-reactive axonal spheroids were treated to a similar degree by both rhSGSH doses and dose frequencies. Our findings indicate that the lower fortnightly dose is sub-optimal for ameliorating existing and preventing further development of disease-related pathology in young MPS IIIA dog brain; however, increasing the dose fivefold but halving the frequency of administration enabled near normalisation of disease-related biomarkers.
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Metadata
Title
Evaluation of enzyme dose and dose-frequency in ameliorating substrate accumulation in MPS IIIA Huntaway dog brain
Authors
Barbara King
Neil Marshall
Helen Beard
Sofia Hassiotis
Paul J. Trim
Marten F. Snel
Tina Rozaklis
Robert D. Jolly
John J. Hopwood
Kim M. Hemsley
Publication date
01-03-2015
Publisher
Springer Netherlands
Published in
Journal of Inherited Metabolic Disease / Issue 2/2015
Print ISSN: 0141-8955
Electronic ISSN: 1573-2665
DOI
https://doi.org/10.1007/s10545-014-9790-8

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