Please use this identifier to cite or link to this item:
Scopus Web of Science® Altmetric
Type: Journal article
Title: Evaluation of enzyme dose and dose-frequency in ameliorating substrate accumulation in MPS IIIA Huntaway dog brain
Author: King, B.
Marshall, N.
Beard, H.
Hassiotis, S.
Trim, P.
Snel, M.
Rozaklis, T.
Jolly, R.
Hopwood, J.
Hemsley, K.
Citation: Journal of Inherited Metabolic Disease, 2015; 38(2):341-350
Publisher: Springer Netherlands
Issue Date: 2015
ISSN: 0141-8955
Statement of
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
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; ; 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.
Keywords: Brain
Mucopolysaccharidosis III
Disease Models, Animal
Heparitin Sulfate
Recombinant Proteins
Drug Administration Schedule
Time Factors
Lysosomal-Associated Membrane Protein 2
Drug Dosage Calculations
Enzyme Replacement Therapy
Infusions, Intraventricular
Rights: © SSIEM 2014
DOI: 10.1007/s10545-014-9790-8
Appears in Collections:Aurora harvest 7
Medicine publications

Files in This Item:
There are no files associated with this item.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.