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Determining the optimal dose\/dose\u2010frequency 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\u2010symptomatic 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\u2010 and frequency\u2010dependent 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\u20102, or quantified activated microglia, the higher fortnightly dose resulted in superior outcomes in affected dogs. Secondary lesions such as accumulation of G<jats:sub>M3<\/jats:sub> ganglioside and development of GAD\u2010reactive 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\u2010optimal for ameliorating existing and preventing further development of disease\u2010related pathology in young MPS IIIA dog brain; however, increasing the dose fivefold but halving the frequency of administration enabled near normalisation of disease\u2010related biomarkers.<\/jats:p>","DOI":"10.1007\/s10545-014-9790-8","type":"journal-article","created":{"date-parts":[[2014,12,2]],"date-time":"2014-12-02T13:21:57Z","timestamp":1417526517000},"page":"341-350","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Evaluation of enzyme dose and dose\u2010frequency in ameliorating substrate accumulation in MPS IIIA Huntaway dog brain"],"prefix":"10.1002","volume":"38","author":[{"given":"Barbara","family":"King","sequence":"first","affiliation":[{"name":"Lysosomal Diseases Research Unit South Australian Health and Medical Research Institute PO Box 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