{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T19:50:33Z","timestamp":1779393033938,"version":"3.53.1"},"reference-count":36,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,2,24]],"date-time":"2016-02-24T00:00:00Z","timestamp":1456272000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"An Australian National Health and Medical Research Council","award":["#565074"],"award-info":[{"award-number":["#565074"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Repeated replacement of sulphamidase via cerebrospinal fluid injection is an effective treatment for pathological changes in the brain in mice and dogs with the lysosomal storage disorder, mucopolysaccharidosis type <jats:styled-content style=\"fixed-case\">IIIA<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">MPS IIIA<\/jats:styled-content>). Investigational trials of this approach are underway in children with this condition, however, infusions require attendance at a specialist medical facility. We sought to comprehensively evaluate the effectiveness of sustained\u2010release (osmotic pump\u2010delivered) enzyme replacement therapy in murine <jats:styled-content style=\"fixed-case\">MPS IIIA<\/jats:styled-content> as this method, if applied to humans, would require only subcutaneous administration of enzyme once the pump was installed. Six\u2010week\u2010old <jats:styled-content style=\"fixed-case\">MPS IIIA<\/jats:styled-content> and unaffected mice were implanted with subcutaneous mini\u2010osmotic pumps connected to an infusion cannula directed at the right lateral ventricle. Either recombinant human sulphamidase or vehicle were infused over the course of 7\u00a0weeks, with pumps replaced part\u2010way through the experimental period. We observed near\u2010normalisation of primarily stored substrate (heparan sulphate) in both hemispheres of the <jats:styled-content style=\"fixed-case\">MPS IIIA<\/jats:styled-content> brain and cervical spinal cord, as determined using tandem mass spectrometry. Immunohistochemistry indicated a reduction in secondarily stored <jats:styled-content style=\"fixed-case\">G<jats:sub>M<\/jats:sub><\/jats:styled-content><jats:sub>3<\/jats:sub> ganglioside and neuroinflammatory markers. A bias towards the infusion side was seen in some, but not all outcomes. The recombinant enzyme appears stable under pump\u2010like conditions for at least 1\u00a0month. Given that infusion pumps are in clinical use in other nervous system disorders, e.g. for treatment of spasticity or brain tumours, this treatment method warrants consideration for testing in large animal models of <jats:styled-content style=\"fixed-case\">MPS IIIA<\/jats:styled-content> and other lysosomal storage disorders that affect the brain.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13533-fig-0010-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\nClinical trials of repeated injection of replacement enzyme into CSF are underway in patients with the inherited neurodegenerative disorder mucopolysaccharidosis type IIIA. In this pre\u2010clinical study, we examined an alternative approach \u2013 slow, continual infusion of enzyme using pumps. We observed significant reductions in substrate accumulation and other disease\u2010based lesions in treated mouse brain. Thus, the strategy warrants consideration for testing in large animal models of MPS IIIA and also in other neurodegenerative lysosomal storage disorders.\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13533","type":"journal-article","created":{"date-parts":[[2016,1,14]],"date-time":"2016-01-14T03:35:11Z","timestamp":1452742511000},"page":"409-422","source":"Crossref","is-referenced-by-count":14,"title":["Low\u2010dose, continuous enzyme replacement therapy ameliorates brain pathology in the neurodegenerative lysosomal disorder mucopolysaccharidosis type IIIA"],"prefix":"10.1111","volume":"137","author":[{"given":"Barbara","family":"King","sequence":"first","affiliation":[{"name":"Lysosomal Diseases Research Unit South Australian Health and Medical Research Institute Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Hassiotis","sequence":"additional","affiliation":[{"name":"Lysosomal Diseases Research Unit South Australian Health and Medical Research Institute Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Rozaklis","sequence":"additional","affiliation":[{"name":"Lysosomal Diseases Research Unit South Australian Health and Medical Research Institute Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Beard","sequence":"additional","affiliation":[{"name":"Lysosomal Diseases Research Unit South Australian Health and Medical Research Institute Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Trim","sequence":"additional","affiliation":[{"name":"Lysosomal Diseases Research Unit South Australian Health and Medical Research Institute Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marten F.","family":"Snel","sequence":"additional","affiliation":[{"name":"Lysosomal Diseases Research Unit South Australian Health and Medical Research Institute Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Hopwood","sequence":"additional","affiliation":[{"name":"Lysosomal Diseases Research Unit South Australian Health and Medical Research Institute Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1038-9884","authenticated-orcid":false,"given":"Kim M.","family":"Hemsley","sequence":"additional","affiliation":[{"name":"Lysosomal Diseases Research Unit South Australian Health and Medical Research Institute Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,2,24]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"crossref","unstructured":"BeardH. 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