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Here, we used a systemic gene transfer approach to demonstrate the therapeutic efficacy of a chimeric sulphamidase, which was engineered by adding the signal peptide (sp) from the highly secreted iduronate\u20102\u2010sulphatase (IDS) and the blood\u2010brain barrier (BBB)\u2010binding domain (BD) from the Apolipoprotein B (ApoB\u2010BD). A single intravascular administration of AAV2\/8 carrying the modified sulphamidase was performed in adult MPS\u2010IIIA mice in order to target the liver and convert it to a factory organ for sustained systemic release of the modified sulphamidase. We showed that while the IDS sp replacement results in increased enzyme secretion, the addition of the ApoB\u2010BD allows efficient BBB transcytosis and restoration of sulphamidase activity in the brain of treated mice. This, in turn, resulted in an overall improvement of brain pathology and recovery of a normal behavioural phenotype. Our results provide a novel feasible strategy to develop minimally invasive therapies for the treatment of brain pathology in MPS\u2010IIIA and other neurodegenerative LSDs.<\/jats:p>\n                  <jats:p>\n                    \u2192See accompanying article\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"emmm.201302668\" ext-link-type=\"doi\">10.1002\/emmm.201302668<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1002\/emmm.201202083","type":"journal-article","created":{"date-parts":[[2013,4,9]],"date-time":"2013-04-09T06:27:59Z","timestamp":1365488879000},"page":"675-690","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":107,"title":["A highly secreted sulphamidase engineered to cross the blood\u2010brain barrier corrects brain lesions of mice with mucopolysaccharidoses type IIIA"],"prefix":"10.1038","volume":"5","author":[{"given":"Nicolina Cristina","family":"Sorrentino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"D'Orsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Sambri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Nusco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciro","family":"Monaco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"Spampanato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Polishchuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Saccone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira","family":"De Leonibus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ballabio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Fraldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,4,9]]},"reference":[{"key":"BFEMMM201202083_CR1","doi-asserted-by":"crossref","first-page":"84ra43","DOI":"10.1126\/scitranslmed.3002254","volume":"3","author":"JK Atwal","year":"2011","unstructured":"Atwal JK, Chen Y, Chiu C, Mortensen DL, Meilandt WJ, Liu Y, Heise CE, Hoyte K, Luk W, Lu Y, et al (2011) A therapeutic antibody targeting BACE1 inhibits amyloid\u2010beta production in vivo. 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