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Most patients manifest with cognitive symptoms, which cannot be treated with enzyme replacement therapy, as native IDS does not cross the blood\u2013brain barrier. We tested a brain\u2010targeted hematopoietic stem cell gene therapy approach using lentiviral IDS fused to ApoEII (IDS.ApoEII) compared to a lentivirus expressing normal IDS or a normal bone marrow transplant. In mucopolysaccharidosis II mice, all treatments corrected peripheral disease, but only IDS.ApoEII mediated complete normalization of brain pathology and behavior, providing significantly enhanced correction compared to IDS. A normal bone marrow transplant achieved no brain correction. Whilst corrected macrophages traffic to the brain, secreting IDS\/IDS.ApoEII enzyme for cross\u2010correction, IDS.ApoEII was additionally more active in plasma and was taken up and transcytosed across brain endothelia significantly better than IDS via both heparan sulfate\/ApoE\u2010dependent receptors and mannose\u20106\u2010phosphate receptors. Brain\u2010targeted hematopoietic stem cell gene therapy provides a promising therapy for MPS II patients.<\/jats:p>","DOI":"10.15252\/emmm.201708730","type":"journal-article","created":{"date-parts":[[2018,6,8]],"date-time":"2018-06-08T03:35:10Z","timestamp":1528428910000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Brain\u2010targeted stem cell gene therapy corrects mucopolysaccharidosis type II via multiple mechanisms"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6138-8916","authenticated-orcid":false,"given":"H\u00e9l\u00e8ne FE","family":"Gleitz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai Yin","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1905-4928","authenticated-orcid":false,"given":"James R","family":"Cook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel F","family":"Rowlston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella MA","family":"Forte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zelpha","family":"D'Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"O'Leary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca J","family":"Holley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9708-1112","authenticated-orcid":false,"given":"Brian W","family":"Bigger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,6,8]]},"reference":[{"key":"BFEMMM201708730_CR1","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.bbmt.2015.02.011","volume":"21","author":"M Aldenhoven","year":"2015","unstructured":"Aldenhoven M, Jones SA, Bonney D, Borrill RE, Coussons M, Mercer J, Bierings MB, Versluys B, van Hasselt PM, Wijburg FA et\u00a0al (2015a) Hematopoietic cell transplantation for mucopolysaccharidosis patients is safe and effective: results after implementation of international guidelines. 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