{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:38:43Z","timestamp":1791189523226,"version":"4.1.0"},"reference-count":39,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2015,3,10]],"date-time":"2015-03-10T00:00:00Z","timestamp":1425945600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy Clinical Development"],"published-print":{"date-parts":[[2015,6,1]]},"abstract":"<jats:p>\n                    No treatment is available for early-onset forms of metachromatic leukodystrophy (MLD), a lysosomal storage disease caused by autosomal recessive defect in arylsulfatase A (\n                    <jats:italic toggle=\"yes\">ARSA<\/jats:italic>\n                    ) gene causing severe demyelination in central and peripheral nervous systems. We have developed a gene therapy approach, based on intracerebral administration of AAVrh.10-hARSA vector, coding for human ARSA enzyme. We have previously demonstrated potency of this approach in MLD mice lacking ARSA expression. We describe herein the preclinical efficacy, safety, and biodistribution profile of intracerebral administration of AAVrh.10-hARSA to nonhuman primates (NHPs). NHPs received either the dose planned for patients adjusted to the brain volume ratio between child and NHP (1\u00d7dose, 1.1\u00d710\n                    <jats:sup>11<\/jats:sup>\n                    vg\/hemisphere, unilateral or bilateral injection) or 5-fold this dose (5\u00d7dose, 5.5\u00d710\n                    <jats:sup>11<\/jats:sup>\n                    vg\/hemisphere, bilateral injection). NHPs were subjected to clinical, biological, and brain imaging observations and were euthanized 7 or 90 days after injection. There was no toxicity based on clinical and biological parameters, nor treatment-related histological findings in peripheral organs. A neuroinflammatory process correlating with brain MRI T2 hypersignals was observed in the brain 90 days after administration of the 5\u00d7dose, but was absent or minimal after administration of the 1\u00d7dose. Antibody response to AAVrh.10 and hARSA was detected, without correlation with brain lesions. After injection of the 1\u00d7dose, AAVrh.10-hARSA vector was detected in a large part of the injected hemisphere, while ARSA activity exceeded the normal endogenous activity level by 14\u201331%. Consistently with other reports, vector genome was detected in off-target organs such as liver, spleen, lymph nodes, or blood, but not in gonads. Importantly, AAVrh.10-hARSA vector was no longer detectable in urine at day 7. Our data demonstrate requisite safe and effective profile for intracerebral AAVrh.10-hARSA delivery in NHPs, supporting its clinical use in children affected with MLD.\n                  <\/jats:p>","DOI":"10.1089\/humc.2014.139","type":"journal-article","created":{"date-parts":[[2015,3,11]],"date-time":"2015-03-11T01:49:29Z","timestamp":1426038569000},"page":"113-124","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":91,"title":["Intracerebral Gene Therapy Using AAVrh.10-hARSA Recombinant Vector to Treat Patients with Early-Onset Forms of Metachromatic Leukodystrophy: Preclinical Feasibility and Safety Assessments in Nonhuman Primates"],"prefix":"10.1177","volume":"26","author":[{"given":"Michel","family":"Zerah","sequence":"first","affiliation":[{"name":"Le Kremlin Bic\u00eatre","place":["France"]},{"name":"Necker Children's Hospital","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Piguet","sequence":"additional","affiliation":[{"name":"Le Kremlin Bic\u00eatre","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Anne","family":"Colle","sequence":"additional","affiliation":[{"name":"INRA UMR U703","place":["France"]},{"name":"Nantes-Atlantic College of Veterinary Medicine","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Raoul","sequence":"additional","affiliation":[{"name":"CHU Nord","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack-Yves","family":"Deschamps","sequence":"additional","affiliation":[{"name":"INRA UMR U703","place":["France"]},{"name":"Nantes-Atlantic College of Veterinary Medicine","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Deniaud","sequence":"additional","affiliation":[{"name":"INRA UMR U703","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benoit","family":"Gautier","sequence":"additional","affiliation":[{"name":"Le Kremlin Bic\u00eatre","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9rique","family":"Toulgoat","sequence":"additional","affiliation":[{"name":"CHU de Nantes","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Bieche","sequence":"additional","affiliation":[{"name":"Facult\u00e9 des Sciences Pharmaceutiques et Biologiques","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Laurendeau","sequence":"additional","affiliation":[{"name":"Facult\u00e9 des Sciences Pharmaceutiques et Biologiques","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolan","family":"Sondhi","sequence":"additional","affiliation":[{"name":"Weill-Cornell Medical College"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark M.","family":"Souweidane","sequence":"additional","affiliation":[{"name":"Weill-Cornell Medical College"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Cartier-Lacave","sequence":"additional","affiliation":[{"name":"Le Kremlin Bic\u00eatre","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Moullier","sequence":"additional","affiliation":[{"name":"INSERM UMR 1089","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald G.","family":"Crystal","sequence":"additional","affiliation":[{"name":"Weill-Cornell Medical College"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Roujeau","sequence":"additional","affiliation":[{"name":"H\u00f4pitaux de Montpellier","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Sevin","sequence":"additional","affiliation":[{"name":"Le Kremlin Bic\u00eatre","place":["France"]},{"name":"Bic\u00eatre Hospital","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Aubourg","sequence":"additional","affiliation":[{"name":"Le Kremlin Bic\u00eatre","place":["France"]},{"name":"Bic\u00eatre Hospital","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2015,3,10]]},"reference":[{"key":"e_1_3_3_2_2","volume-title":"The Online Metabolic and Molecular Bases of Inherited Disease","author":"Gieselmann V","year":"2014","unstructured":"Gieselmann V, , Kr\u00e4geloh-Mann Issou. Metachromatic leukodystrophy. In: The Online Metabolic and Molecular Bases of Inherited Disease. Valle D, , Beaudet AL, , Vogelstein B, et al., eds. (McGraw-Hill, New York, NY). 2014; chapter 148."},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-004-0883-6"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.2011.04028.x"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.2008.00648.x"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2010.252"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/00062752-199911000-00004"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2013.01.010"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28873"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200419205"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1233158"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.57.110104.115650"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-090711-163739"},{"key":"e_1_3_3_14_2","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1042\/BST0381465","article-title":"Treatments for lysosomal storage disorders","volume":"38","author":"Lachmann R","year":"2010","unstructured":"Lachmann R. 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