{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:30:09Z","timestamp":1792701009103,"version":"4.5.0"},"reference-count":42,"publisher":"SAGE Publications","issue":"11-12","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"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"],"published-print":{"date-parts":[[2021,6]]},"abstract":"\n Niemann\u2013Pick disease type C1 (NPC1) is a fatal congenital neurodegenerative disorder caused by mutations in the\n NPC1<\/jats:italic>\n gene, which is involved in cholesterol transport in lysosomes. Broad clinical manifestations of NPC1 include liver failure, pulmonary disorder, neurological deficits, and psychiatric symptoms. The main cause of death in NPC1 patients involves central nervous system (CNS) dysfunction; there is no essential treatment. We generated a tyrosine-mutant adeno-associated virus (AAV) 9\/3 vector that expresses human\n NPC1<\/jats:italic>\n under a cytomegalovirus (CMV) promoter (AAV-CMV-\n hNPC1<\/jats:italic>\n ) and injected it into the left lateral ventricle (5\u2009\u03bcL) and cisterna magna (10\u2009\u03bcL) of\n Npc1<\/jats:italic>\n homo-knockout (\n Npc1<\/jats:italic>\n \n \u2212\n \/<\/jats:italic>\n \u2212\n <\/jats:sup>\n ) mice. Each mouse received total 1.35\u2009\u00d7\u200910\n 11<\/jats:sup>\n vector genome on days 4 or 5 of life. AAV-treated\n Npc1<\/jats:italic>\n \n \u2212\n \/<\/jats:italic>\n \u2212\n <\/jats:sup>\n mice (\n n<\/jats:italic>\n \u2009=\u200911) had an average survival of >28 weeks, while all saline-treated\n Npc1<\/jats:italic>\n \n \u2212\n \/<\/jats:italic>\n \u2212\n <\/jats:sup>\n mice (\n n<\/jats:italic>\n \u2009=\u200911) and untreated\n Npc1<\/jats:italic>\n \n \u2212\n \/<\/jats:italic>\n \u2212\n <\/jats:sup>\n mice (\n n<\/jats:italic>\n \u2009=\u20096) died within 16 weeks. Saline-treated and untreated\n Npc1<\/jats:italic>\n \n \u2212\n \/<\/jats:italic>\n \u2212\n <\/jats:sup>\n mice lost body weight from 7 weeks until death. However, the average body weight of AAV-treated\n Npc1<\/jats:italic>\n \n \u2212\n \/<\/jats:italic>\n \u2212\n <\/jats:sup>\n mice increased until 15 weeks. AAV-treated\n Npc1<\/jats:italic>\n \n \u2212\n \/<\/jats:italic>\n \u2212\n <\/jats:sup>\n mice also showed a significant improvement in the rotarod test performance. A pathological analysis at 11 weeks showed that cerebellar Purkinje cells were preserved in AAV-treated\n Npc1<\/jats:italic>\n \n \u2212\n \/<\/jats:italic>\n \u2212\n <\/jats:sup>\n mice. In contrast, untreated\n Npc1<\/jats:italic>\n \n \u2212\n \/<\/jats:italic>\n \u2212\n <\/jats:sup>\n mice showed an almost total loss of cerebellar Purkinje cells. Combined injection into both the lateral ventricle and cisterna magna achieved broader delivery of the vector to the CNS, leading to better outcomes than noted in previous reports, with injection into the lateral ventricles or veins alone. In AAV-treated\n Npc1<\/jats:italic>\n \n \u2212\n \/<\/jats:italic>\n \u2212\n <\/jats:sup>\n mice, vector genome DNA was detected widely in the CNS and liver. Human\n NPC1<\/jats:italic>\n RNA was detected in the brain, liver, lung, and heart. Accumulated unesterified cholesterol in the liver was reduced in the AAV-treated\n Npc1<\/jats:italic>\n \n \u2212\n \/<\/jats:italic>\n \u2212\n <\/jats:sup>\n mice. Our results suggest the feasibility of gene therapy for patients with NPC1.\n <\/jats:p>","DOI":"10.1089\/hum.2020.175","type":"journal-article","created":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T02:40:16Z","timestamp":1606790416000},"page":"589-598","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":38,"title":["Gene Therapy in a Mouse Model of Niemann\u2013Pick Disease Type C1"],"prefix":"10.1177","volume":"32","author":[{"given":"Yoshie","family":"Kurokawa","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Jichi Medical University, Tochigi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Osaka","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Jichi Medical University, Tochigi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kouga","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Jichi Medical University, Tochigi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eriko","family":"Jimbo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Jichi Medical University, Tochigi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Muramatsu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Jichi Medical University, Tochigi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachie","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Jichi Medical University, Tochigi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Takayanagi","sequence":"additional","affiliation":[{"name":"Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Tochigi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsushi","family":"Onaka","sequence":"additional","affiliation":[{"name":"Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Tochigi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-ichi","family":"Muramatsu","sequence":"additional","affiliation":[{"name":"Division of Neurological Gene Therapy, Center for Open Innovation, Jichi Medical University, Tochigi, Japan."},{"name":"Center for Gene and Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Yamagata","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Jichi Medical University, Tochigi, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2021,6,16]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5323.228"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.25"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1086\/302626"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/320599"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.08.038"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20184392"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0985-1"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-019-00445-w"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182563b82"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0785-7"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2004.08.011"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/neup.12380"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-018-0844-0"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-013-0217-2"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006951"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31465-4"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23509"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2013.08.001"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M071274"},{"key":"e_1_3_5_21_2","first-page":"52","article-title":"Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1","volume":"26","author":"Chandler RJ","year":"2017","unstructured":"Chandler RJ, , Williams IM, , Gibson AL, et al. 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