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Alliance"],"accepted":{"date-parts":[[2026,3,17]]},"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:p>\n                    Niemann\u2013Pick disease, type C1 (NPC1), is a rare, fatal neurodegenerative disorder caused by pathological variants in\n                    <jats:italic>NPC1<\/jats:italic>\n                    , which encodes a lysosomal cholesterol transporter. FDA-approved treatments are limited and do not target the underlying genetic defect. Both systemic and central nervous system delivery of AAV9-h\n                    <jats:italic>NPC1<\/jats:italic>\n                    have shown significant disease amelioration in NPC1 murine models. To assess the impact of dose in null\n                    <jats:italic>Npc1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>m1N\/m1N<\/jats:italic>\n                    <\/jats:sup>\n                    mice, we systemically administered three different doses of AAV9-h\n                    <jats:italic>NPC1<\/jats:italic>\n                    at 4 wk old. Then, to assess the impact of age, we administered the medium dose before phenotypic onset or at early or late stage of disease progression (4, 6, or 8 wk old, respectively). Higher vector doses and earlier treatment were associated with significantly increased lifespan, slower disease progression, and enhanced central nervous system transduction. In\n                    <jats:italic>Npc1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>I1061T\/I1061T<\/jats:italic>\n                    <\/jats:sup>\n                    mice, a model recapitulating a common human hypomorphic variant, similar benefits ensued. Our findings help define dose ranges, treatment ages, and efficacy in hypomorphic models of NPC1 deficiency and suggest that higher doses of AAV9-h\n                    <jats:italic>NPC1<\/jats:italic>\n                    in presymptomatic disease states are likely to yield better outcomes in NPC1 individuals.\n                  <\/jats:p>","DOI":"10.26508\/lsa.202402874","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T06:21:42Z","timestamp":1773814902000},"page":"e202402874","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Optimization of systemic AAV9 gene therapy in Niemann\u2013Pick disease, type C1 mice"],"prefix":"10.26508","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8741-4008","authenticated-orcid":true,"given":"Avani V","family":"Mylvara","sequence":"first","affiliation":[{"name":"Department of Human Health and Services, Eunice Kennedy Shriver 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