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Zolgensma, an adeno-associated virus (AAV)-based\n                    <jats:italic>SMN1<\/jats:italic>\n                    gene-replacement therapy, is approved for SMA, though its long-term efficacy and safety remain uncertain. This study compares a Zolgensma-like benchmark vector with a 2nd-generation vector featuring a codon-optimized\n                    <jats:italic>SMN1<\/jats:italic>\n                    transgene under the control of an endogenous\n                    <jats:italic>SMN1<\/jats:italic>\n                    promoter. In SMA mice, intracerebroventricular delivery of the 2nd-generation vector improved survival and phenotypic outcomes compared with the benchmark. However, motor impairment was observed in wild-type mice 20 months post-injection with the 2nd-generation vector. Notably, cardiac thrombosis and hepatocellular carcinoma were associated with the benchmark vector, but not with the 2nd-generation vector. While AAV-related tumorigenesis appears to be species-specific to mice, these findings underscore the need for careful long\u2011term monitoring in patients treated with Zolgensma.\n                  <\/jats:p>","DOI":"10.1038\/s41467-026-73545-8","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T03:34:52Z","timestamp":1779507292000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Long-term comparative analysis of AAV9-mediated gene replacement therapies for spinal muscular atrophy in mice"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5916-3953","authenticated-orcid":false,"given":"Xiupeng","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Nath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mojiao","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2112-127X","authenticated-orcid":false,"given":"Yasemin \u00d6zg\u00fcr","family":"G\u00fcnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2495-2236","authenticated-orcid":false,"given":"Tapan","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengtian","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ailing","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjia","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia Y.","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boonying","family":"Wassamon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2468-8941","authenticated-orcid":false,"given":"Mengyao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph Yunxi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy P.","family":"Fitzgibbons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veena","family":"Kumanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijie","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7856-3159","authenticated-orcid":false,"given":"Heather L.","family":"Gray-Edwards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6381-6902","authenticated-orcid":false,"given":"Thomas L.","family":"Gallagher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7409-8344","authenticated-orcid":false,"given":"Phillip W. 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