Nature communications · 2026
Long-term comparative analysis of AAV9-mediated gene replacement therapies for spinal muscular atrophy in mice.
СтатьяСравнительное исследованиеНазвание и аннотация: Перевод в очереди
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Chen Xiupeng, Xie Qing, Nath Sarah J, Tang Mojiao, Ma Hong, Günes Yasemin Özgür, Sharma Tapan, Liu Hao, Cui Mengtian, Du Ailing, Lu Mengjia, Liu Sophia Y, Wassamon Boonying, Xu Mengyao, Wu Joseph Yunxi, Su Qin, Fitzgibbons Timothy P, Liu Jinghua, Wan Fang, Kumanan Veena, He Ran, Ma Yijie, Yang Jun, Gray-Edwards Heather L, Gallagher Thomas L, Tai Phillip W L, Gao Guangping, Xie Jun
Аннотация
Spinal muscular atrophy (SMA) results from a deficiency of the survival motor neuron (SMN) protein. Zolgensma, an adeno-associated virus (AAV)-based SMN1 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 SMN1 transgene under the control of an endogenous SMN1 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‑term monitoring in patients treated with Zolgensma.