Long-term comparative analysis of AAV9-mediated gene replacement therapies for spinal muscular atrophy in mice
- Xiupeng Chen
- Qing Xie
- Sarah J. Nath
- Mojiao Tang
- Hong Ma
- Yasemin Özgür Günes
- Tapan Sharma
- Hao Liu
- Mengtian Cui
- Ailing Du
- Mengjia Lu
- Sophia Y. Liu
- Boonying Wassamon
- Mengyao Xu
- Joseph Yunxi Wu
- Qin Su
- Timothy P. Fitzgibbons
- Jinghua Liu
- Fang Wan
- Veena Kumanan
- Ran He
- Yijie Ma
- Jun Yang
- Heather L. Gray-Edwards
- Thomas L. Gallagher
- Phillip W. L. Tai
- Guangping Gao
- Jun Xie
2026-05-23
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.