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<p>Spinal muscular atrophy (SMA) results from a deficiency of the survival motor neuron (SMN) protein. Zolgensma, an adeno-associated virus (AAV)-based <i>SMN1</i> 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 <i>SMN1</i> transgene under the control of an endogenous <i>SMN1</i> 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.</p>

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Long-term comparative analysis of AAV9-mediated gene replacement therapies for spinal muscular atrophy in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月23日

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  • 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

摘要

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.