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

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.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2026-05-23
DOI
https://doi.org/10.1038/s41467-026-73545-8
Primary Topic
Neurogenetic and Muscular Disorders Research
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Timothy P. Fitzgibbons, Yasemin Özgür Günes, Qing Xie, Ailing Du et al.
Nature Communications
Neurogenetic and Muscular Disorders Research
article

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

Timothy P. Fitzgibbons, Yasemin Özgür Günes, Qing Xie, Ailing Du, Yijie Ma, Xiupeng Chen, Heather Gray‐Edwards, Phillip W.L. Tai, Guangping Gao, Boonying Wassamon, Ran He, Mojiao Tang, Hong Ma, Fang Wan, Sophia Y. Liu, Jinghua Liu, Hao Liu, Mengtian Cui, Jun Yang, Jun Xie, Sarah J. Nath, Tapan Sharma, Thomas L. Gallagher, Joseph Yunxi Wu, Veena Kumanan, Mengyao Xu, Mengjia Lu, Qin Su
article en

Abstract

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.

Nature Communications
UMass Memorial Health Care (US), University of Massachusetts Chan Medical School (US), Bridge Pharma (United States) (US), UMass Memorial Medical Center (US)
Good health and well-being
Openalex Percentile: Top 6%
Neurogenetic and Muscular Disorders Research
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.