OSCR

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

Overview

Authors: Xiupeng Chen1,2, Qing Xie1,2, Sarah J. Nath1,2, Mojiao Tang1,3, Hong Ma1,3, Yasemin Özgür Günes1,2, Tapan Sharma1,2, Hao Liu1,2, Mengtian Cui1,2, Ailing Du1,2, Mengjia Lu1,2, Sophia Y. Liu1,2, Boonying Wassamon1,2, Mengyao Xu1,2, Joseph Yunxi Wu1, Qin Su1,3,4, Timothy P. Fitzgibbons5, Jinghua Liu1,2, Fang Wan1,2, Veena Kumanan1,2
and 8 other authorsRan He1,3, Yijie Ma6, Jun Yang6, Heather L. Gray-Edwards1,2, Thomas L. Gallagher1, Phillip W. L. Tai1,2,4, Guangping Gao1,2,4, Jun Xie1,3,4
ORCID iDs: Xiupeng Chen, Yasemin Özgür Günes, Tapan Sharma, Mengyao Xu, Heather L. Gray-Edwards, Thomas L. Gallagher, Phillip W. L. Tai, Guangping Gao, Jun Xie
  1. Horae Gene Therapy Center, Department of Genetic and Cellular Medicine, UMass Chan Medical School,Worcester, MA USA
  2. Li Weibo Institute for Rare Diseases Research, UMass Chan Medical School,Worcester, MA USA
  3. Viral Vector Core, UMass Chan Medical School,Worcester, MA USA
  4. Department of Microbiology, UMass Chan Medical School,Worcester, MA USA
  5. Division of Cardiovascular Medicine, Department of Medicine, UMass Chan Medical School,Worcester, MA USA
  6. CANbridge Pharmaceuticals, Burlington, MA USA
Institutions: University of Massachusetts Chan Medical School (United States); University of Vermont (United States); Burlington School District (United States)
Journal: Nature communications, volume 17, issue 1, article 6767
Dates: received 17 June 2025; accepted 6 May 2026; published online 23 May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41467-026-73545-8 · PMID 42177183 · PMCID PMC13385853 · OpenAlex W7162132260
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), other condition (population)
Methods: Statistics, Smoothing, state filtering, decompositions, Physiology & signal measures
Keywords: Gene therapy, Motor neuron disease
MeSH: Dependovirus*, Genetic Therapy*, Genetic Vectors*, Muscular Atrophy, Spinal*, Survival of Motor Neuron 1 Protein*, Animals, Carcinoma, Hepatocellular, Disease Models, Animal, Female, Gene Therapy Agents, Humans, Liver Neoplasms, Male, Mice, Mice, Inbred C57BL, Promoter Regions, Genetic, Recombinant Fusion Proteins, Transgenes (* major topic)
Topic: Neurogenetic and Muscular Disorders Research (Genetics, Medicine), according to OpenAlex
Funding: Canbridge Pharm partially supports the study through a Sponsor research agreement
Citations: not cited yet (Europe PMC); 100 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

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Data

Datasets cited

Data availability

The gene expression data reported here have been deposited in the NCBI Sequence Read Archive (SRA) under the accession number: PRJNA1365939 (https://www.ncbi.nlm.nih.gov/sra/PRJNA1365939). Source data are provided with this paper.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 28 authors, 2 keywords, 18 MeSH terms, 1 funder, 97 references.

Cite

This paper

Chen, X., Xie, Q., Nath, S. J., Tang, M., Ma, H., Günes, Y. Ö., Sharma, T., Liu, H., Cui, M., Du, A., Lu, M., Liu, S. Y., Wassamon, B., Xu, M., Wu, J. Y., Su, Q., Fitzgibbons, T. P., Liu, J., Wan, F., . . . Xie, J. (2026). Long-term comparative analysis of AAV9-mediated gene replacement therapies for spinal muscular atrophy in mice. Nature communications, 17(1), 6767. https://doi.org/10.1038/s41467-026-73545-8

BibTeX

@article{chen2026long,
author = {Chen, Xiupeng and Xie, Qing and Nath, Sarah J. and Tang, Mojiao and Ma, Hong and Günes, Yasemin Özgür and Sharma, Tapan and Liu, Hao and Cui, Mengtian and Du, Ailing and Lu, Mengjia and Liu, Sophia Y. and Wassamon, Boonying and Xu, Mengyao and Wu, Joseph Yunxi and Su, Qin and Fitzgibbons, Timothy P. and Liu, Jinghua and Wan, Fang and Kumanan, Veena and He, Ran and Ma, Yijie and Yang, Jun and Gray-Edwards, Heather L. and Gallagher, Thomas L. and Tai, Phillip W. L. and Gao, Guangping and Xie, Jun},
title = {{Long-term comparative analysis of AAV9-mediated gene replacement therapies for spinal muscular atrophy in mice}},
journal = {Nature communications},
year = {2026},
month = may,
volume = {17},
number = {1},
pages = {6767},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/s41467-026-73545-8},
url = {https://doi.org/10.1038/s41467-026-73545-8},
pmid = {42177183},
pmcid = {PMC13385853}
}

RIS

TY - JOUR
AU - Chen, Xiupeng
AU - Xie, Qing
AU - Nath, Sarah J.
AU - Tang, Mojiao
AU - Ma, Hong
AU - Günes, Yasemin Özgür
AU - Sharma, Tapan
AU - Liu, Hao
AU - Cui, Mengtian
AU - Du, Ailing
AU - Lu, Mengjia
AU - Liu, Sophia Y.
AU - Wassamon, Boonying
AU - Xu, Mengyao
AU - Wu, Joseph Yunxi
AU - Su, Qin
AU - Fitzgibbons, Timothy P.
AU - Liu, Jinghua
AU - Wan, Fang
AU - Kumanan, Veena
AU - He, Ran
AU - Ma, Yijie
AU - Yang, Jun
AU - Gray-Edwards, Heather L.
AU - Gallagher, Thomas L.
AU - Tai, Phillip W. L.
AU - Gao, Guangping
AU - Xie, Jun
TI - Long-term comparative analysis of AAV9-mediated gene replacement therapies for spinal muscular atrophy in mice
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/05/23
VL - 17
IS - 1
SP - 6767
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/s41467-026-73545-8
UR - https://doi.org/10.1038/s41467-026-73545-8
LA - en
ER -

CSL-JSON

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