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Comparison of AAV9-driven motor neuron transduction following different CNS-directed delivery methods in mice.

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LICENSE at commit cb74d7c, under CC0-1.0 · at the source

Overview

Authors: Alannah J Mortimer1, Chiara F Sander1, Amisha R Parmar1, Ailsa J Williams1, Mimoun Azzouz1, Guillaume M Hautbergue1, Pamela J Shaw1, Laura Ferraiuolo1, Richard J Mead1
ORCID iDs: Alannah J Mortimer, Mimoun Azzouz
  1. Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
Institutions: University of Sheffield (United Kingdom)
Journal: Scientific reports, volume 16, issue 1, article 12107
Dates: received 14 November 2025; accepted 28 January 2026; published online 4 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41598-026-38039-z · PMID 41781412 · PMCID PMC13076636 · OpenAlex W7133523162
Open access: gold, a free copy (OpenAlex)
Status: empty repository
Categories: mouse (organism)
Methods: Preprocessing, Evoked potentials
Keywords: Gene therapy, Motor neuron, AAV9, ICM, ICV, Neurology, Neuroscience
MeSH: Dependovirus*, Gene Transfer Techniques*, Genetic Vectors*, Motor Neurons*, Transduction, Genetic*, Animals, Astrocytes, Central Nervous System, Genetic Therapy, Green Fluorescent Proteins, Mice, Spinal Cord (* major topic)
Topic: Amyotrophic Lateral Sclerosis Research (Neurology, Medicine), according to OpenAlex
Funding: MND Scotland (2023/MNDS/6501/791MEA); Motor Neurone Disease Association (2023/MNDS/6501/791MEA)
Citations: cited by 3 papers (Europe PMC); 71 references in the paper

Abstract

Gene therapies are promising for diseases previously considered incurable. Adeno-associated virus serotype 9 (AAV9) demonstrates remarkable tropism for motor neurons (MNs) and represents an exciting candidate to target genetic causes of motor neuron diseases like amyotrophic lateral sclerosis (ALS). However, systemic delivery risks immunogenicity and off-target effects, therefore localised delivery to the CNS is advantageous. We assessed MN transduction in wild-type post-natal mice using AAV9-controlled, cytomegalovirus-promoter driven, enhanced GFP expression. Intra-cisterna magna (ICM) and intra-cerebroventricular (ICV) methods were compared. Four weeks post-delivery, GFP positivity in MN and astrocytes were quantified via immunohistochemical approaches and viral genome copy number determined by qPCR. All delivery methods achieved high MN transduction in lumbar spinal cord (> 68%). Unilateral ICV delivery provided the highest and most consistent levels (89 ± 3%), and minimal peripheral viral copies. ICV delivery resulted in higher astrocytic transduction, most notably in the cortex. Brainstem MN transduction was high with all methods (> 55%). We failed to find evidence of neuronal transduction in motor cortex. Viral genome copies trended higher in spinal cord and brainstem with ICV approaches, however further work is required to understand how bilateral repeated dose delivery leads to more profound increases. Whilst several routes of administration into cerebrospinal fluid exist, direct comparisons for targeting MNs in vivo remain limited. Overall, all methods of CNS-directed delivery result in high levels of motor neuron transduction in the lumbar spinal cord and brainstem, but not in motor cortex. Unilateral ICV appears to provide the best balance between consistent, high levels of transduction and low off-target effects. However, ICM might be the better option if seeking to avoid astrocytic transduction.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-026-38039-z.

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

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CFSander/CellProfiler_astrocyte_pipelines

License: CC0-1.0
State: the link answers, verified on 30 September 2026
Evidence: files inventoried
Commit: cb74d7c7afff621aaaf1b03fcdc6b6710ab060c8, 29 October 2024
Size: 7 files, 0 scripts
Software Heritage: not archived
Found in: the text, “Quantification and statistical analysis”
Holds: license file
Not found: README, CITATION.cff, environment file, tests, continuous integration, documentation
Availability: 1 check, the latest on 30 September 2026: the link answers
  • 30 September 2026: the link answers
1 file
At the source: github.com/CFSander/CellProfiler_astrocyte_pipelines.git

Tracing map

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Data availability

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 7 keywords, 12 MeSH terms, 2 funders, 71 references.

Cite

This paper

Mortimer, A. J., Sander, C. F., Parmar, A. R., Williams, A. J., Azzouz, M., Hautbergue, G. M., Shaw, P. J., Ferraiuolo, L., & Mead, R. J. (2026). Comparison of AAV9-driven motor neuron transduction following different CNS-directed delivery methods in mice. Scientific reports, 16(1), 12107. https://doi.org/10.1038/s41598-026-38039-z

BibTeX

@article{mortimer2026comparison,
author = {Mortimer, Alannah J and Sander, Chiara F and Parmar, Amisha R and Williams, Ailsa J and Azzouz, Mimoun and Hautbergue, Guillaume M and Shaw, Pamela J and Ferraiuolo, Laura and Mead, Richard J},
title = {{Comparison of AAV9-driven motor neuron transduction following different CNS-directed delivery methods in mice}},
journal = {Scientific reports},
year = {2026},
month = mar,
volume = {16},
number = {1},
pages = {12107},
publisher = {Nature Publishing Group},
issn = {2045-2322},
doi = {10.1038/s41598-026-38039-z},
url = {https://doi.org/10.1038/s41598-026-38039-z},
pmid = {41781412},
pmcid = {PMC13076636}
}

RIS

TY - JOUR
AU - Mortimer, Alannah J
AU - Sander, Chiara F
AU - Parmar, Amisha R
AU - Williams, Ailsa J
AU - Azzouz, Mimoun
AU - Hautbergue, Guillaume M
AU - Shaw, Pamela J
AU - Ferraiuolo, Laura
AU - Mead, Richard J
TI - Comparison of AAV9-driven motor neuron transduction following different CNS-directed delivery methods in mice
T2 - Scientific reports
J2 - Sci Rep
PY - 2026
DA - 2026/03/04
VL - 16
IS - 1
SP - 12107
SN - 2045-2322
PB - Nature Publishing Group
DO - 10.1038/s41598-026-38039-z
UR - https://doi.org/10.1038/s41598-026-38039-z
LA - en
ER -

CSL-JSON

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