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Cited by 114Virus-based gene therapy researchRNA Interference and Gene DeliveryBarrier Structure and Function Studies

Optimization of adeno-associated viral vector-mediated transduction of the corticospinal tract: comparison of four promoters

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Nieuwenhuis, Bart, Haenzi, Barbara, Hilton, Sam, Carnicer-Lombarte, Alejandro, Hobo, Barbara, Verhaagen, Joost, Fawcett, James W.·2021·Gene Therapy
DOI 10.1038/s41434-020-0169-1PMC PMC7902269
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Abstract

Adeno-associated viral vectors are widely used as vehicles for gene transfer to the nervous system. The promoter and viral vector serotype are two key factors that determine the expression dynamics of the transgene. A previous comparative study has demonstrated that AAV1 displays efficient transduction of layer V corticospinal neurons, but the optimal promoter for transgene expression in corticospinal neurons has not been determined yet. In this paper, we report a side-by-side comparison between four commonly used promoters: the short CMV early enhancer/chicken β actin (sCAG), human cytomegalovirus (hCMV), mouse phosphoglycerate kinase (mPGK) and human synapsin (hSYN) promoter. Reporter constructs with each of these promoters were packaged in AAV1, and were injected in the sensorimotor cortex of rats and mice in order to transduce the corticospinal tract. Transgene expression levels and the cellular transduction profile were examined after 6 weeks. The AAV1 vectors harbouring the hCMV and sCAG promoters resulted in transgene expression in neurons, astrocytes and oligodendrocytes. The mPGK and hSYN promoters directed the strongest transgene expression. The mPGK promoter did drive expression in cortical neurons and oligodendrocytes, while transduction with AAV harbouring the hSYN promoter resulted in neuron-specific expression, including perineuronal net expressing interneurons and layer V corticospinal neurons. This promoter comparison study contributes to improve transgene delivery into the brain and spinal cord. The optimized transduction of the corticospinal tract will be beneficial for spinal cord injury research.

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  • The ability of the recombinant AAV genome to persist as an episome in post-mitotic cells, such as neurons, ensures long-term expression even after a single administration.

    “Especially considering the ability of the recombinant AAV genome to persist as an episome in post-mitotic cells, such as neurons, which ensures long-term expression even after a single administration [130-132].”

    From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [130]

    The Conclusions report neuronal transgene expression in mice and rats six weeks after AAV injection, supporting expression after administration. They do not say that the recombinant AAV genome persists as an episome in post-mitotic cells or that this mechanism ensures long-term expression; those parts of the claim are unsupported by our copy. (LLM, conf=0.84)

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References 87 · Cited by 114

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Authors
Nieuwenhuis, B., Haenzi, B., Hilton, S., Carnicer-Lombarte, A., Hobo, B., Verhaagen, J., & Fawcett, J. W.
Affiliations
  • Netherlands Institute for Neuroscience (NL)
  • University of Cambridge (GB)
Corresponding author
Nieuwenhuis, Bart
ORCID
Venue
Gene Therapy
Publisher
Springer Science and Business Media LLC
Published
2020-06-23
Volume
28
Issue
1-2
Pages
56-74
ISSN
  • 0969-7128 (ISSN-L)
  • 1476-5462
DOI
10.1038/s41434-020-0169-1
PMC
PMC7902269
OpenAlex
W3035790625
Cited by
114
References
87
Citations by year
2026: 14 · 2025: 20 · 2024: 11 · 2023: 20 · 2022: 33 · 2021: 13 · 2020: 3
FWCI
10.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Gene Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
  • KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Figshare (submittedVersion, cc-by)
  • VU Research Portal (submittedVersion, other-oa)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
  • Figshare (cc-by)
Funders
  • Cancer Research UK
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (013-16-002)
  • Medical Research Council (MR/R004463/1, MR/R004544/1, MR/V002694/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
adeno-associated virus vectors, AAV1, corticospinal tract, promoter, transgene expression, phosphoglycerate kinase promoter, synapsin promoter, cytomegalovirus promoter, CAG promoter, sensorimotor cortex, neuron-specific expression, oligodendrocytes, astrocytes, spinal cord injury
MeSH terms
Dependovirus, Animals, Genetic Vectors, Promoter Regions, Genetic, Pyramidal Tracts, Transduction, Genetic, Transgenes, Mice, Rats

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