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Cited by 23Virus-based gene therapy researchNeuroinflammation and Neurodegeneration MechanismsRNA Interference and Gene Delivery

Simple and highly specific targeting of resident microglia with adeno‐associated virus

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Serrano, Carolina, Cananzi, Sergio, Shen, Tianjin, Wang, Lei-Lei, Zhang, Chun-Li·2024·iScience
DOI 10.1016/j.isci.2024.110706PMC PMC11407971

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Abstract

ABSTRACT Microglia, as the immune cells of the central nervous system (CNS), play dynamic roles in both health and diseased conditions. The ability to genetically target microglia using viruses is crucial for understanding their functions and advancing microglia-based treatments. We here show that resident microglia can be simply and specifically targeted using adeno-associated virus (AAV) vectors containing a 466-bp DNA fragment from the human IBA1 ( hIBA1 ) promoter. This targeting approach is applicable to both resting and reactive microglia. When combining the short hIBA1 promoter with the target sequence of miR124, up to 95% of transduced cells are identified as microglia. Such a simple and highly specific microglia-targeting strategy may be further optimized for research and therapeutics. Significance Statement Brain microglia play critical roles in human health and diseases. Genetic manipulation of these cells will offer numerous therapeutic opportunities. However, there is a lack of relevant strategies to target these cells with high specificity since they are traditionally considered to be refractory to virus transduction. Through in vivo screening of many promoters, this study identified a short promoter from the human IBA1 gene. When incorporated into lentivirus or adeno-associated virus vectors, this promoter proves effective in driving gene expression with high specificity for brain microglia. Such a simple strategy will facilitate specific approaches for microglia-based research.

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  • The IBA1 promoter paired with an artificial miRNA scaffold is a well-established strategy for microglia-specific gene manipulation.

    “This promoter, paired with an artificial miRNA scaffold embedded in the miR‐RNA backbone, is a well‐established strategy for microglia‐specific gene manipulation. 33 , 34 , 35”

    From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [33]

    The Results section on miR124T reports that the hIBA1a promoter combined with miR124 target sites produced highly microglia-specific expression. It does not describe an artificial miRNA scaffold embedded in a miR-RNA backbone; the Introduction presents this promoter-based approach as a finding of the study rather than a well-established strategy. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The IBA1 promoter has been validated extensively for microglial specificity, with reported transduction specificity of up to 95% in resident microglia.

    “The IBA1 promoter used in this study has been validated extensively for microglial specificity, with reported transduction specificity of up to 95% in resident microglia. 33 , 34 , 35”

    From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [33]

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Cited by

Sorted by citations

Authors
Serrano, C., Cananzi, S., Shen, T., Wang, L.-L., & Zhang, C.-L.
Affiliations
The University of Texas Southwestern Medical Center (US)
Corresponding author
Zhang, Chun-Li
ORCID
Venue
iScience
Publisher
Elsevier BV
Published
2024-09
Volume
27
Issue
9
Pages
110706
ISSN
2589-0042 (ISSN-L)
DOI
10.1016/j.isci.2024.110706
PMC
PMC11407971
OpenAlex
W4401502523
Cited by
23
References
10
Citations by year
2026: 13 · 2025: 9 · 2024: 1
FWCI
5.66
Type
journal article
Language
en
Open access
Licence
Locations
  • iScience (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (NS127375, NS117065, NS111776)
  • University of Florida
  • Texas Alzheimer's Research and Care Consortium
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
microglia, adeno-associated virus vectors, AAV, reactive microglia, miR-124, viral vector design

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