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PreprintCited by 2Virus-based gene therapy researchRNA Interference and Gene DeliveryBarrier Structure and Function Studies

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Bridge protein-mediated viral targeting of cells expressing endogenous μ-opioid G protein-coupled receptors in the mouse and monkey brain

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Kamaguchi, Riki, Amemori, Satoko, Amemori, Ken-ichi, Osakada, Fumitaka·2025·Neuroscience Research
DOI 10.1101/2025.02.08.637063

Preprint — published as 10.1016/j.neures.2025.02.007 · Paper page

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Abstract

Targeting specific cell types is essential for understanding their functional roles in the brain. Although genetic approaches enable cell-type-specific targeting in animals, their application to higher mammalian species, such as nonhuman primates, remains challenging. Here, we developed a nontransgenic method using bridge proteins to direct viral vectors to cells endogenously expressing μ-opioid receptors (MORs), a G protein-coupled receptor. The bridge protein comprises the avian viral receptor TVB, the MOR ligand β-endorphin (βed), and an interdomain linker. EnvB-enveloped viruses bind to the TVB component, followed by the interaction of βed with MORs, triggering viral infection in MOR-expressing cells. We optimized the secretion signals, domain configurations, and interdomain linkers of the bridge proteins to maximize viral targeting efficiency and specificity. Alternative configurations incorporating different ligands and viral receptors also induced viral infection in MOR-expressing cells. The optimized βed-f2-TVB bridge protein with EnvB-pseudotyped lentiviruses induced infection in MOR-expressing cells in the striatum of mice and monkeys. An intersectional approach combining βed-f2-TVB with a neuron-specific promoter refined cell-type specificity. This study establishes the foundation for the rational bridge protein design and the feasibility of targeting G protein-coupled receptors beyond tyrosine kinase receptors, thereby expanding targetable cell types in the brain and throughout the body. Graphical abstract:

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Metadata

Authors
Kamaguchi, R., Amemori, S., Amemori, K.-I., & Osakada, F.
Affiliations
  • Nagoya University (JP)
  • Japan Society for the Promotion of Science (JP)
  • Kyoto University (JP)
  • Japan Science and Technology Agency (JP)
Corresponding author
Osakada, Fumitaka
ORCID
Venue
Neuroscience Research
Publisher
openRxiv
Published
2025-02-08
Volume
213
Pages
35-50
ISSN
0168-0102 (ISSN-L)
DOI
10.1101/2025.02.08.637063
OpenAlex
W4407438968
Cited by
2
References
2
Citations by year
2026: 2
FWCI
1.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuroscience Research (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Naito Foundation
  • Suzuken Memorial Foundation
  • Takeda Science Foundation
  • Japan Agency for Medical Research and Development (JP24wm0625110h)
  • Japan Society for the Promotion of Science (23K20319, 18H02706, 21H05168, 23K24034, 21K19428, 21H04812, 20K21476, 21K07259, 22KJ1760, 20H03555, 21H05169, 21J40030)
  • Japan Science and Technology Agency (JPMJCR1851, JPMJPR14F6)
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
viral vector targeting, mu-opioid receptor, G protein-coupled receptors, beta-endorphin, striatum, non-human primates
MeSH terms
Animals, Brain, Genetic Vectors, Humans, Mice, Inbred C57BL, Neurons, Lentivirus, Receptors, Opioid, mu, Mice, HEK293 Cells

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