Blood-brain barrier shuttle peptides enhance AAV transduction in the brain after systemic administration
Open accessAbstract
The adeno-associated virus (AAV) vector has been used in preclinical and clinical trials of gene therapy for central nervous system (CNS) diseases. One of the biggest challenges of effectively delivering AAV to the brain is to surmount the blood-brain barrier (BBB). Herein, we identified several potential BBB shuttle peptides that significantly enhanced AAV8 transduction in the brain after a systemic administration, the best of which was the THR peptide. The enhancement of AAV8 brain transduction by THR is dose-dependent, and neurons are the primary THR targets. Mechanism studies revealed that THR directly bound to the AAV8 virion, increasing its ability to cross the endothelial cell barrier. Further experiments showed that binding of THR to the AAV virion did not interfere with AAV8 infection biology, and that THR competitively blocked transferrin from binding to AAV8. Taken together, our results demonstrate, for the first time, that BBB shuttle peptides are able to directly interact with AAV and increase the ability of the AAV vectors to cross the BBB for transduction enhancement in the brain. These results will shed important light on the potential applications of BBB shuttle peptides for enhancing brain transduction with systemic administration of AAV vectors.
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THR peptide can increase BBB-crossing efficiency of AAV9 and improve brain transduction in a dose-dependent manner in mice.
“can increase the BBB-crossing efficiency of AAV9 and improve brain transduction in a dose-dependent manner in mice.”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [143]
Results §3.2 (page unavailable) reports dose-dependent improvement in brain transduction in mice given THR-treated AAV8. Results §3.3 links THR to increased AAV8 crossing of the BBB. The cited experiments concern AAV8, not the AAV9 specified in the claim. (LLM, conf=0.90)
Experimental — accuracy not yet measuredTHR peptide increased AAV8 transcytosis in hCMEC/D3 endothelial cells and delivered more virion across the BBB to the brain parenchyma.
“further mechanistic study revealed the THR peptide increased the AAV8 transcytosis in hCMEC/D3 endothelial cells and delivered more virion across the BBB to the brain parenchyma [143].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [143]
THR peptide specifically binds to transferrin receptor 1 (TfR1).
“a BBB shuttle peptide THR, which specifically binds to the transferrin receptor 1 (TfR1) [143]”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [143]
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- Authors
- Zhang, X., He, T., Chai, Z., Samulski, R. J., & Li, C.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Li, Chengwen
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 176
- Pages
- 71-83
- ISSN
- 0142-9612 (ISSN-L)
- PMC
- PMC5999585
- OpenAlex
- W2804578605
- Cited by
- 65
- References
- 51
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 9 · 2023: 9 · 2022: 5 · 2021: 13 · 2020: 8 · 2019: 5 · 2018: 2 · 2017: 1
- FWCI
- 3.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01AI117408, P30-CA016086-35-37, R01HL125749, U54-CA151652-01-04)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- 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
- Keywords
- blood-brain barrier, adeno-associated virus, AAV8, systemic gene delivery, transferrin, CNS gene therapy
- MeSH terms
- Dependovirus, Animals, Blood-Brain Barrier, Cell Line, Cell Survival, Endothelium, Vascular, Female, Genetic Vectors, Humans, Luciferases, Mice, Inbred C57BL, Peptides, Permeability, Plasmids, Transduction, Genetic, Virion
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