Customized blood-brain barrier shuttle peptide to increase AAV9 vector crossing the BBB and augment transduction in the brain
Open accessAbstract
Recombinant adeno-associated virus (rAAV) vectors have been widely used as favored delivery vehicles for the treatment of inherited diseases in clinical trials, including neurological diseases. However, the noninvasive systemic delivery of rAAV to the central nervous system is severely hampered by the blood-brain barrier (BBB). Several approaches have been exploited to enhance AAV vector brain transduction after systemic administration, including genetic modification of AAV capsids and physical methods. However, these approaches are not always predictive of desirable outcomes in humans and induce complications. It is imperative to explore novel strategies to increase the ability of AAV9 to cross the BBB for enhanced brain transduction. Herein, we have conducted a combinatorial in vivo/in vitro phage display library screening in mouse brains and purified AAV9 virions to identify a customized BBB shuttle peptide, designated as PB5-3. The PB5-3 peptide specifically bound to AAV9 virions and enhanced widespread transduction of AAV9 in mouse brains, especially in neuronal cells, after systemic administration. Further study demonstrated that systemic administration of AAV9 vectors encoding IDUA complexed with PB5-3 increased the phenotypic correction in the brains of MPS I mice. Mechanistic studies revealed that the PB5-3 peptide effectively increased AAV9 trafficking and transcytosis efficiency in the human BBB model hCMEC/D3 cell line but did not interfere with AAV9 binding to the receptor terminal N-linked galactosylated glycans. Additionally, the PB5-3 peptide slowed the clearance of AAV9 from blood without hepatic toxicity. This study highlights, for the first time, the potential of this combinatorial approach for the isolation of peptides that interact with specific AAV vectors for enhanced and targeted AAV transduction. This promising approach will open new combined therapeutic avenues and shed light on the potential applications of peptides for the treatment of human diseases in future clinical trials with AAV vector-mediated gene delivery.
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AAV9-PB5-3 complex used to express IDUA in the MPS I mouse model achieved more than twofold higher expression with successful phenotypic correction in the brains.
“Thus, AAV9-PB5-3 complex was used to express IDUA in the mucopolysaccharidosis type I (MPS I) mouse model and achieved more than twofold higher expression with successful phenotypic correction in the brains.”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [144]
The Results section on the IDUA−/− mouse model reports more than twofold higher brain IDUA activity with AAV9-PB5-3 than with AAV9 alone, and significantly lower GAG levels. The Discussion describes increased phenotypic correction in the brains of MPS I mice. The reported twofold measure was enzyme activity, however, not a direct measure of IDUA expression. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPB5-3 peptide specifically binds to AAV9 serotype and enhances transduction efficiency in different brain cells in mice.
“Another PB5-3 peptide specifically bound to AAV9 serotype and enhanced transduction efficiency in different brain cells in mice [144].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [144]
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- Authors
- Zhang, X., Chai, Z., Lee Dobbins, A., Itano, M. S., Askew, C., Miao, Z., Niu, H., Samulski, R. J., & Li, C.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Li, Chengwen
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2022-02
- Volume
- 281
- Pages
- 121340
- ISSN
- 0142-9612 (ISSN-L)
- PMC
- PMC8810684
- OpenAlex
- W4205094052
- Cited by
- 23
- References
- 51
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 3 · 2023: 4 · 2022: 3
- FWCI
- 1.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- The University of North Carolina at Chapel Hill (P30-CA016086-35-37, P30NS045892, P50HD103573, U54-CA151652-01-04)
- Chan Zuckerberg Initiative
- University of North Carolina (SCR_019060)
- National Institutes of Health (2019-198107, R01AI117408, R01HL125749, R01HL144661)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- AAV9, blood-brain barrier, phage display, systemic gene delivery, mucopolysaccharidosis type I, alpha-L-iduronidase, hCMEC/D3 cells, transcytosis, gene therapy
- MeSH terms
- Dependovirus, Animals, Blood-Brain Barrier, Brain, Genetic Vectors, Peptides, Transduction, Genetic, Gene Transfer Techniques, Mice
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