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Rapid evolution of blood-brain-barrier-penetrating AAV capsids by RNA-driven biopanning
Open accessAbstract
Therapeutic payload delivery to the central nervous system (CNS) remains a major challenge in gene therapy. Recent studies using function-driven evolution of adeno-associated virus (AAV) vectors have successfully identified engineered capsids with improved blood-brain barrier (BBB) penetration and CNS tropism in mouse. However, these strategies require transgenic animals and thus are limited to rodents. To address this issue, we developed a directed evolution approach based on recovery of capsid library RNA transcribed from CNS-restricted promoters. This RNA-driven screen platform, termed TRACER (Tropism Redirection of AAV by Cell-type-specific Expression of RNA), was tested in the mouse with AAV9 peptide display libraries and showed rapid emergence of dominant sequences. Ten individual variants were characterized and showed up to 400-fold higher brain transduction over AAV9 following systemic administration. Our results demonstrate that the TRACER platform allows rapid selection of AAV capsids with robust BBB penetration and CNS tropism in non-transgenic animals.
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“including 9P31 with up to 400-fold higher brain transduction [130].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [130]
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“Voyager Therapeutics built up another platform called TRACER (Tropism Redirection of AAV by Cell-type-specific Expression of RNA) and identified ten enhanced variants in C57BL/6 mice”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [130]
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- Hordeaux, 2018, The Neurotropic Properties of AAV-PHP.B Are Limited to C57BL/6J Mice, Mol. Ther., 26, 664, 10.1016/j.ymthe.2018.01.018 · DOI · Paper page
- Hordeaux, 2019, The GPI-Linked Protein LY6A Drives AAV-PHP.B Transport across the Blood-Brain Barrier, Mol. Ther., 27, 912, 10.1016/j.ymthe.2019.02.013 · DOI · Paper page
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Metadata
- Authors
- Nonnenmacher, M., Wang, W., Child, M. A., Ren, X.-Q., Huang, C., Ren, A. Z., Tocci, J., Chen, Q., Bittner, K., Tyson, K., Pande, N., Chung, C. H.-Y., Paul, S. M., & Hou, J.
- Affiliations
- Voyager Therapeutics (United States) (US)
- Corresponding author
- Nonnenmacher, Mathieu
- Hou, Jay
- ORCID
- Venue
- Molecular Therapy - Methods & Clinical Development
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 20
- Pages
- 366-378
- ISSN
- 2329-0501 (ISSN-L)
- PMC
- PMC7841218
- OpenAlex
- W3115131581
- Cited by
- 168
- References
- 49
- Citations by year
- 2026: 25 · 2025: 46 · 2024: 32 · 2023: 27 · 2022: 28 · 2021: 9
- FWCI
- 9.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Therapy — Methods & Clinical Development (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- 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
- adeno-associated virus vectors, blood-brain barrier penetration
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