Cited by 168Virus-based gene therapy researchBarrier Structure and Function StudiesRNA Interference and Gene Delivery

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Rapid evolution of blood-brain-barrier-penetrating AAV capsids by RNA-driven biopanning

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Nonnenmacher, Mathieu, Wang, Wei, Child, Matthew A., Ren, Xiao-Qin, Huang, Carol, Ren, Amy Zhen, Tocci, Jenna, Chen, Qingmin, Bittner, Kelsey, Tyson, Katherine, Pande, Nilesh, Chung, Charlotte Hiu-Yan, Paul, Steven M., Hou, Jay·2021·Molecular Therapy - Methods & Clinical Development

DOI 10.1016/j.omtm.2020.12.006PMC PMC7841218

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Abstract

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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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: Nonnenmacher, Mathieu
Wang, Wei
Huang, Carol
Chen, Qingmin
Chung, Charlotte Hiu-Yan
Paul, Steven M.
Hou, Jay
Venue: Molecular Therapy - Methods & Clinical Development
Publisher: Elsevier BV
Published: 2021-03
Volume: 20
Pages: 366-378
ISSN: 2329-0501 (ISSN-L)
DOI: 10.1016/j.omtm.2020.12.006
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: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
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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Rapid evolution of blood-brain-barrier-penetrating AAV capsids by RNA-driven biopanning

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