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Targeting AAV vectors to the central nervous system by engineering capsid–receptor interactions that enable crossing of the blood–brain barrier

Viruses have evolved the ability to bind and enter cells through interactions with a wide variety of cell macromolecules. We engineered peptide-modified adeno-associated virus (AAV) capsids that transduce the brain through the introduction of de novo interactions with 2 proteins expressed on the mou...

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Autores principales: Huang, Qin, Chen, Albert T., Chan, Ken Y., Sorensen, Hikari, Barry, Andrew J., Azari, Bahar, Zheng, Qingxia, Beddow, Thomas, Zhao, Binhui, Tobey, Isabelle G., Moncada-Reid, Cynthia, Eid, Fatma-Elzahraa, Walkey, Christopher J., Ljungberg, M. Cecilia, Lagor, William R., Heaney, Jason D., Chan, Yujia A., Deverman, Benjamin E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10355383/
https://www.ncbi.nlm.nih.gov/pubmed/37467291
http://dx.doi.org/10.1371/journal.pbio.3002112
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author Huang, Qin
Chen, Albert T.
Chan, Ken Y.
Sorensen, Hikari
Barry, Andrew J.
Azari, Bahar
Zheng, Qingxia
Beddow, Thomas
Zhao, Binhui
Tobey, Isabelle G.
Moncada-Reid, Cynthia
Eid, Fatma-Elzahraa
Walkey, Christopher J.
Ljungberg, M. Cecilia
Lagor, William R.
Heaney, Jason D.
Chan, Yujia A.
Deverman, Benjamin E.
author_facet Huang, Qin
Chen, Albert T.
Chan, Ken Y.
Sorensen, Hikari
Barry, Andrew J.
Azari, Bahar
Zheng, Qingxia
Beddow, Thomas
Zhao, Binhui
Tobey, Isabelle G.
Moncada-Reid, Cynthia
Eid, Fatma-Elzahraa
Walkey, Christopher J.
Ljungberg, M. Cecilia
Lagor, William R.
Heaney, Jason D.
Chan, Yujia A.
Deverman, Benjamin E.
author_sort Huang, Qin
collection PubMed
description Viruses have evolved the ability to bind and enter cells through interactions with a wide variety of cell macromolecules. We engineered peptide-modified adeno-associated virus (AAV) capsids that transduce the brain through the introduction of de novo interactions with 2 proteins expressed on the mouse blood–brain barrier (BBB), LY6A or LY6C1. The in vivo tropisms of these capsids are predictable as they are dependent on the cell- and strain-specific expression of their target protein. This approach generated hundreds of capsids with dramatically enhanced central nervous system (CNS) tropisms within a single round of screening in vitro and secondary validation in vivo thereby reducing the use of animals in comparison to conventional multi-round in vivo selections. The reproducible and quantitative data derived via this method enabled both saturation mutagenesis and machine learning (ML)-guided exploration of the capsid sequence space. Notably, during our validation process, we determined that nearly all published AAV capsids that were selected for their ability to cross the BBB in mice leverage either the LY6A or LY6C1 protein, which are not present in primates. This work demonstrates that AAV capsids can be directly targeted to specific proteins to generate potent gene delivery vectors with known mechanisms of action and predictable tropisms.
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spelling pubmed-103553832023-07-20 Targeting AAV vectors to the central nervous system by engineering capsid–receptor interactions that enable crossing of the blood–brain barrier Huang, Qin Chen, Albert T. Chan, Ken Y. Sorensen, Hikari Barry, Andrew J. Azari, Bahar Zheng, Qingxia Beddow, Thomas Zhao, Binhui Tobey, Isabelle G. Moncada-Reid, Cynthia Eid, Fatma-Elzahraa Walkey, Christopher J. Ljungberg, M. Cecilia Lagor, William R. Heaney, Jason D. Chan, Yujia A. Deverman, Benjamin E. PLoS Biol Methods and Resources Viruses have evolved the ability to bind and enter cells through interactions with a wide variety of cell macromolecules. We engineered peptide-modified adeno-associated virus (AAV) capsids that transduce the brain through the introduction of de novo interactions with 2 proteins expressed on the mouse blood–brain barrier (BBB), LY6A or LY6C1. The in vivo tropisms of these capsids are predictable as they are dependent on the cell- and strain-specific expression of their target protein. This approach generated hundreds of capsids with dramatically enhanced central nervous system (CNS) tropisms within a single round of screening in vitro and secondary validation in vivo thereby reducing the use of animals in comparison to conventional multi-round in vivo selections. The reproducible and quantitative data derived via this method enabled both saturation mutagenesis and machine learning (ML)-guided exploration of the capsid sequence space. Notably, during our validation process, we determined that nearly all published AAV capsids that were selected for their ability to cross the BBB in mice leverage either the LY6A or LY6C1 protein, which are not present in primates. This work demonstrates that AAV capsids can be directly targeted to specific proteins to generate potent gene delivery vectors with known mechanisms of action and predictable tropisms. Public Library of Science 2023-07-19 /pmc/articles/PMC10355383/ /pubmed/37467291 http://dx.doi.org/10.1371/journal.pbio.3002112 Text en © 2023 Huang et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Methods and Resources
Huang, Qin
Chen, Albert T.
Chan, Ken Y.
Sorensen, Hikari
Barry, Andrew J.
Azari, Bahar
Zheng, Qingxia
Beddow, Thomas
Zhao, Binhui
Tobey, Isabelle G.
Moncada-Reid, Cynthia
Eid, Fatma-Elzahraa
Walkey, Christopher J.
Ljungberg, M. Cecilia
Lagor, William R.
Heaney, Jason D.
Chan, Yujia A.
Deverman, Benjamin E.
Targeting AAV vectors to the central nervous system by engineering capsid–receptor interactions that enable crossing of the blood–brain barrier
title Targeting AAV vectors to the central nervous system by engineering capsid–receptor interactions that enable crossing of the blood–brain barrier
title_full Targeting AAV vectors to the central nervous system by engineering capsid–receptor interactions that enable crossing of the blood–brain barrier
title_fullStr Targeting AAV vectors to the central nervous system by engineering capsid–receptor interactions that enable crossing of the blood–brain barrier
title_full_unstemmed Targeting AAV vectors to the central nervous system by engineering capsid–receptor interactions that enable crossing of the blood–brain barrier
title_short Targeting AAV vectors to the central nervous system by engineering capsid–receptor interactions that enable crossing of the blood–brain barrier
title_sort targeting aav vectors to the central nervous system by engineering capsid–receptor interactions that enable crossing of the blood–brain barrier
topic Methods and Resources
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10355383/
https://www.ncbi.nlm.nih.gov/pubmed/37467291
http://dx.doi.org/10.1371/journal.pbio.3002112
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