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A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism

Adeno-associated virus (AAV) capsid modification enables the generation of recombinant vectors with tailored properties and tropism. Most approaches to date depend on random screening, enrichment, and serendipity. The approach explored here, called BRAVE (barcoded rational AAV vector evolution), ena...

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Autores principales: Davidsson, Marcus, Wang, Gang, Aldrin-Kirk, Patrick, Cardoso, Tiago, Nolbrant, Sara, Hartnor, Morgan, Mudannayake, Janitha, Parmar, Malin, Björklund, Tomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936499/
https://www.ncbi.nlm.nih.gov/pubmed/31818949
http://dx.doi.org/10.1073/pnas.1910061116
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author Davidsson, Marcus
Wang, Gang
Aldrin-Kirk, Patrick
Cardoso, Tiago
Nolbrant, Sara
Hartnor, Morgan
Mudannayake, Janitha
Parmar, Malin
Björklund, Tomas
author_facet Davidsson, Marcus
Wang, Gang
Aldrin-Kirk, Patrick
Cardoso, Tiago
Nolbrant, Sara
Hartnor, Morgan
Mudannayake, Janitha
Parmar, Malin
Björklund, Tomas
author_sort Davidsson, Marcus
collection PubMed
description Adeno-associated virus (AAV) capsid modification enables the generation of recombinant vectors with tailored properties and tropism. Most approaches to date depend on random screening, enrichment, and serendipity. The approach explored here, called BRAVE (barcoded rational AAV vector evolution), enables efficient selection of engineered capsid structures on a large scale using only a single screening round in vivo. The approach stands in contrast to previous methods that require multiple generations of enrichment. With the BRAVE approach, each virus particle displays a peptide, derived from a protein, of known function on the AAV capsid surface, and a unique molecular barcode in the packaged genome. The sequencing of RNA-expressed barcodes from a single-generation in vivo screen allows the mapping of putative binding sequences from hundreds of proteins simultaneously. Using the BRAVE approach and hidden Markov model-based clustering, we present 25 synthetic capsid variants with refined properties, such as retrograde axonal transport in specific subtypes of neurons, as shown for both rodent and human dopaminergic neurons.
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spelling pubmed-69364992019-12-31 A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism Davidsson, Marcus Wang, Gang Aldrin-Kirk, Patrick Cardoso, Tiago Nolbrant, Sara Hartnor, Morgan Mudannayake, Janitha Parmar, Malin Björklund, Tomas Proc Natl Acad Sci U S A PNAS Plus Adeno-associated virus (AAV) capsid modification enables the generation of recombinant vectors with tailored properties and tropism. Most approaches to date depend on random screening, enrichment, and serendipity. The approach explored here, called BRAVE (barcoded rational AAV vector evolution), enables efficient selection of engineered capsid structures on a large scale using only a single screening round in vivo. The approach stands in contrast to previous methods that require multiple generations of enrichment. With the BRAVE approach, each virus particle displays a peptide, derived from a protein, of known function on the AAV capsid surface, and a unique molecular barcode in the packaged genome. The sequencing of RNA-expressed barcodes from a single-generation in vivo screen allows the mapping of putative binding sequences from hundreds of proteins simultaneously. Using the BRAVE approach and hidden Markov model-based clustering, we present 25 synthetic capsid variants with refined properties, such as retrograde axonal transport in specific subtypes of neurons, as shown for both rodent and human dopaminergic neurons. National Academy of Sciences 2019-12-26 2019-12-09 /pmc/articles/PMC6936499/ /pubmed/31818949 http://dx.doi.org/10.1073/pnas.1910061116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Davidsson, Marcus
Wang, Gang
Aldrin-Kirk, Patrick
Cardoso, Tiago
Nolbrant, Sara
Hartnor, Morgan
Mudannayake, Janitha
Parmar, Malin
Björklund, Tomas
A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism
title A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism
title_full A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism
title_fullStr A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism
title_full_unstemmed A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism
title_short A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism
title_sort systematic capsid evolution approach performed in vivo for the design of aav vectors with tailored properties and tropism
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936499/
https://www.ncbi.nlm.nih.gov/pubmed/31818949
http://dx.doi.org/10.1073/pnas.1910061116
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