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

Marcus Davidsson, Gang Wang, Patrick Aldrin-Kirk, Tiago Cardoso, Sara Nolbrant, Morgan Hartnor, Janitha Mudannayake, Malin Parmar, Tomas Björklund

Research output: Contribution to journalArticlepeer-review

36 Citations (SciVal)
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Abstract

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.

Original languageEnglish
Pages (from-to)27053-27062
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number52
Early online date2019 Dec 9
DOIs
Publication statusPublished - 2019 Dec 26

Bibliographical note

Copyright © 2019 the Author(s). Published by PNAS.

Subject classification (UKÄ)

  • Neurosciences

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