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


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.

SUBMITTER: Davidsson M 

PROVIDER: S-EPMC6936499 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Davidsson Marcus M   Wang Gang G   Aldrin-Kirk Patrick P   Cardoso Tiago T   Nolbrant Sara S   Hartnor Morgan M   Mudannayake Janitha J   Parmar Malin M   Björklund Tomas T  

Proceedings of the National Academy of Sciences of the United States of America 20191209 52


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 generat  ...[more]

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