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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
Enheter & grupper
Externa organisationer
  • Lund University
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Neurovetenskaper
Originalspråkengelska
Sidor (från-till)27053-27062
Antal sidor10
TidskriftProceedings of the National Academy of Sciences of the United States of America
Volym116
Utgåva nummer52
Tidigt onlinedatum2019 dec 9
StatusPublished - 2019 dec 26
PublikationskategoriForskning
Peer review utfördJa

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