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

Author:
  • Marcus Davidsson
  • Gang Wang
  • Patrick Aldrin-Kirk
  • Tiago Cardoso
  • Sara Nolbrant
  • Morgan Hartnor
  • Janitha Mudannayake
  • Malin Parmar
  • Tomas Björklund
Publishing year: 2019-12-26
Language: English
Pages: 27053-27062
Publication/Series: Proceedings of the National Academy of Sciences of the United States of America
Volume: 116
Issue: 52
Document type: Journal article
Publisher: National Acad Sciences
Additional info: Copyright © 2019 the Author(s). Published by PNAS.

Abstract english

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.

Keywords

  • Neurosciences

Other

Published
  • Molecular Neuromodulation
  • Developmental and Regenerative Neurobiology
  • ISSN: 1091-6490
Marcus Davidsson
E-mail: marcus [dot] davidsson [at] med [dot] lu [dot] se

Molecular Neuromodulation unit
Wallenberg Neuroscience Center
Department of Experimental Medical Science
BMC A10, 221 84 Lund, Sweden
 
Phone: +46 46 222 68 36
e-Mail: tomas [dot] bjorklund [at] med [dot] lu [dot] se