In:
PLOS Biology, Public Library of Science (PLoS), Vol. 21, No. 7 ( 2023-7-19), p. e3002112-
Abstract:
Viruses have evolved the ability to bind and enter cells through interactions with a wide variety of cell macromolecules. We engineered peptide-modified adeno-associated virus (AAV) capsids that transduce the brain through the introduction of de novo interactions with 2 proteins expressed on the mouse blood–brain barrier (BBB), LY6A or LY6C1. The in vivo tropisms of these capsids are predictable as they are dependent on the cell- and strain-specific expression of their target protein. This approach generated hundreds of capsids with dramatically enhanced central nervous system (CNS) tropisms within a single round of screening in vitro and secondary validation in vivo thereby reducing the use of animals in comparison to conventional multi-round in vivo selections. The reproducible and quantitative data derived via this method enabled both saturation mutagenesis and machine learning (ML)-guided exploration of the capsid sequence space. Notably, during our validation process, we determined that nearly all published AAV capsids that were selected for their ability to cross the BBB in mice leverage either the LY6A or LY6C1 protein, which are not present in primates. This work demonstrates that AAV capsids can be directly targeted to specific proteins to generate potent gene delivery vectors with known mechanisms of action and predictable tropisms.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3002112
DOI:
10.1371/journal.pbio.3002112.g001
DOI:
10.1371/journal.pbio.3002112.g002
DOI:
10.1371/journal.pbio.3002112.g003
DOI:
10.1371/journal.pbio.3002112.g004
DOI:
10.1371/journal.pbio.3002112.t001
DOI:
10.1371/journal.pbio.3002112.s001
DOI:
10.1371/journal.pbio.3002112.s002
DOI:
10.1371/journal.pbio.3002112.s003
DOI:
10.1371/journal.pbio.3002112.s004
DOI:
10.1371/journal.pbio.3002112.s005
DOI:
10.1371/journal.pbio.3002112.s006
DOI:
10.1371/journal.pbio.3002112.s007
DOI:
10.1371/journal.pbio.3002112.s008
DOI:
10.1371/journal.pbio.3002112.s009
DOI:
10.1371/journal.pbio.3002112.s010
DOI:
10.1371/journal.pbio.3002112.s011
DOI:
10.1371/journal.pbio.3002112.s012
DOI:
10.1371/journal.pbio.3002112.s013
DOI:
10.1371/journal.pbio.3002112.s014
DOI:
10.1371/journal.pbio.3002112.s015
DOI:
10.1371/journal.pbio.3002112.s016
DOI:
10.1371/journal.pbio.3002112.s017
DOI:
10.1371/journal.pbio.3002112.s018
DOI:
10.1371/journal.pbio.3002112.s019
DOI:
10.1371/journal.pbio.3002112.s020
DOI:
10.1371/journal.pbio.3002112.s021
DOI:
10.1371/journal.pbio.3002112.s022
DOI:
10.1371/journal.pbio.3002112.s023
DOI:
10.1371/journal.pbio.3002112.s024
DOI:
10.1371/journal.pbio.3002112.s025
DOI:
10.1371/journal.pbio.3002112.s026
DOI:
10.1371/journal.pbio.3002112.s027
DOI:
10.1371/journal.pbio.3002112.s028
DOI:
10.1371/journal.pbio.3002112.s029
DOI:
10.1371/journal.pbio.3002112.s030
DOI:
10.1371/journal.pbio.3002112.s031
DOI:
10.1371/journal.pbio.3002112.s032
DOI:
10.1371/journal.pbio.3002112.s033
DOI:
10.1371/journal.pbio.3002112.s034
DOI:
10.1371/journal.pbio.3002112.s035
DOI:
10.1371/journal.pbio.3002112.s036
DOI:
10.1371/journal.pbio.3002112.s037
DOI:
10.1371/journal.pbio.3002112.s038
DOI:
10.1371/journal.pbio.3002112.s039
DOI:
10.1371/journal.pbio.3002112.r001
DOI:
10.1371/journal.pbio.3002112.r002
DOI:
10.1371/journal.pbio.3002112.r003
DOI:
10.1371/journal.pbio.3002112.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2126773-X
Bookmarklink