Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design.

ABSTRACT: Adeno-associated virus (AAV) capsids can deliver transformative gene therapies, but our understanding of AAV biology remains incomplete. We generated the complete first-order AAV2 capsid fitness landscape, characterizing all single-codon substitutions, insertions, and deletions across multiple functions relevant for in vivo delivery. We discovered a frameshifted gene in the VP1 region that expresses a membrane-associated accessory protein that limits AAV production through competitive exclusion. Mutant biodistribution revealed the importance of both surface-exposed and buried residues, with a few phenotypic profiles characterizing most variants. Finally, we algorithmically designed and experimentally verified a diverse in vivo targeted capsid library with viability far exceeding random mut

SUBMITTER: Ogden PJ 

PROVIDER: S-EPMC7197022 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature