Development of Patient-specific AAV Vectors After Neutralizing Antibody Selection for Enhanced Muscle Gene Transfer.

Journal Article (Journal Article)

A major hindrance in gene therapy trials with adeno-associated virus (AAV) vectors is the presence of neutralizing antibodies (NAbs) that inhibit AAV transduction. In this study, we used directed evolution techniques in vitro and in mouse muscle to select novel NAb escape AAV chimeric capsid mutants in the presence of individual patient serum. AAV mutants isolated in vitro escaped broad patient-specific NAb activity but had poor transduction ability in vivo. AAV mutants isolated in vivo had enhanced NAb evasion from cognate serum and had high muscle transduction ability. More importantly, structural modeling identified a 100 amino acid motif from AAV6 in variable region (VR) III that confers this enhanced muscle tropism. In addition, a predominantly AAV8 capsid beta barrel template with a specific preference for AAV1/AAV9 in VR VII located at threefold symmetry axis facilitates NAb escape. Our data strongly support that chimeric AAV capsids composed of modular and nonoverlapping domains from various serotypes are capable of evading patient-specific NAbs and have enhanced muscle transduction.

Full Text

Duke Authors

Cited Authors

  • Li, C; Wu, S; Albright, B; Hirsch, M; Li, W; Tseng, Y-S; Agbandje-McKenna, M; McPhee, S; Asokan, A; Samulski, RJ

Published Date

  • February 2016

Published In

Volume / Issue

  • 24 / 1

Start / End Page

  • 53 - 65

PubMed ID

  • 26220272

Pubmed Central ID

  • PMC4754536

Electronic International Standard Serial Number (EISSN)

  • 1525-0024

Digital Object Identifier (DOI)

  • 10.1038/mt.2015.134


  • eng

Conference Location

  • United States