Restoring the natural tropism of AAV2 vectors for human liver

Restoring the natural tropism of AAV2 vectors for human liver.

Full text not available from this repository.
Item Type: Article
Status: Published
Official URL: https://doi.org/10.1126/scitranslmed.aba3312
Journal or Publication Title: Science Translational Medicine
Volume: 12
Number: 560
Page Range: eaba3312
Date: 2020
Divisions: Liver Injury and Cancer
Depositing User: General Admin
Identification Number: 10.1126/scitranslmed.aba3312
ISSN: 1946-6234
Date Deposited: 04 Jan 2021 02:31
Abstract:

Recent clinical successes in gene therapy applications have intensified interest in using adeno-associated viruses (AAVs) as vectors for therapeutic gene delivery. Although prototypical AAV2 shows robust in vitro transduction of human hepatocyte–derived cell lines, it has not translated into an effective vector for liver-directed gene therapy in vivo. This is consistent with observations made in Fah−/−/Rag2−/−/Il2rg−/− (FRG) mice with humanized livers, showing that AAV2 functions poorly in this xenograft model. Here, we derived naturally hepatotropic AAV capsid sequences from primary human liver samples. We demonstrated that capsid mutations, likely acquired as an unintentional consequence of tissue culture propagation, attenuated the intrinsic human hepatic tropism of natural AAV2 and related human liver AAV isolates. These mutations resulted in amino acid changes that increased binding to heparan sulfate proteoglycan (HSPG), which has been regarded as the primary cellular receptor mediating AAV2 infection of human hepatocytes. Propagation of natural AAV variants in vitro showed tissue culture adaptation with resulting loss of tropism for human hepatocytes. In vivo readaptation of the prototypical AAV2 in FRG mice with a humanized liver resulted in restoration of the intrinsic hepatic tropism of AAV2 through decreased binding to HSPG. Our results challenge the notion that high affinity for HSPG is essential for AAV2 entry into human hepatocytes and suggest that natural AAV capsids of human liver origin are likely to be more effective for liver-targeted gene therapy applications than culture-adapted AAV2.

Creators:
Creators
Email
Cabanes-Creus, Marti
UNSPECIFIED
Hallwirth, Claus V.
UNSPECIFIED
Westhaus, Adrian
UNSPECIFIED
Ng, Boaz H.
UNSPECIFIED
Liao, Sophia H.Y.
UNSPECIFIED
Zhu, Erhua
UNSPECIFIED
Navarro, Renina Gale
UNSPECIFIED
Baltazar, Grober
UNSPECIFIED
Drouyer, Matthieu
UNSPECIFIED
Scott, Suzanne
UNSPECIFIED
Logan, Grant J.
UNSPECIFIED
Santilli, Giorgia
UNSPECIFIED
Bennett, Antonette
UNSPECIFIED
Ginn, Samantha L.
UNSPECIFIED
McCaughan, Geoff
UNSPECIFIED
Thrasher, Adrian J.
UNSPECIFIED
Agbandje-McKenna, Mavis
UNSPECIFIED
Alexander, Ian E.
UNSPECIFIED
Lisowski, Leszek
UNSPECIFIED
Last Modified: 04 Jan 2021 02:31
URI: https://eprints.centenary.org.au/id/eprint/777

Actions (login required)

View Item View Item