Cited by 453Virus-based gene therapy researchRNA Interference and Gene DeliveryBarrier Structure and Function Studies

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Selection and evaluation of clinically relevant AAV variants in a xenograft liver model

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Lisowski, Leszek, Dane, Allison P., Chu, Kirk, Zhang, Yue, Cunningham, Sharon C., Wilson, Elizabeth M., Nygaard, Sean, Grompe, Markus, Alexander, Ian E., Kay, Mark A.·2014·Nature

DOI 10.1038/nature12875PMC PMC3939040

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Abstract

Recombinant adeno-associated viral (rAAV) vectors have shown early promise in clinical trials. The therapeutic transgene cassette can be packaged in different AAV capsid pseudotypes, each having a unique transduction profile. At present, rAAV capsid serotype selection for a specific clinical trial is based on effectiveness in animal models. However, preclinical animal studies are not always predictive of human outcome. Here, in an attempt to further our understanding of these discrepancies, we used a chimaeric human-murine liver model to compare directly the relative efficiency of rAAV transduction in human versus mouse hepatocytes in vivo. As predicted from preclinical and clinical studies, rAAV2 vectors functionally transduced mouse and human hepatocytes at equivalent but relatively low levels. However, rAAV8 vectors, which are very effective in many animal models, transduced human hepatocytes rather poorly-approximately 20 times less efficiently than mouse hepatocytes. In light of the limitations of the rAAV vectors currently used in clinical studies, we used the same murine chimaeric liver model to perform serial selection using a human-specific replication-competent viral library composed of DNA-shuffled AAV capsids. One chimaeric capsid composed of five different parental AAV capsids was found to transduce human primary hepatocytes at high efficiency in vitro and in vivo, and provided species-selected transduction in primary liver, cultured cells and a hepatocellular carcinoma xenograft model. This vector is an ideal clinical candidate and a reagent for gene modification of human xenotransplants in mouse models of human diseases. More importantly, our results suggest that humanized murine models may represent a more precise approach for both selecting and evaluating clinically relevant rAAV serotypes for gene therapeutic applications.

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Authors: Lisowski, L., Dane, A. P., Chu, K., Zhang, Y., Cunningham, S. C., Wilson, E. M., Nygaard, S., Grompe, M., Alexander, I. E., & Kay, M. A.
Affiliations: Salk Institute for Biological Studies (US)
Stanford Medicine (US)
Children's Medical Research Institute (AU)
Yecuris (United States) (US)
Oregon Health & Science University (US)
The University of Sydney (AU)
Corresponding author: Kay, Mark A.
ORCID: Lisowski, Leszek
Zhang, Yue
Cunningham, Sharon C.
Wilson, Elizabeth M.
Nygaard, Sean
Grompe, Markus
Alexander, Ian E.
Kay, Mark A.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2013-12-25
Volume: 506
Issue: 7488
Pages: 382-386
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature12875
PMC: PMC3939040
OpenAlex: W1981950767
Cited by: 450
References: 36
Citations by year: 2026: 20 · 2025: 28 · 2024: 36 · 2023: 39 · 2022: 45 · 2021: 34 · 2020: 42 · 2019: 36 · 2018: 32 · 2017: 41 · 2016: 35 · 2015: 46 · 2014: 14 · 2013: 1
FWCI: 21.18
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Heart, Lung, and Blood Institute (HL064274, HL092096, R01HL092096, R01HL064274)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK048252, DK048252)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords: recombinant adeno-associated virus, AAV serotype 2, xenotransplantation, DNA shuffling, gene therapy vectors
MeSH terms: Dependovirus, Animals, Capsid, Cells, Cultured, Chimera, Clinical Trials as Topic, Disease Models, Animal, Female, Genetic Vectors, Carcinoma, Hepatocellular, Humans, Liver, Male, Species Specificity, Transduction, Genetic, Genetic Therapy, Transgenes, Hepatocytes, Capsid Proteins, Cell Line, Tumor, Mice, Heterografts

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Selection and evaluation of clinically relevant AAV variants in a xenograft liver model

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