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Nature. 2014 Feb 20;506(7488):382-6. doi: 10.1038/nature12875. Epub 2013 Dec 25.

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

Author information

1
1] Stanford University, School of Medicine, Departments of Pediatrics and Genetics, 269 Campus Drive, Stanford, California 94305, USA [2] Gene Transfer, Targeting and Therapeutics Core, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd, San Diego, California 92037, USA (L.L.); Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK (A.P.D.).
2
1] Gene Therapy Research Unit, The Children's Hospital at Westmead and Children's Medical Research Institute, Locked Bag 4001, Westmead, 2145 New South Wales, Australia [2] Gene Transfer, Targeting and Therapeutics Core, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd, San Diego, California 92037, USA (L.L.); Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK (A.P.D.).
3
Stanford University, School of Medicine, Departments of Pediatrics and Genetics, 269 Campus Drive, Stanford, California 94305, USA.
4
Gene Therapy Research Unit, The Children's Hospital at Westmead and Children's Medical Research Institute, Locked Bag 4001, Westmead, 2145 New South Wales, Australia.
5
Yecuris Corporation, Portland, Oregon 97062, USA.
6
Oregon Stem Cell Center, Oregon Health and Science University, Portland, Oregon 97239, USA.
7
1] Gene Therapy Research Unit, The Children's Hospital at Westmead and Children's Medical Research Institute, Locked Bag 4001, Westmead, 2145 New South Wales, Australia [2] Discipline of Paediatrics and Child Health, The University of Sydney, 2145 New South Wales, Australia.

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.

PMID:
24390344
PMCID:
PMC3939040
DOI:
10.1038/nature12875
[Indexed for MEDLINE]
Free PMC Article
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