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Selection and evaluation of clinically relevant AAV variants in a xenograft liver model
Open accessAbstract
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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“AAV-NP59 also elicited reduced anti-AAV IgG than AAV-LK03 (119) and AAV8, but not as good as previously discovered engineer capsid AAV-DJ.”
From A versatile toolkit for overcoming AAV immunity (2022) · cites this paper as [119]
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Self-citationElkouby, L., Armour, S. M., Toso, R., DiPietro, M. A., Davidson, R. J., Nguyen, G. N., Willet, M., Kutza, S., Silverberg, J., Frick, J. E., et al. (2021) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2021.11.005 · Cited by 18
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New Directions in Pulmonary Gene Therapy
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“158 AAV-LK03 shares 98.9% of its amino acid sequence with AAV3B, in spite of also having sequence homology with AAV2, AAV4, AAV8, and AAV9 mainly at the N-terminus of VP1.”
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Self-citationAAV-Mediated Gene Delivery to the Mouse Liver
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Liver-directed gene-based therapies for inborn errors of metabolism
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A comprehensive study of AAV tropism across C57BL/6 mice, BALB/c mice, and crab-eating macaques
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“11,22,23 For instance, AAV-PHP.”
Prospect of gene therapy for cardiomyopathy in hereditary muscular dystrophy
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“may provide some hints.[32,212,213] It should be noted that emerging new technologies such as genome editing with CRISPR/Cas9 not only brings in new hopes, they are”
BackgroundHepatocellular Carcinoma Is a Natural Target for Adeno-Associated Virus (AAV) 2 Vectors
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“AAV3, a naturally occurring human AAV serotype, and AAV3-derived engineered capsids (AAV3-Y single and double-mutants, LK03 and AAV3-ST) were reported to show enhanced tropism for human xenograft HCC tissue, with higher efficiency than other AAV serotypes [14,16,27].”
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“22,33 Moreover, the present data with the 12 chimeric AAPs in Fig.”
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“The rAAVs can transduce liver cells with high efficiency and are showing promise in clinical trials [29,30].”
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Insights into Gene Therapy for Urea Cycle Defects by Mathematical Modeling
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“…which are at present the leading system for liver-targeted gene transfer, this translates to a research focus on the identifi-cation of capsids with enhanced tropism in primary human hepatocytes 34,35 rather than optimization of expression cassettes to achieve higher levels of transgene expression.”
Self-citationGene therapy for neurotransmitter‐related disorders
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“26,27 Many novel capsids are being tested in clinical trials, for example, AAV-LK03 (liver-tropic, 28 for haemophilia A (NCT03003533) 29 ), and Anc80 (liver, muscle and retina-targetting, 30 for Wilson disease [NCT04537377]).”
Current and Emerging Issues in Adeno-Associated Virus Vector-Mediated Liver-Directed Gene Therapy
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An In Vitro Whole-Organ Liver Engineering for Testing of Genetic Therapies
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Selecting the Best AAV Capsid for Human Studies
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Self-citationRecent progress in gene therapy for familial hypercholesterolemia treatment
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Therapeutic Advances in Hematology
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“From a gene delivery perspective, this would include pseudo-serotyping the rAAV vector with a highly human liver tropic capsid such as the AAV-SYDs 53 or AAV-LK03, 54 rather than the murine liver tropic AAV8 capsid serotype.”
BackgroundSelf-citationEscape or Fight: Inhibitors in Hemophilia A
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“The humanized mouse liver system has been used to evaluate clinically relevant AAVs [29] and to improve AAV capsid selection [30].”
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The Evolution of Gene Therapy in the Treatment of Metabolic Liver Diseases
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“More recently, a chimera comprising seven different AAV serotypes (1, 2, 3B, 4, 6, 8 and 9) was engineered, which preferentially transduced human hepatocytes at higher efficiencies than rAAV8, rAAV3B and rAAV-DJ [50].”
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A humanized mouse model for adeno-associated viral gene therapy
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“Unfortunately, many AAV serotypes validated for transduction ef fi ciency in humanized mice transduce murine hepatocytes much better than human hepatocytes 12,13 .”
BackgroundRescue of lysosomal acid lipase deficiency in mice by rAAV8 liver gene transfer
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“In addition, novel rAAV serotypes could be tested to reduce immunogenicity and increase liver targeting speci fi city 69,70 , potentially reducing the required rAAV dose.”
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Potential Applications for Targeted Gene Therapy to Protect Against Anthracycline Cardiotoxicity
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“This same phenomenon was observed in a study that clearly demonstrated capsid-mediated differences in the transduction efficiency of rAAV between human and mouse cells using a xenograft mouse model with a humanized liver (46).”
BackgroundSelf-citation
Metadata
- 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
- Venue
- Nature
- Published
- 2013-12-25
- Volume
- 506
- Issue
- 7488
- Pages
- 382-386
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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