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 elicited reduced anti-AAV IgG than AAV-LK03 and AAV8, but not as good as previously discovered engineered capsid AAV-DJ.
“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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BackgroundAdeno-associated virus 2 bound to its cellular receptor AAVR
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“We used the AAV8 serotype, which is highly homologous to AAV2 (49) but has a greater capacity to transduce murine hepatocytes (50).”
MethodSystemic delivery of adeno-associated viral vectors
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Gene therapy for hemophilia: what does the future hold?
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Using a barcoded AAV capsid library to select for clinically relevant gene therapy vectors
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“38,39 In these mice, rAAV8 and 9 vectors showed higher transduction of mouse hepatocytes compared with a capsid modified AAV3 vector, which in turn was superior in transducing human hepatocytes.”
The Promise and Challenge of In Vivo Delivery for Genome Therapeutics
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“An example of directed evolution entailed use of mutated capsids, generated by DNA shuffling, which were exposed to rounds of selective pressure by neutralizing antibodies [119,122].”
BackgroundAAV vector development, back to the future
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“93,94 The "shuffling approach" has undergone continuous refinement for over 2 decades.”
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“…have taken a more holistic directed evolution approach by generating libraries of novel AAV sequences either by random mutagenesis (100 – 102) or shuf fl ing of capsid sequences across multiple serotypes followed by selection on either a target cell population (99, 103 – 107) or in vivo (108 – 113).”
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“We conducted another experiment in which we treated steatotic mice with AAV8-H1-shCD47 (shCD47) to silence CD47 in hepatocytes (34, 46).”
MethodLiver induced transgene tolerance with AAV vectors
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“In seven clinical trials, AAV8 and AAV9 capsids are used for delivery to the CNS. Capsid evolution techniques are becoming increasingly sophisticated, enabling highly specific transduction of specific cell types.”
Marsic, D., Lakshmanan Govindasamy, A., Currlin, S., Markusic, D. M., Tseng, Y.-S., Herzog, R. W., Agbandje‐McKenna, M., & Zolotukhin, S. (2014) · Molecular Therapy · doi:10.1038/mt.2014.139 · Cited by 73 · see citing works
- 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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