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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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BackgroundSelf-citationLiver‐directed gene therapy for inherited metabolic diseases
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Self-citationCRISPR/Cas9: at the cutting edge of hepatology
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“These include the ability to transduce nondividing cells such as quiescent hepatocytes, and a low propensity to induce liver inflammation and high tropism of selected serotypes for primary human hepatocytes in vivo.(9,11-14) Therapeutic promise in the liver is exemplified by multiyear therapeutic efficacy following a…”
Self-citationEndothelial Retargeting of AAV9 In Vivo
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“An example is AAV-LK03, the first chimeric capsid isolated from a library screen in a humanized liver model to be used in a clinical trial.(22,34,35) This capsid has been shown to result in similar if not higher levels of human factor VIII when compared with a trial utilizing AAV5 at 30–50 times lower doses.”
Self-citationGene therapy for mitochondrial disorders
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“42,43 Tissue tropism of rAAVs is illustrated in Figure 1B. rAAVs are designed with the purpose of delivering a therapeutic transgene within an expression cassette instead of the original AAV genome and therefore lack the ability to replicate in the host. rAAVs have a packaging capacity that is…”
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Cross-Packaging and Capsid Mosaic Formation in Multiplexed AAV Libraries
Schmit, P. F., Pacouret, S., Zinn, E. M., Telford, E., Nicolaou, F., Broucque, F., Andrés‐Mateos, E., Xiao, R., Penaud‐Budloo, M., Bouzelha, M., et al. (2019) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2019.11.014 · Cited by 34
“This high VP-genome correlation within mosaic populations would also explain how novel, tissue-specific AAV variants could be discovered via directed evolution of AAV libraries produced in saturation conditions.(8,25)”
BackgroundViral vectors for gene delivery to the inner ear
Maguire, C. A., & Corey, D. P. (2020) · Hearing Research · doi:10.1016/j.heares.2020.107927 · Cited by 33
Redirecting AAV vectors to extrahepatic tissues
Asokan, A., & Shen, S. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.10.005 · Cited by 36
Obstacles and future of gene therapy for hemophilia
Arruda, V. R., & Samelson-Jones, B. J. (2015) · Expert Opinion on Orphan Drugs · doi:10.1517/21678707.2015.1069179 · Cited by 33
“Development of novel AAV serotypes based on direct evolution [46], and, more recently, using mouse models chimeric with human hepatocytes are also promising approaches to identify more efficient AAV vectors [47].”
BackgroundLiver directed adeno‐associated viral vectors to treat metabolic disease
Chuecos, M. A., & Lagor, W. R. (2023) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12637 · Cited by 34
“40 Studies in human liver chimeric mice have shown that AAV3B 41 and the engineered variants AAV-LK-03 42 and AAV-NP-59 43 have dramatically improved selectivity for human hepatocytes.”
BackgroundGene Editing: A New Tool for Viral Disease
Kennedy, E. M., & Cullen, B. R. (2016) · Annual Review of Medicine · doi:10.1146/annurev-med-051215-031129 · Cited by 33
“Fortunately, the liver is a particularly good target for infection by AAV vectors, including especially AAV8 and derivatives thereof (14), so it is in principle entirely feasible to transduce every HBV-infected hepatocyte in vivo.”
BackgroundAn ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1
Zheng, Z., Nayak, L. V., Wang, W., Yurdagul, A., Wang, X., Cai, B., Lapping, S. D., Özcan, L., Ramakrishnan, R., Pestell, R. G., et al. (2018) · Blood · doi:10.1182/blood-2018-07-864843 · Cited by 40
Lee, Q., Padula, M., Pinello, N., Williams, S., O'Rourke, M. B., Fumagalli, M., Orkin, J. D., Song, R.-H., Shaban, B., Brenner, O., et al. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008262 · Cited by 27
“If anti-ChPV antibodies are uncommon in humans then recombinant parvoviral vectors packaged into ChPV capsid might be better able to evade pre-existing antibody-mediated immunity than AAV vectors presently used in the clinic.”
BackgroundInfluentialShokouhi, A., Aslanoglou, S., Nisbet, D. R., Voelcker, N. H., & Elnathan, R. (2020) · Materials Horizons · doi:10.1039/d0mh01016b · Cited by 34
New approaches to gene and cell therapy for hemophilia
Ohmori, T., Mizukami, H., OZAWA, K., Sakata, Y., & Nishimura, S. (2015) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12926 · Cited by 33
Efficient in vivo editing of OTC-deficient patient-derived primary human hepatocytes
Ginn, S. L., Amaya, A. K., Liao, S. H. Y., Zhu, E., Cunningham, S. C., Lee, M., Hallwirth, C. V., Logan, G. J., Tay, S. S., Cesare, A. J., et al. (2019) · JHEP Reports · doi:10.1016/j.jhepr.2019.100065 · Cited by 32
Self-citationOrganoids and microphysiological systems: Promising models for accelerating AAV gene therapy studies
Ramamurthy, R. M., Atala, A., Porada, C. D., & Almeida-Porada, G. D. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1011143 · Cited by 35
Hemophilia Gene Therapy: Ready for Prime Time?
VandenDriessche, T., & Chuah, M. (2017) · Human Gene Therapy · doi:10.1089/hum.2017.116 · Cited by 32
“Initially AAV2 was used, followed by other naturally occurring serotypes ( i.e. , AAV8, AAV9, AAV5) or capsid variants obtained by evolution and selection 74,75 or containing specific point mutations.”
Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice
Sugahara, G., Ishida, Y., Sun, J. C., Tateno, C., & Saito, T. (2020) · Seminars in Liver Disease · doi:10.1055/s-0040-1701444 · Cited by 31
Gene therapy for hemophilia: Progress to date and challenges moving forward
Gollomp, K. L., Doshi, B. S., & Arruda, V. R. (2019) · Transfusion and Apheresis Science · doi:10.1016/j.transci.2019.08.012 · Cited by 32
Gene therapy for urea cycle defects: An update from historical perspectives to future prospects
Duff, C. E., Alexander, I. E., & Baruteau, J. (2023) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12609 · Cited by 30
“…with AAV-LK03 versus AAV8 capsids with a relative higher expression of Factor VIII at similar doses, for example, 16% – 194% (NCT03003533) versus 54% – 69% (NCT03370172) Factor VIII activity at peak following injection of 6 (cid:1) 10 12 vg/kg in adults with severe haemophilia A, respectively.”
Self-citationKok, C., Tsurusaki, S., Cabanes‐Creus, M., Igoor, S., Rao, R., Skelton, R. J. P., Liao, S. H. Y., Ginn, S. L., Knight, M., Scott, S., et al. (2023) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2023.08.010 · Cited by 32
Self-citationThe promising novel therapies for familial hypercholesterolemia
Chen, R., Lin, S., & Chen, X. (2022) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.24552 · Cited by 30
Callan, M. B., Haskins, M. E., Wang, P., Zhou, S., High, K. A., & Arruda, V. R. (2016) · PLoS ONE · doi:10.1371/journal.pone.0151800 · Cited by 29
Gene therapy decreases seizures in a model of Incontinentia pigmenti
Dogbevia, G., Töllner, K., Körbelin, J., Bröer, S., Ridder, D. A., Graßhoff, H., Brandt, C., Wenzel, J., Straub, B. K., Trepel, M., et al. (2017) · Annals of Neurology · doi:10.1002/ana.24981 · Cited by 30
Identification of adeno-associated virus capsid proteins using ZipChip CE/MS
Zhang, Y., Wang, Y., Sosic, Z., Zang, L., Bergelson, S., & Zhang, W. (2018) · Analytical Biochemistry · doi:10.1016/j.ab.2018.06.006 · Cited by 27
Self-citationCabrera-Pérez, R., Vila‐Julià, F., Hirano, M., Mingozzi, F., Torres‐Torronteras, J., & Martí, R. (2019) · Human Gene Therapy · doi:10.1089/hum.2018.217 · Cited by 28
Ran, G., Chen, X., Xie, Y., Zheng, Q., Xie, J., Yu, C., Pittman, N., Qi, S., Yu, F., Agbandje‐McKenna, M., et al. (2020) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2020.03.007 · Cited by 29
Cabanes‐Creus, M., Navarro, R. G., Liao, S. H. Y., Baltazar, G., Drouyer, M., Zhu, E., Scott, S., Luong, C., Wilson, L. O. W., Alexander, I. E., et al. (2021) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2021.04.010 · Cited by 29
Self-citationAAV-p40 Bioengineering Platform for Variant Selection Based on Transgene Expression
Westhaus, A., Cabanes‐Creus, M., Jonker, T., Sallard, E., Navarro, R. G., Zhu, E., Torres, G. B., Lee, S. D., Wilmott, P., Gonzalez-Cordero, A., et al. (2022) · Human Gene Therapy · doi:10.1089/hum.2021.278 · Cited by 28
Self-citationBiswas, M., Marsic, D., Li, N., Zou, C., González‐Aseguinolaza, G., Zolotukhin, I., Kumar, S. R. P., Rana, J., Butterfield, J. S. S., Kondratov, O., et al. (2020) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2020.09.019 · Cited by 28
Tharp, K. M., Khalifeh‐Soltani, A., Park, H. M., Yurek, D. A., Falcon, A., Wong, L. X., Feng, R., Atabai, K., & Stahl, A. (2016) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00316.2015 · Cited by 27
Michler, T., Große, S., Mockenhaupt, S., Röder, N., Stückler, F., Knapp, B. L., Ko, C., Heikenwälder, M. F., Protzer, U., & Grimm, D. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201506172 · Cited by 27
“In addition, we can readily foresee that required vector doses in humans will further drop as an increasing number of superior—more efficient and more specific—AAV capsids are molecularly evolved in liver cells and may enter the clinic, such as AAV-DJ (Grimm et al, 2008) or AAVLK03 (Lisowski et al, 2014).”
BackgroundChai, Z., Sun, J., Rigsbee, K. M., Wang, M., Samulski, R. J., & Li, C. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.08.005 · Cited by 28
“Other approaches to select AAV variants through error-prone PCR or a DNA shuffling library might be able to enhance transduction efficiency [23,44,45] or to escape pre-existing antibodies [21,46].”
BackgroundAdeno-associated virus (AAV) capsid engineering in liver-directed gene therapy
Rodríguez-Márquez, E., Meumann, N., & Büning, H. (2020) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2021.1865303 · Cited by 29
The Arrival of Gene Therapy for Patients with Hemophilia A
Castaman, G., Minno, G. D., CRISTOFARO, R. D., & Peyvandi, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810228 · Cited by 27
“Nevertheless, expression of FVIII in hepatocytes generates a functional and physiological protein that has restored hemostasis in animal models and clinical studies [81,82].”
Background
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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