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Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8
Open accessAbstract
It has been recently shown that recombinant adeno-associated virus serotype 8 (rAAV8) is a robust alternative serotype vector that overcomes many of the limitations of rAAV2 and transduces various tissues efficiently and globally through systemic vector administration. AAV9 is a serotype newly isolated from human tissues, but our knowledge of the biology of rAAV9 in vivo is currently limited. Here, we demonstrate by a series of comprehensive side-by-side experiments with rAAV8 and 9 vectors delivered via different routes or at various doses in mice that rAAV9 vectors share the robustness of rAAV8, i.e., (1) very high liver transduction efficiency irrespective of whether vectors are administered intravascularly or extravascularly and (2) substantial transduction in the heart, skeletal muscle, and pancreas by peripheral vein injection. Importantly, rAAV9 transduced myocardium 5- to 10-fold higher than rAAV8, resulting in over 80% cardiomyocyte transduction following tail vein injection of as low as 1.0 x 10(11) particles per mouse. Thus rAAV9, as well as rAAV8, is a robust vector for gene therapy applications and rAAV9 is superior to rAAV8 specifically for cardiac gene delivery by systemic vector administration.
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“AAV9 was chosen for its ability to highly transduce most mouse tissues.25”
From Adeno-Associated Virus Serotype-Specific Inverted Terminal Repeat Sequence Role in Vector Transgene Expression (2020) · cites this paper as [25]
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“We selected AAV9 capsid and EF1a promoter to ensure maximal distribution to most tissues (Inagaki et al., 2006 and Supplementary Table S1)”
From Gene Therapy-Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice (2024) · cites this paper as Inagaki et al., 2006
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“Immunohistochemistry with anti-eGFP antibodies at 1 month PI, showed a viral transduction efficiency of 20–50% of eGFP-positive cells depending on the tissue (Supporting Information Fig S1E and F) (Foust et al, 2009; Inagaki et al, 2006; Zincarelli et al, 2008).”
From Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer (2012) · cites this paper as Inagaki et al, 2006
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“In particular, AAV9 has shown efficient transduction in a broad range of tissues, with high tropism for liver, heart and skeletal muscle (Inagaki et al, 2006).”
From Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer (2012) · cites this paper as Inagaki et al, 2006
In the citing paper
“AAV-9 has been shown to have superior cardiotropism than other serotypes in small rodents”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Inagaki, et al., 2006
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Cites
Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy
Gao, G.-P., Alvira, M. R., Wang, L., Calcedo, R., Johnston, J., & Wilson, J. M. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182412299 · Cited by 1,520
Clades of Adeno-Associated Viruses Are Widely Disseminated in Human Tissues
Gao, G., Vandenberghe, L. H., Alvira, M. R., Lu, Y., Calcedo, R., Zhou, X., & Wilson, J. M. (2004) · Journal of Virology · doi:10.1128/jvi.78.12.6381-6388.2004 · Cited by 1,070
Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart
Wang, Z., Zhu, T., Qiao, C., Zhou, L., Wang, B., Zhang, J., Chen, C., Li, J., & Xiao, X. (2005) · Nature Biotechnology · doi:10.1038/nbt1073 · Cited by 622
Systemic delivery of genes to striated muscles using adeno-associated viral vectors
Gregorevic, P., Blankinship, M. J., Allen, J. M., Crawford, R. W., Meuse, L., Miller, D. G., Russell, D. W., & Chamberlain, J. S. (2004) · Nature Medicine · doi:10.1038/nm1085 · Cited by 620
Gene therapy vectors based on adeno-associated virus type 1
Xiao, W., Chirmule, N., Berta, S. C., McCullough, B., Gao, G., & Wilson, J. M. (1999) · Journal of Virology · doi:10.1128/jvi.73.5.3994-4003.1999 · Cited by 541
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Nakai, H., Yant, S. R., Storm, T. A., Fuess, S., Meuse, L., & Kay, M. A. (2001) · Journal of Virology · doi:10.1128/jvi.75.15.6969-6976.2001 · Cited by 478
Self-citationRutledge, E. A., Halbert, C. L., & Russell, D. W. (1998) · Journal of Virology · doi:10.1128/jvi.72.1.309-319.1998 · Cited by 452
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Chan, K. Y., Jang, M. J., Yoo, B. B., Greenbaum, A., Ravi, N., Wu, W.-L., Sánchez-Guardado, L., Lois, C., Mazmanian, S. K., Deverman, B. E., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4593 · Cited by 1,578
Analysis of AAV Serotypes 1–9 Mediated Gene Expression and Tropism in Mice After Systemic Injection
Zincarelli, C., Soltys, S., Rengo, G., & Rabinowitz, J. E. (2008) · Molecular Therapy · doi:10.1038/mt.2008.76 · Cited by 1,490
Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes
Foust, K. D., Nurre, E., Montgomery, C. L., Hernandez, A., Chan, C. M., & Kaspar, B. K. (2009) · Nature Biotechnology · doi:10.1038/nbt.1515 · Cited by 1,456
Functional screening identifies miRNAs inducing cardiac regeneration
Eulalio, A., Mano, M., Ferro, M. D., Zentilin, L., Sinagra, G., Zacchigna, S., & Giacca, M. (2012) · Nature · doi:10.1038/nature11739 · Cited by 1,029
Therapeutic in vivo gene transfer for genetic disease using AAV: Progress and challenges
Mingozzi, F., & High, K. A. (2011) · Nature Reviews Genetics · doi:10.1038/nrg2988 · Cited by 893
Metadata
- Authors
- Inagaki, K., Fuess, S., Storm, T. A., Gibson, G. A., Mctiernan, C. F., Kay, M. A., & Nakai, H.
- Affiliations
- University of Pittsburgh (US)
- Stanford Medicine (US)
- Corresponding author
- Nakai, Hiroyuki
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 14
- Issue
- 1
- Pages
- 45-53
- ISSN
- 1525-0016 (ISSN-L)
- OpenAlex
- W2065380345
- Cited by
- 610
- References
- 25
- Citations by year
- 2026: 26 · 2025: 19 · 2024: 21 · 2023: 18 · 2022: 25 · 2021: 24 · 2020: 27 · 2019: 38 · 2018: 29 · 2017: 24 · 2016: 33 · 2015: 30 · 2014: 25 · 2013: 39 · 2012: 45
- FWCI
- 21.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL66948, U01HL066948)
- National Institute of Diabetes and Digestive and Kidney Diseases (R21DK068636, DK68636)
- 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
- Health Sciences › Medicine › Genetics (clinical) › Neurogenetic and Muscular Disorders Research
- Keywords
- AAV9, AAV8, adeno-associated virus vectors, systemic gene delivery, cardiac gene transfer, liver transduction, tail vein injection, skeletal muscle transduction, vector dose, gene therapy vectors
- MeSH terms
- Dependovirus, Animals, Female, Genetic Vectors, Lac Operon, Liver, Male, Mice, Inbred C57BL, Myocardium, Pancreas, Tissue Distribution, Genetic Therapy, Muscle, Skeletal, Mice
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