Production of High-Titer Recombinant Adeno-Associated Virus Vectors in the Absence of Helper Adenovirus

Xiao, Xiao; Li, Juan; Samulski, Richard Jude

doi:10.1128/jvi.72.3.2224-2232.1998

Cited by 1,381Virus-based gene therapy researchRNA Interference and Gene DeliveryViral Infectious Diseases and Gene Expression in Insects

Production of High-Titer Recombinant Adeno-Associated Virus Vectors in the Absence of Helper Adenovirus

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Xiao, Xiao, Li, Juan, Samulski, Richard Jude·1998·Journal of Virology

DOI 10.1128/jvi.72.3.2224-2232.1998PMC PMC109519

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Abstract

Recently, efficient and long-term in vivo gene transfer by recombinant adeno-associated virus type 2 (rAAV) vectors has been demonstrated in a variety of tissues. Further improvement in vector titer and purity will expedite this in vivo exploration and provide preclinical information required for use in human gene therapy. In an effort to obtain higher titers, we constructed a novel AAV helper plasmid which utilizes translational control of AAV Rep genes (J. Li et al., J. Virol. 71:5236–5243, 1997). To address the issue of purity, in this study we report the first rAAV production method which is completely free of adenovirus (Ad) helper virus. The new production system uses a plasmid construct which contains a mini-Ad genome capable of propagating rAAV in the presence of AAV Rep and Cap genes. This construct is missing some of the early and most of the late Ad genes and is incapable of producing infectious Ad. Transfection of 293 cells with the new mini-Ad helper and AAV packaging plasmids results in high-titer rAAV vectors with yields greater than 1,000 transducing units, or 10 5 viral particles per cell. When rAAV vectors were produced by using this production scheme and compared to traditional heat-inactivated rAAV preparations in vitro and in vivo, we observed transduction equivalent to or better than normal levels. The complete removal of infectious Ad from AAV production should facilitate a better understanding of immune response to AAV vectors in vivo, eliminate the need for developing replication-competent Ad assays, and provide a more defined reagent for clinical use.

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Recombinant AAV vector production platforms rely on an AAV2 Rep-AAV2 ITR replication and packaging system.
“Currently, recombinant AAV (rAAV) vector production platforms rely on an AAV2 Rep—AAV2 ITR replication and packaging system.11”
From Adeno-Associated Virus Serotype-Specific Inverted Terminal Repeat Sequence Role in Vector Transgene Expression (2020) · cites this paper as [11]

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Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors
Ferrari, F. K., Samulski, T., Shenk, T., & Samulski, R. J. (1996) · Journal of Virology · doi:10.1128/jvi.70.5.3227-3234.1996 · Cited by 761 · see citing works
Self-citation
In vivo model of adeno-associated virus vector persistence and rescue
Afione, S. A., Conrad, C. K., Kearns, W. G., Chunduru, S., Adams, R., Reynolds, T. C., Guggino, W. B., Cutting, G. R., Carter, B. J., & Flotte, T. R. (1996) · Journal of Virology · doi:10.1128/jvi.70.5.3235-3241.1996 · Cited by 223 · see citing works
Recombinant Adeno-Associated Viral Vectors Mediate Long-Term Transgene Expression in Muscle
Clark, K. R., Sferra, T. J., & Johnson, P. R. (1997) · Human Gene Therapy · doi:10.1089/hum.1997.8.6-659 · Cited by 153 · see citing works

Flagged first, then by citations

Research works printed but not linked: 9

[3]3. Bett, A. J., W. Haddara, L. Prevec, and F. L. Graham. 1994. An efficient and flexible system for construction of adenovirus vectors with insertions or deletions in early regions 1 and 3. Proc. Natl. Acad. Sci. USA 91: 8802-8806.
[14]14. Flannery, J. G., S. Zolotukhin, M. I. Vaquero, M. M. LaVail, N. Muzyczka, and W. W. Hauswirth. 1997. Efficient photoreceptor-targeted gene expression in vivo by recombinant adeno-associated virus. Proc. Natl. Acad. Sci. USA 94: 6916-6921.
[16]16. Flotte, T. R., S. A. Afione, C. Conrad, S. A. McGrath, R. Solow, H. Oka, P. L. Zeitlin, W. B. Guggino, and B. J. Carter. 1993. Stable in vivo expression of the cystic fibrosis transmembrane conductance regulator with an adenoassociated virus vector. Proc. Natl. Acad. Sci. USA 90: 10613-10617.
[20]20. Hermonat, P. L., and N. Muzyczka. 1984. Use of adeno-associated virus as a mammalian DNA cloning vector: transduction of neomycin resistance into mammalian tissue culture cells. Proc. Natl. Acad. Sci. USA 81: 6466-6470.
[21]21. Herzog, R. W., J. N. Hagstrom, S. H. Kung, S. J. Tai, J. M. Wilson, K. J. Fisher, and K. A. High. 1997. Stable gene transfer and expression of human blood coagulation factor IX after intramuscular injection of recombinant adeno-associated virus. Proc. Natl. Acad. Sci. USA 94: 5804-5809.
[24]24. Kessler, P. D., G. M. Podsakoff, X. Chen, S. A. McQuiston, P. C. Colosi, L. A. Matelis, G. J. Kurtzman, and B. J. Byrne. 1996. Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein. Proc. Natl. Acad. Sci. USA 93: 14082-14087.
[25]25. Koeberl, D. D., I. E. Alexander, C. L. Halbert, D. W. Russell, and A. D. Miller. 1997. Persistent expression of human clotting factor IX from mouse liver after intravenous injection of adeno-associated virus vectors. Proc. Natl. Acad. Sci. USA 94: 1426-1431.
[32]32. Monahan, P. E., J. Tazelaar, X. Xiao, T. C. Nicols, D. A. Bellinger, M. S. Read, C. E. Walsh, and R. J. Samulski. Direct intramuscular injection with recombinant AAV vectors results in sustained expression in a dog model of hemophilia. Gene Ther., in press.
[50]50. Yang, Y., F. A. Nunes, K. Berencsi, E. E. Furth, E. Gonczol, and J. M. Wilson. 1994. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc. Natl. Acad. Sci. USA 91: 4407-4411.

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Gorbatyuk, O. S., Warrington, K. H., Gorbatyuk, M. S., Zolotukhin, I., Lewin, A. S., & Muzyczka, N. (2019) · Virus Research · doi:10.1016/j.virusres.2019.197771 · Cited by 18 · see citing works
Deleterious effect of peptide insertions in a permissive site of the AAV2 capsid
Douar, A. M., Poulard, K., & Danos, O. (2003) · Virology · doi:10.1016/s0042-6822(03)00186-7 · Cited by 17 · see citing works
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Anderson, H., & Weir, R. F. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.245461 · Cited by 14 · see citing works
Endogenous aspartoacylase expression is responsive to glutamatergic activity in vitro and in vivo
Francis, J. S., Strande, L., Pu, A., & Leone, P. (2011) · Glia · doi:10.1002/glia.21187 · Cited by 12 · see citing works

Authors: Xiao, X., Li, J., & Samulski, R. J.
Affiliations: Gene Therapy Center,1
University of North Carolina at Chapel Hill (US)
ORCID: Xiao, Xiao
Li, Juan
Samulski, Richard Jude
Venue: Journal of Virology
Publisher: American Society for Microbiology
Published: 1998-03
Volume: 72
Issue: 3
Pages: 2224-2232
ISSN: 0022-538X (ISSN-L)
1098-5514
DOI: 10.1128/jvi.72.3.2224-2232.1998
PMC: PMC109519
OpenAlex: W2148223197
Cited by: 1,381
References: 3
Citations by year: 2026: 23 · 2025: 33 · 2024: 46 · 2023: 37 · 2022: 35 · 2021: 37 · 2020: 40 · 2019: 57 · 2018: 34 · 2017: 59 · 2016: 37 · 2015: 45 · 2014: 41 · 2013: 40 · 2012: 40
FWCI: 29.99
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Journal of Virology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01hl048347-09)
National Heart, Lung, and Blood Institute (P01HL051818, HL 48347, HL51818)
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
Keywords: recombinant adeno-associated virus, transduction efficiency, vector titer, gene therapy vectors, 293 cells
MeSH terms: Dependovirus, Adenoviridae, Cell Line, Transformed, Cell Transformation, Viral, Genetic Vectors, Helper Viruses, Humans, Plasmids, Recombination, Genetic

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Production of High-Titer Recombinant Adeno-Associated Virus Vectors in the Absence of Helper Adenovirus

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