Cross-Packaging of a Single Adeno-Associated Virus (AAV) Type 2 Vector Genome into Multiple AAV Serotypes Enables Transduction with Broad Specificity

Rabinowitz, Joseph E.; Rolling, Fabienne; Li, Chengwen; Conrath, Hervè; Xiao, Weidong; Xiao, Xiao; Samulski, R. Jude

doi:10.1128/jvi.76.2.791-801.2002

Cited by 762Virus-based gene therapy researchRNA Interference and Gene DeliveryViral Infectious Diseases and Gene Expression in Insects

Cross-Packaging of a Single Adeno-Associated Virus (AAV) Type 2 Vector Genome into Multiple AAV Serotypes Enables Transduction with Broad Specificity

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Rabinowitz, Joseph E., Rolling, Fabienne, Li, Chengwen, Conrath, Hervè, Xiao, Weidong, Xiao, Xiao, Samulski, R. Jude·2002·Journal of Virology

DOI 10.1128/jvi.76.2.791-801.2002PMC PMC136844

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Abstract

The serotypes of adeno-associated virus (AAV) have the potential to become important resources for clinical gene therapy. In an effort to compare the role of serotype-specific virion shells on vector transduction, we cloned each of the serotype capsid coding domains into a common vector backbone containing AAV type 2 replication genes. This strategy allowed the packaging of AAV2 inverted terminal repeat vectors into each serotype-specific virions. Each of these helper plasmids (pXR1 through pXR5) efficiently replicated the transgene DNA and expressed helper proteins at nearly equivalent levels. In this study, we observed a correlation between the amount of transgene replication and packaging efficiency. The physical titer of these hybrid vectors ranged between 1.3 × 10 11 and 9.8 × 10 12 /ml (types 1 and 2, respectively). Of the five serotype vectors, only types 2 and 3 were efficiently purified by heparin-Sepharose column chromatography, illustrating the high degree of similarity between these virions. We analyzed vector transduction in reference and mutant Chinese hamster ovary cells deficient in heparan sulfate proteoglycan and saw a correlation between transduction and heparan sulfate binding data. In this analysis, types 1 and 5 were most consistent in transduction efficiency across all cell lines tested. In vivo each serotype was ranked after comparison of transgene levels by using different routes of injection and strains of rodents. Overall, in this analysis, type 1 was superior for efficient transduction of liver and muscle, followed in order by types 5, 3, 2, and 4. Surprisingly, this order changed when vector was introduced into rat retina. Types 5 and 4 were most efficient, followed by type 1. These data established a hierarchy for efficient serotype-specific vector transduction depending on the target tissue. These data also strongly support the need for extending these analyses to additional animal models and human tissue. The development of these helper plasmids should facilitate direct comparisons of serotypes, as well as begin the standardization of production for further clinical development.

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AAV2 Rep proteins can replicate and cross-package AAV genomes with ITRs from serotypes 1, 3, 4, and 6 into non-AAV2 capsids.
“Even with these differences, the AAV2 Reps are capable of replicating and cross-packaging genomes from serotypes 1, 3, 4, and 6 into numerous, non-AAV2 capsids.9,10”
From Adeno-Associated Virus Serotype-Specific Inverted Terminal Repeat Sequence Role in Vector Transgene Expression (2020) · cites this paper as [9]
The Discussion describes packaging AAV2-ITR vectors into serotype-specific shells, which supports cross-packaging into non-AAV2 capsids. But it says the study chose AAV2 ITRs rather than testing genomes with ITRs from serotypes 1, 3, 4, and 6, and examined shells from serotypes 1–5, not 6. (LLM, conf=0.90)
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Authors: Rabinowitz, J. E., Rolling, F., Li, C., Conrath, H., Xiao, W., Xiao, X., & Samulski, R. J.
Affiliations: Gene Therapy Center
Centre Hospitalier Universitaire de Nantes (FR)
Laboratoire de Thérapie Génique, CHU Hotel-DIEU, 44035 Nantes Cedex 01, France
Children's Hospital of Philadelphia (US)
University of Pittsburgh (US)
University of North Carolina at Chapel Hill (US)
Corresponding author: Samulski, R. Jude
ORCID: Li, Chengwen
Xiao, Weidong
Xiao, Xiao
Samulski, R. Jude
Venue: Journal of Virology
Publisher: American Society for Microbiology
Published: 2002-01-15
Volume: 76
Issue: 2
Pages: 791-801
ISSN: 0022-538X (ISSN-L)
1098-5514
DOI: 10.1128/jvi.76.2.791-801.2002
PMC: PMC136844
OpenAlex: W1963623233
Cited by: 762
References: 7
Citations by year: 2026: 10 · 2025: 14 · 2024: 13 · 2023: 16 · 2022: 13 · 2021: 12 · 2020: 21 · 2019: 25 · 2018: 10 · 2017: 27 · 2016: 10 · 2015: 39 · 2014: 43 · 2013: 25 · 2012: 34
FWCI: 33.42
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Journal of Virology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
UNC Libraries
Funders: National Institutes of Health (5r01dk054419-04)
National Institute of General Medical Sciences (GM 59290, R01GM059290)
National Institute of Diabetes and Digestive and Kidney Diseases (DK54419)
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: adeno-associated virus, AAV serotypes, hybrid vectors, helper plasmid, transduction efficiency, heparan sulfate binding, liver, muscle, retina, gene therapy vectors, packaging efficiency
MeSH terms: Dependovirus, Amino Acid Sequence, Animals, Haplorhini, Capsid, Cell Line, Chromatography, Affinity, Genetic Vectors, Cricetinae, Helper Viruses, Heparin, Humans, Mice, Inbred Strains, Molecular Sequence Data, Retina, Rodentia, Sensitivity and Specificity, Serotyping, Species Specificity, Transduction, Genetic, Gene Expression Regulation, Viral, Genome, Viral, Virus Assembly, Transgenes, Mice, Rats

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Cross-Packaging of a Single Adeno-Associated Virus (AAV) Type 2 Vector Genome into Multiple AAV Serotypes Enables Transduction with Broad Specificity

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