Efficient mouse airway transduction following recombination between AAV vectors carrying parts of a larger gene

Halbert, Christine L.; Allen, James M.; Miller, A. Dusty

doi:10.1038/nbt0702-697

Cited by 121Virus-based gene therapy researchRNA Interference and Gene DeliveryViral Infectious Diseases and Gene Expression in Insects

Efficient mouse airway transduction following recombination between AAV vectors carrying parts of a larger gene

Halbert, Christine L., Allen, James M., Miller, A. Dusty·2002·Nature Biotechnology

DOI 10.1038/nbt0702-697

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Abstract

The small packaging capacity of adeno-associated virus (AAV) vectors limits the utility of this promising vector system for transfer of large genes. We explored the possibility that larger genes could be reconstituted following homologous recombination between AAV vectors carrying overlapping gene fragments. An alkaline phosphatase (AP) gene was split between two such AAV vectors (rec vectors) and packaged using AAV2 or AAV6 capsid proteins. Rec vectors having either capsid protein recombined to express AP in cultured cells at about 1-2% of the rate observed for an intact vector. Surprisingly, the AAV6 rec vectors transduced lung cells in mice almost as efficiently as did an intact vector, with 10% of airway epithelial cells, the target for treatment of cystic fibrosis (CF), being positive. Thus AAV rec vectors may be useful for diseases such as CF that require transfer of large genes.

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Simultaneous infection of cells with two vectors containing an overlapping fragment of 440 or 1000 bases of the AP gene could successfully transduce HT-1080 cells, although only at 1-2% efficiency of a vector that expressed AP from a single vector genome.
“simultaneous infection of cells with two vectors containing an overlapping fragment of 440 or 1000 bases of the AP gene could successfully transduce HT-1080 cells, although only at 1-2% efficiency of a vector that expressed AP from a single vector genome. 43”
From Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids (2016) · cites this paper as [43]
In mice, the best overlapping vector pair yielded almost identical transduction of the airway epithelium compared with the single-genome virus.
“In vivo , the best overlapping vector pair yielded almost identical transduction of the airway epithelium when compared with the single-genome virus.”
From Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids (2016) · cites this paper as [43]
Transduction with overlapping vector pairs was detected only with vector pairs that shared either 440 or 1000-base regions of homology but not with vector pairs without homology.
“they could detect transduction only with vector pairs that shared either 440or 1000-base regions of homology but not with vector pairs without homology. 43”
From Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids (2016) · cites this paper as [43]

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Authors: Halbert, C. L., Allen, J. M., & Miller, A. D.
Affiliations: Fred Hutch Cancer Center (US)
Corresponding author: Miller, A. Dusty
ORCID: Halbert, Christine L.
Allen, James M.
Miller, A. Dusty
Venue: Nature Biotechnology
Publisher: Springer Science and Business Media LLC
Published: 2002-07
Volume: 20
Issue: 7
Pages: 697-701
ISSN: 0733-222X (ISSN-L)
1087-0156
1546-1696
DOI: 10.1038/nbt0702-697
OpenAlex: W2042805311
Cited by: 121
References: 25
Citations by year: 2026: 3 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 6 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 4 · 2017: 7 · 2016: 3 · 2015: 9 · 2014: 5 · 2013: 5 · 2012: 5
FWCI: 2.65
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Biotechnology (publishedVersion)
PubMed (publishedVersion)
Funders: Ministry of Earth Sciences
Ministry of Education, India
National Institutes of Health
National Heart, Lung, and Blood Institute (U01HL066947, HL-66947)
National Institute of Diabetes and Digestive and Kidney Diseases (DK-47754, P30DK047754)
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 vectors, homologous recombination, alkaline phosphatase reporter, airway epithelial cells, cystic fibrosis gene therapy
MeSH terms: Dependovirus, Animals, Gene Expression Regulation, Genetic Vectors, Humans, Lung, Mice, Inbred C57BL, Recombination, Genetic, Transduction, Genetic, Respiratory Mucosa, Capsid Proteins, Mice

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Efficient mouse airway transduction following recombination between AAV vectors carrying parts of a larger gene

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