Enhancing transduction of the liver by adeno-associated viral vectors

Nathwani, A C; Cochrane, M; McIntosh, J; Ng, C Y C; Zhou, J; Gray, J T; Davidoff, A M

doi:10.1038/gt.2008.137

Cited by 77Virus-based gene therapy researchRNA Interference and Gene DeliveryHemophilia Treatment and Research

Enhancing transduction of the liver by adeno-associated viral vectors

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Nathwani, A C, Cochrane, M, McIntosh, J, Ng, C Y C, Zhou, J, Gray, J T, Davidoff, A M·2009·Gene Therapy

DOI 10.1038/gt.2008.137PMC PMC2615795

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Abstract

A number of distinct factors acting at different stages of the adeno-associated virus vector (AAV)-mediated gene transfer process were found to influence murine hepatocyte transduction. Foremost among these was the viral capsid protein. Self-complementary (sc) AAV pseudotyped with capsid from serotype 8 or rh.10 mediated fourfold greater hepatocyte transduction for a given vector dose when compared with vector packaged with AAV7 capsid. An almost linear relationship between vector dose and transgene expression was noted for all serotypes with vector doses as low as 1 x 10(7) vg per mouse (4 x 10(8) vg kg(-1)) mediating therapeutic levels of human FIX (hFIX) expression. Gender significantly influenced scAAV-mediated transgene expression, with twofold higher levels of expression observed in male compared with female mice. Pretreatment of mice with the proteasome inhibitor bortezomib increased scAAV-mediated hFIX expression from 4+/-0.6 to 9+/-2 microg ml(-1) in female mice, although the effect of this agent was less profound in males. Exposure of mice to adenovirus 10-20 weeks after gene transfer with AAV vectors augmented AAV transgene expression twofold by increasing the level of proviral mRNA. Hence, optimization of individual steps in the AAV gene transfer process can further enhance the potency of AAV-mediated transgene expression, thus increasing the probability of successful gene therapy.

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Two other studies using AAV8 showed that bortezomib improved transduction in mice and dogs.
“Two other studies using AAV8 showed that bortezomib improved transduction in mice (66) and dogs (67).”
From A versatile toolkit for overcoming AAV immunity (2022) · cites this paper as [66]

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Authors: Nathwani, A. C., Cochrane, M., McIntosh, J., Ng, C. Y. C., Zhou, J., Gray, J. T., & Davidoff, A. M.
Affiliations: University College London (GB)
St. Jude Children's Research Hospital (US)
Corresponding author: Nathwani, A C
ORCID: Nathwani, A C
Cochrane, M
McIntosh, J
Ng, C Y C
Gray, J T
Davidoff, A M
Venue: Gene Therapy
Publisher: Springer Science and Business Media LLC
Published: 2008-08-14
Volume: 16
Issue: 1
Pages: 60-69
ISSN: 0969-7128 (ISSN-L)
1476-5462
DOI: 10.1038/gt.2008.137
PMC: PMC2615795
OpenAlex: W2084114153
Cited by: 77
References: 41
Citations by year: 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 8 · 2021: 3 · 2020: 1 · 2019: 10 · 2018: 4 · 2017: 6 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 3 · 2012: 3
FWCI: 3.81
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Gene Therapy (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
UCL Discovery (University College London) (submittedVersion)
Funders: American Lebanese Syrian Associated Charities
National Institute for Health and Care Research
University College London Hospitals NHS Foundation Trust
National Heart, Lung, and Blood Institute (HL073838, R01HL094396, R01HL073838)
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 › Hematology › Hemophilia Treatment and Research
Keywords: adeno-associated virus vectors, liver gene transfer, hepatocyte transduction, self-complementary AAV, capsid protein, AAV serotypes, AAV8, factor VIII, bortezomib, proteasome inhibition, sex differences, transgene expression
MeSH terms: Bortezomib, Dependovirus, Animals, Antibodies, Viral, Boronic Acids, Factor IX, Female, Genetic Vectors, Humans, Injections, Intravenous, Liver, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Protease Inhibitors, Pyrazines, Transduction, Genetic, Genetic Therapy, Gene Expression, Transgenes, Mice

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Enhancing transduction of the liver by adeno-associated viral vectors

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