Cited by 170Virus-based gene therapy researchRNA Interference and Gene DeliveryNeurogenetic and Muscular Disorders Research

Neutralizing antibodies against AAV serotypes 1, 2, 6, and 9 in sera of commonly used animal models

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Rapti, Kleopatra, Louis-Jeune, Vedell, Kohlbrenner, Erik, Ishikawa, Kiyotake, Ladage, Dennis, Zolotukhin, Sergei, Hajjar, Roger J, Weber, Thomas·2012·Molecular Therapy

Abstract

Adeno-associated virus (AAV)-based vectors are promising gene delivery vehicles for human gene transfer. One significant obstacle to AAV-based gene therapy is the high prevalence of neutralizing antibodies in humans. Until now, it was thought that, except for nonhuman primates, pre-existing neutralizing antibodies are not a problem in small or large animal models for gene therapy. Here, we demonstrate that sera of several animal models of cardiovascular diseases harbor pre-existing antibodies against the cardiotropic AAV serotypes AAV1, AAV6, and AAV9 and against AAV2. The neutralizing antibody titers vary widely both between species and between serotypes. Of all species tested, rats displayed the lowest levels of neutralizing antibodies. Surprisingly, naive mice obtained directly from commercial vendors harbored neutralizing antibodies. Of the large animal models tested, the neutralization of AAV6 transduction by dog sera was especially pronounced. Sera of sheep and rabbits showed modest neutralization of AAV transduction whereas porcine sera strongly inhibited transduction by all AAV serotypes and displayed the largest variation between individual animals. Importantly, neutralizing antibody titers as low as 1/4 completely prevented in vivo transduction by AAV9 in rats. Our results suggest that prescreening of animals for neutralizing antibodies will be important for future gene transfer experiments in these animal models.

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  • Different laboratory animal models have different levels of neutralizing antibodies against various AAV serotypes, which can limit transduction efficiency.

    “different laboratory animal models have different levels of neutralizing antibodies against various AAV serotypes which can limit the efficiency of transduction”

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Authors
Rapti, K., Louis-Jeune, V., Kohlbrenner, E., Ishikawa, K., Ladage, D., Zolotukhin, S., Hajjar, R. J., & Weber, T.
Affiliations
  • Mount Sinai Hospital (US)
  • University of Florida Health (US)
Corresponding author
Weber, Thomas
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2012-01
Volume
20
Issue
1
Pages
73-83
ISSN
1525-0016 (ISSN-L)
OpenAlex
W2044050006
Cited by
170
References
54
Citations by year
2026: 3 · 2025: 7 · 2024: 16 · 2023: 14 · 2022: 18 · 2021: 13 · 2020: 13 · 2019: 10 · 2018: 12 · 2017: 11 · 2016: 8 · 2015: 11 · 2014: 5 · 2013: 16 · 2012: 12
FWCI
6.78
Type
journal article
Language
en
Open access
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Massachusetts General Hospital
  • University of Pennsylvania
  • University of Missouri
  • Deutsches Krebsforschungszentrum
  • National Institutes of Health (HL097088)
  • University of North Carolina at Chapel Hill
  • National Heart, Lung, and Blood Institute (P20HL100396, HL-097088, HL100396, R01HL097088, HL-007824, T32HL007824, HL-088434, R01HL088434)
  • National Institute of General Medical Sciences (GM082946, R01GM082946)
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 › Neurogenetic and Muscular Disorders Research
Keywords
adeno-associated virus, neutralizing antibodies, AAV serotypes, AAV1, AAV2, AAV6, AAV9, animal models, gene therapy, pre-existing antibodies, dogs, sheep, rabbits, pigs, rats, mice, cardiovascular disease models
MeSH terms
Dependovirus, Animals, Dogs, Genetic Vectors, Humans, Male, Neutralization Tests, Rabbits, Serotyping, Sheep, Swine, Transduction, Genetic, Rats, Sprague-Dawley, Gene Transfer Techniques, Mice, Rats, Antibodies, Neutralizing, HEK293 Cells

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