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

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

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

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.

Original languageEnglish
Pages (from-to)73-83
Number of pages11
JournalMolecular Therapy
Volume20
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

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