Detection of Intact rAAV Particles up to 6 Years After Successful Gene Transfer in the Retina of Dogs and Primates

Gene transfer to the retina using recombinant adeno-associated viral (rAAV) vectors has proven to be an effective option for the treatment of retinal degenerative diseases in several animal models and has recently advanced into clinical trials in humans. To date, intracellular trafficking of AAV vec...

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Bibliographic Details
Published in:Molecular therapy 2009-03, Vol.17 (3), p.516-523
Main Authors: Stieger, Knut, Schroeder, Josef, Provost, Nathalie, Mendes-Madeira, Alexandra, Belbellaa, Brahim, Meur, Guylène Le, Weber, Michel, Deschamps, Jack-Yves, Lorenz, Birgit, Moullier, Philippe, Rolling, Fabienne
Format: Article
Language:English
Subjects:
Animals
Capsid Proteins - genetics
Capsid Proteins - metabolism
Clinical trials
Dependovirus - genetics
Dependovirus - ultrastructure
Dogs
Gene therapy
Gene Transfer Techniques
Genetic Vectors - administration & dosage
Genetic Vectors - genetics
Growth factors
Heparan sulfate
Hypotheses
Kinases
Labeling
Life Sciences
Localization
Microscopy
Microscopy, Immunoelectron
Monkeys & apes
Original
Photoreceptors
Primates
Primates - genetics
Primates - metabolism
Proteins
Retina
Retina - metabolism
Time Factors
Vectors (Biology)
Virion - genetics
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Summary:Gene transfer to the retina using recombinant adeno-associated viral (rAAV) vectors has proven to be an effective option for the treatment of retinal degenerative diseases in several animal models and has recently advanced into clinical trials in humans. To date, intracellular trafficking of AAV vectors and subsequent capsid degradation has been studied only in vitro, but the fate of AAV particles in transduced cells following subretinal injection has yet to be elucidated. Using electron microscopy and western blot, we analyzed retinas of one primate and four dogs that had been subretinally injected with AAV2/4, -2/5, or -2/2 serotypes and that displayed efficient gene transfer over several years. We show that intact AAV particles are still present in retinal cells, for up to 6 years after successful gene transfer in these large animals. The persistence of intact vector particles in the target organ, several years postadministration, is totally unexpected and, therefore, represents a new and unanticipated safety issue to consider at a time when gene therapy clinical trials raise new immunological concerns.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2008.283