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• W2070304834 abstract "The choice of appropriate adeno-associated virus serotypes for gene therapy to the human lung can differ depending on the animal model and model system in which such serotypes are evaluated. In the present study, we sought to compare the efficiency of rAAV2/1, rAAV2/2, and rAAV2/5 vector transduction in polarized human airway epithelia. Since similar vector purity is paramount to such a comparison, we developed a uniform procedure for purification of these serotype vectors using an adenovirus-free packaging system and HPLC. Results from these experiments demonstrated that apical transduction of human polarized airway epithelia with rAAV2/1 was 100-fold more efficient than rAAV2/2 and rAAV2/5. Additionally, the profile of apical transduction in human airway epithelia (rAAV2/1>>rAAV2/2=rAAV2/5) was significantly different than that seen following nasal administration of these vectors to mouse lung (rAAV2/5>rAAV2/1>>rAAV2/2), emphasizing differences in transduction of these serotypes between these two species. In stark contrast to rAAV2/2 and rAAV2/5 vectors, which demonstrated much greater transduction efficiencies from the basolateral membranes, rAAV2/1 transduced both apical and basolateral membrane of human airway epithelia with similar efficiency. Such serotype-specific difference in apical and basolateral transduction mirrored differences in internalization of vector genomes at short time points post-infection for a given serotype. However, the overall level of transduction across serotypes did not correlate with vector internalization. These results suggested that enhanced receptor-mediated endocytosis was not likely responsible for the greater rAAV2/1 transduction of human airway epithelia. With the hypothesis that differences in post-entry barriers influenced the efficiency of apical transduction with these three serotypes in the human airway, we tested the effectiveness of proteasome inhibitors (LLnL and doxorubicin, known to augment intracellular processing of rAAV2 and rAAV5 to the nucleus) to augment transduction with these three serotypes. Augmentation of rAAV2/1 apical transduction of human polarized airway epithelia was 10-fold lower than that for rAAV2/2 and rAAV2/5. Cellular fractionation assays demonstrated that proteasome inhibitors significantly increased virion nuclear uptake for rAAV2/2 and rAAV2/5, but not for rAAV2/1. Cumulatively, these findings suggest that the ubiquitin/proteasome pathway is less of a barrier for rAAV2/1 as compared to the other AAV serotypes. They also demonstrate that AAV1 serotype transduction biology is quite different from AAV2 and AAV5 in human airway epithelia and is potentially a more efficient vector for gene therapy to the airway." @default.
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• W2070304834 date "2006-01-01" @default.
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• W2070304834 title "10. Adeno-Associated Virus Type-1 Vectors Transduce Human Polarized Airway Epithelia without Polarity Preference" @default.
• W2070304834 doi "https://doi.org/10.1016/j.ymthe.2006.08.020" @default.
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