Journal
GENE THERAPY
Volume 14, Issue 21, Pages 1543-1548Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gt.3303014
Keywords
AAV; species; tropism; sialic acid; lung; cystic fibrosis
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Funding
- NHLBI NIH HHS [R01 HL58340, R01 HL058340, R01 HL058340-11] Funding Source: Medline
- NIDDK NIH HHS [DK54759, P30 DK054759] Funding Source: Medline
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Differences between rodent and human airway cell biology have made it difficult to translate recombinant adeno-associated virus (rAAV)-mediated gene therapies to the lung for cystic fibrosis (CF). As new ferret and pig models for CF become available, knowledge about host cell/ vector interactions in these species will become increasingly important for testing potential gene therapies. To this end, we have compared the transduction biology of three rAAV serotypes (AAV1, 2 and 5) in human, ferret, pig and mouse- polarized airway epithelia. Our results indicate that apical transduction of ferret and pig airway epithelia with these rAAV serotypes closely mirrors that observed in human epithelia (rAAV1 > rAAV2 congruent to rAAV5), while transduction of mouse epithelia was significantly different (rAAV1 > rAAV5 >= rAAV2). Similarly, ferret, pig and human epithelia also shared serotype-specific differences in the polarity (apical vs basolateral) and proteasome dependence of rAAV transduction. Despite these parallels, N-linked sialic acid receptors were required for rAAV1 and rAAV5 transduction of human and mouse airway epithelia, but not ferret or pig airway epithelia. Hence, although the airway tropisms of rAAV serotypes 1, 2 and 5 are conserved better among ferret, pig and human as compared to mouse, viral receptors/ co- receptors appear to maintain considerable species diversity.
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