Adeno-associated virus type 6 (AAV6) vectors mediate efficient transduction of airway epithelial cells in mouse lungs compared to that of AAV2 vectors

Although vectors derived from adeno-associated virus type 2 (AAV2) promote gene transfer and expression in many somatic tissues, studies with animal m odels and cultured cells show that the apical surface of airway epithelia i s resistant to transduction by AAV2 vectors. Approaches to increase transdu ction rates include increasing the amount of vector and perturbing the inte grity of the epithelia. In this study, we explored the use of vectors based on AAV6 to increase transduction rates in airways. AAV vectors were made u sing combinations of rep, cap, and packaged genomes from AAV2 or AAV6. The packaged genomes encoded human placental alkaline phosphatase and contained terminal repeat sequences from AAV2 or AAV6. We found that transduction ef ficiency was primarily dependent on the source of Cap protein, defined here as the vector pseudotype. The AAV6 and AAV2 pseudotype vectors exhibited d ifferent tropisms in tissue-cultured cells, and cell transduction by AAV6 v ectors was not inhibited by heparin, nor did they compete for entry in a tr ansduction assay, indicating that AAV6 and AAV2 capsid bind different recep tors. In vivo analysis of vectors showed that AAV2 pseudotype vectors gave high transduction rates in alveolar cells but much lower rates in the airwa y epithelium. In contrast, the AAV6 pseudotype vectors exhibited much more efficient transduction of epithelial cells in large and small airways, show ing up to 80% transduction in some airways. These results, combined,vith ou r previous results showing lower immunogenicity of AAV6 than of AAV2 vector s, indicate that AAV6 vectors may provide significant advantages over AAV2 for gene therapy of lung diseases like cystic fibrosis.