Repeat administration of adenoassociated virus 5 in murine airways. (2005)

Sumner-Jones, S. G., Gill, D. R. & Hyde, S. C.

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Recombinant AAV is a promising vector for long term gene transfer, since studies in mouse, dog and non-human primate models resulted in transgene expression for over 12 months. rAAV5 has attracted attention for the development of airway gene transfer as it uses apically-localised sialic acid as receptor. We have shown that expression from rAAV5/5Lux (luciferase) persists in mouse nose for at least 7 months, and in mouse lungs for at least 12 months. However for chronic diseases such as Cystic Fibrosis, it is likely that repeat administration of the virus will be required due to turnover of the terminally differentiated airway cells. We detected anti-AAV neutralising activity in the serum within 1 week of exposure to the virus, which was maintained for the duration of the studies (over 7 months in nose, 12 months in lung). We have tested the impact of this on the efficacy of repeated administration with rAAV5 vectors in the mouse airways. In lung, Lux gene expression following a second dose of rAAV5 was reduced (0.23±0.06 RLU/mg protein) compared to a single dose (19.33±5.12 RLU/mg protein), and abolished following a third dose (0.07±0.04 RLU/mg protein, p>0.05 compared with naÔve mice). Neither increasing the gap between exposures, nor using a vector expressing the immunosuppressor CTLA4Ig, allowed any Lux expression from a second or third dose of virus. Similarly, no combination of any two rAAV5 vectors led to Lux expression from the second dose in the nose. In each case, lack of expression correlated with the presence of anti-AAV5 antibodies in serum. We also analysed sera for antibodies against transgenes expressed by the vectors and found that only CTLA4Ig induced a response. So, in general, transgenes expressed by rAAV5 in the airways did not lead to an antibody response, however a strong response against rAAV5 was detected in all groups tested. This suggests that further advances in strategies to block the immune response are still required to facilitate efficacious repeated administration of rAAV5.

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