AAV2-mediated transfer of the human aquaporin-1 cDNA restores fluid secretion from irradiated miniature pig parotid glands

Abstract

Previously (Shan et al, 2005), we reported that adenoviral vector-mediated transfer of the human aquaporin-1 (hAQP1) cDNA to minipig parotid glands following irradiation (IRti) transiently restored salivary flow to near normal levels. This study evaluated a serotype 2, adeno-associated viral (AAV2) vector for extended correction of IR (single dose; 20 Gy)-induced, parotid salivary hypofunction in minipigs. Sixteen weeks following IR, parotid salivary flow decreased by 85-90%. AAV2hAQP1 administration at week 17 transduced only duct cells and resulted in a dose-dependent increase in salivary flow to ∼35% of pre-IR levels (to ∼1ml/10min) after 8 weeks (peak response). Administration of a control AAV2 vector or saline, was without effect. Little change was observed in clinical chemistry and hematology values after AAV2hAQP1 delivery. Vector treated animals generated high anti-AAV2 neutralizing antibody titers by week 4 (∼1:1600) and significant elevations in salivary (∼15%), but not serum, GM-CSF levels. Following vector administration, salivary [Na+] was dramatically increased, from ∼10mM to ∼55 (at 4 weeks) and 39 mM (8 weeks). The findings demonstrate that localized delivery of AAV2hAQP1 to IR-damaged parotid glands leads to increased fluid secretion from surviving duct cells, and may be useful in providing extended relief of salivary hypofunction in previously irradiated patients.